This version of the presentation includes corrections to errors in the original presentation contained on slide 22 clarifying footnotes on slides 20 amp 21 and a post-meeting addition (slide 23)

2

This presentation contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws including statements regarding Agenus and AgenTus clinical development and regulatory plans and timelines expected timing for clinical trials and releasing clinical data anticipated milestones from partnership transactions and goals for 2020 These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially These risks and uncertainties include among others the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission filed with the Securities and Exchange Commission and made available on our website at wwwagenusbiocom Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this presentation These statements speak only as of the date of this presentation and Agenus undertakes no obligation to update or revise the statements other than to the extent required by law All forward-looking statements are expressly qualified in their entirety by this cautionary statement

Forward-Looking Statements

2

This presentation contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws including statements regarding Agenus and AgenTus clinical development and regulatory plans and timelines expected timing for clinical trials and releasing clinical data anticipated milestones from partnership transactions and goals for 2020 These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially These risks and uncertainties include among others the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission filed with the Securities and Exchange Commission and made available on our website at wwwagenusbiocom Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this presentation These statements speak only as of the date of this presentation and Agenus undertakes no obligation to update or revise the statements other than to the extent required by law All forward-looking statements are expressly qualified in their entirety by this cautionary statement

Forward-Looking Statements

3

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER

AND BETTER

bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries

Investor Day

Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center

From AgenusFrom the Experts

Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners

Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center

Garo Armen PhDChairman and CEO

Jennifer Buell PhDPresident and COO

Julie DeSanderVice President Business Development amp Alliance Management

Dhan Chand PhDHead of Drug Discovery

Mark Exley PhDVice President Cellular Immunology

Anna Wijatyk MDHead of Clinical Development

5

Delivering Some of Our 2020 Goals Today

bull 6 Clinical Data Readouts Zalifrelimab and Balstilimab Balstilimab AGEN1181

AGEN1223AGEN2373GS-1423

2020 Objectives Shared at Agenusrsquo November 2019 RampD Day

bull 2 INDsbull 2 BLA filings

6

Dr Bradley J Monk MD FACOG FACS

bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic

Cancer Intergroup (GCIG)

7

The Enemy

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

bull Pivotal Trial Clinical Data on Balstilimab and Zalifrelimabbull AGEN1181 Beyond a Next-Generation CTLA-4bull New Discoveries

Investor Day

Tyler Curiel MD MPH FACPThe Daisy M Skinner Professor of Cancer Immunology ResearchProfessor of Medicine Microbiology Immunology amp Medical GeneticsUT Health San AntonioMays Cancer Center

From AgenusFrom the Experts

Bradley Monk MD FACS FACOGProfessor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network)Co-Director of GOG Partners

Charles Drake MD PhDCo-Director Cancer Immunotherapy Program Columbia University Herbert Irving Comprehensive Cancer Center

Garo Armen PhDChairman and CEO

Jennifer Buell PhDPresident and COO

Julie DeSanderVice President Business Development amp Alliance Management

Dhan Chand PhDHead of Drug Discovery

Mark Exley PhDVice President Cellular Immunology

Anna Wijatyk MDHead of Clinical Development

5

Delivering Some of Our 2020 Goals Today

bull 6 Clinical Data Readouts Zalifrelimab and Balstilimab Balstilimab AGEN1181

AGEN1223AGEN2373GS-1423

2020 Objectives Shared at Agenusrsquo November 2019 RampD Day

bull 2 INDsbull 2 BLA filings

6

Dr Bradley J Monk MD FACOG FACS

bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic

Cancer Intergroup (GCIG)

7

The Enemy

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

5

Delivering Some of Our 2020 Goals Today

bull 6 Clinical Data Readouts Zalifrelimab and Balstilimab Balstilimab AGEN1181

AGEN1223AGEN2373GS-1423

2020 Objectives Shared at Agenusrsquo November 2019 RampD Day

bull 2 INDsbull 2 BLA filings

6

Dr Bradley J Monk MD FACOG FACS

bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic

Cancer Intergroup (GCIG)

7

The Enemy

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

6

Dr Bradley J Monk MD FACOG FACS

bull Professor of Gynecologic Oncologybull University of Arizonabull Arizona Oncology (US Oncology Network)bull Co-Director gt GOG Partnersbull Chair Cervical Cancer Committee gt Gynecologic

Cancer Intergroup (GCIG)

7

The Enemy

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

7

The Enemy

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

8

Three Decades Recurrent amp Metastatic Cervical Cancer

bull Seven randomized phase 3 trialsbull Cisplatin (Cis) 50 mgm2 plus paclitaxel (Pac) 135 mgm2 IV over

24 hrs standard therapybull Median overall survival (OS) le12 monthsbull Majority of patients with recurrent cervical cancer pre-treated with

cisplatin-based chemoradiation for locally advanced disease (1999 onwards)

Tewari KS et al Curr Oncol Rep 20057(6)419-434 Monk BJ et al J Clin Oncol 200725(20)2952-2965 Tewari KS et al Onkologie 200832(10)552-554 Monk BJ et al J Clin Oncol 200927(28)4649-4655 Tewari KS et al Semin Oncol 200936(2)170-180 Tewari KS et al Clin Adv Hematol Oncol 20108(2)108-115 Tewari KS Am J Hematol Oncol 2010931-34 Tewari KS Clin Ovarian Cancer 2011490-93

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

9

New England Journal of Medicineand THE LANCET

Tewari KS et al N Engl J Med 2014370(8)734-743 Tewari KS et al Lancet 2017390(10103)1654-1663

Articles

wwwthelancetcom Published online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0 1

Bevacizumab for advanced cervical cancer final overall survival and adverse event analysis of a randomised controlled open-label phase 3 trial (Gynecologic Oncology Group 240) Krishnansu S Tewari Michael W Sill Richard T Penson Helen Huang Lois M Ramondetta Lisa M Landrum Ana Oaknin Thomas J Reid Mario M Leitao Helen E Michael Philip J DiSaia Larry J Copeland William T Creasman Frederick B Stehman Mark F Brady Robert A Burger J Tate Thigpen Michael J Birrer Steven E Waggoner David H Moore Katherine Y Look Wui-Jin Koh Bradley J Monk

SummaryBackground On Aug 14 2014 the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial In this study we report the prespecified final analysis of the primary objectives OS and adverse events

Methods In this randomised controlled open-label phase 3 trial we recruited patients with metastatic persistent or recurrent cervical carcinoma from 81 centres in the USA Canada and Spain Inclusion criteria included a GOG performance status score of 0 or 1 adequate renal hepatic and bone marrow function adequately anticoagulated thromboembolism a urine protein to creatinine ratio of less than 1 and measurable disease Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible We randomly allocated patients 1111 (blocking used block size of four) to intravenous chemotherapy of either cisplatin (50 mgmsup2 on day 1 or 2) plus paclitaxel (135 mgmsup2 or 175 mgmsup2 on day 1) or topotecan (0middot75 mgmsup2 on days 1ndash3) plus paclitaxel (175 mgmsup2 on day 1) with or without intravenous bevacizumab (15 mgkg on day 1) in 21 day cycles until disease progression unacceptable toxic effects voluntary withdrawal by the patient or complete response We stratified randomisation by GOG performance status (0 vs 1) previous radiosensitising platinum-based chemotherapy and disease status (recurrent or persistent vs metastatic) We gave treatment open label Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information) assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board The cutoff for final analysis was 450 patients with 346 deaths This trial is registered with ClinicalTrialsgov number NCT00803062

Findings Between April 6 2009 and Jan 3 2012 we enrolled 452 patients (225 [50] in the two chemotherapy-alone groups and 227 [50] in the two chemotherapy plus bevacizumab groups) By March 7 2014 348 deaths had occurred meeting the prespecified cutoff for final analysis The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups 16middot8 months in the chemotherapy plus bevacizumab groups versus 13middot3 months in the chemotherapy-alone groups (hazard ratio 0middot77 [95 CI 0middot62ndash0middot95] p=0middot007) Final OS among patients not receiving previous pelvic radiotherapy was 24middot5 months versus 16middot8 months (0middot64 [0middot37ndash1middot10] p=0middot11) Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8middot4 months) and chemotherapy-alone groups (7middot1 months 0middot83 [0middot66ndash1middot05] p=0middot06) Fistula (any grade) occurred in 32 (15) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1) of 220 in the chemotherapy-alone groups (all previously irradiated) Grade 3 fistula developed in 13 (6) versus one (lt1) No fistulas resulted in surgical emergencies sepsis or death

Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated After progression while receiving bevacizumab we did not observe a negative rebound effect (ie shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped) These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer

Funding National Cancer Institute

Published Online July 27 2017 httpdxdoiorg101016S0140-6736(17)31607-0

See OnlineComment httpdxdoiorg101016S0140-6736(17)31965-7

Division of Gynecologic Oncology University of California Irvine Medical Center Orange CA USA (Prof K S Tewari MD Prof P J DiSaia MD) Roswell Park Cancer Institute State University of New York at Buffalo Buffalo NY USA (M W Sill PhD H Huang MS Prof M F Brady PhD) Massachusetts General Hospital Boston MA USA (R T Penson MD Prof M J Birrer MD) MD Anderson Cancer Center Houston TX USA (Prof L M Ramondetta MD) Division of Gynecologic Oncology University of Oklahoma Oklahoma City OK USA (L M Landrum MD) Vall drsquoHebron University Hospital Barcelona Spain (A Oaknin MD) University of Cincinnati College of Medicine Cincinnati OH USA and Womenrsquos Cancer Center at Kettering Cincinnati OH USA (T J Reid MD) Memorial Sloan-Kettering Cancer Center New York NY USA (M M Leitao MD) Indiana University School of Medicine Indianapolis IN USA (Prof H E Michael MD Prof F B Stehman MD) Ohio State University Medical Center Columbus OH USA (Prof L J Copeland MD) Department of Obstetrics and Gynecology Medical University of South Carolina Charleston SC USA (Prof W T Creasman MD) Division of Gynecologic Oncology University of

IntroductionWith an estimated annual incidence of 529 800 new cases and 275 100 deaths globally in 2011 cervical cancer

continues to represent a substantial cause of morbidity and mortality among predominantly young and middle-aged women (20ndash60 years) throughout the world1

FDA approved for 1-L metastatic disease Aug 14 2014

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

10

FDA Accelerated Approval of Pembrolizumab(June 12 2018)

FDA Press Release httpswwwfdagovDrugsInformationOnDrugsApprovedDrugsucm610572htm Accessed October 31 2019

Companion DiagnosticPD-L1 IHC 22C3CPSge1

ORR 143(95 CI 74 241)

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

11

R Wendel Naumann1 Ana Oaknin2 Timothy Meyer3 Jose Maria Lopez-Picazo4 Christopher Lao5Yung-Jue Bang6 Valentina Boni7 William H Sharfman8 Jong Chul Park9 Lot A Devriese10 KenichiHarano11 Christine H Chung12 Suzanne L Topalian8 Kamarul Zaki3 Tian Chen13 Junchen Gu13 BinLi13 Adam Barrows13 Andrea Horvath13 Kathleen N Moore14

Efficacy and Safety of Nivolumab + Ipilimumabin Patients with RecurrentMetastatic Cervical Cancer Results From CheckMate 358

1Levine Cancer Institute Atrium Health Charlotte NC USA 2Vall dacuteHebron University Hospital Vall dacuteHebron Institute of Oncology Barcelona Spain3University College London London UK 4Clinica Universidad de Navarra Navarra Spain 5University of Michigan Comprehensive Cancer Center AnnArbor MI USA 6Seoul National University Hospital Seoul South Korea 7START Madrid CIOCC Hospital Madrid Norte Sanchinarro Madrid Spain8Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center Baltimore MD USA 9Dana Farber CancerInstitute Beth Israel Deaconess Medical Center and Massachusetts General Hospital Boston MA USA 10Universitair Medisch Centrum UtrechtUtrecht The Netherlands 11National Cancer Center Hospital East Kashiwa Japan 12H Lee Moffitt Cancer Center Tampa FL USA 13Bristol-MyersSquibb Lawrence NJ USA 14Stephenson Cancer Center at the University of Oklahoma Oklahoma City OK USA and Sarah Cannon Research InstituteNashville TN USA

Colead authors

Proof of Concept for Combo PD-1 + CTLA-4 in Cervical

Abstract Number 5630

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

12

Study Design and Current Analysis

Treatment(until toxicity or progression or a

maximum of 24 mo)

Current AnalysisScreening Follow-up

NIVO+IPI Regimen

NIVO1+IPI3 (n = 46)NIVO 1 mgkg + IPI 3 mgkg

q3w x 4 followed by NIVO 240 mg q2w

bull Imaging every 8 wks for yr 1 of treatment

bull Imaging every 12 wks beyond yr 1

R

bull Histologically confirmedSCC of the cervixbull RM disease

bull le2 PSTs for RM diseasebull ge1 target lesionbull ECOG PS 0ndash1bull HPV positive or unknown

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2combination regimens of nivolumab + ipilimumab for RM disease

Database lockJune 26 2019

Median follow-up (range)NIVO3+IPI1 107 mo (08ndash321)NIVO1+IPI3 139 mo (05ndash293)

ECOG Eastern Cooperative Oncology Group IPI ipilimumab NIVO nivolumab ORR objective response rate PFS progression-free survival PS performance status PST prior systemic therapy q2w every 2 weeks q3w every 3 weeks RECIST response evaluation criteria in solid tumors SCC squamous cell carcinoma

bull Primary endpoint Investigator-assessed ORR by RECIST 11bull Secondary endpoints OS PFS duration of response

bull Study start date October 2015bull Estimated completion date December 2019

NIVO3+IPI1 (n = 45)NIVO 3 mgkg q2w +

IPI 1 mgkg q6w

CheckMate 358

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

13

Patient Characteristics

Baseline characteristicsNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Age median (range) y 480 (32ndash76) 445 (26ndash74)

ECOG PS n ()01

23 (511)22 (489)

26 (565)20 (435)

AJCC stage n ()II (AndashB)III (AndashC)IV (AndashB)

3 (66)1 (22)

41 (911)

0 (00)8 (174)

38 (826)

Tumor cell PD-L1 expression dagger n ()Evaluable

ge1lt1

Not evaluablenot reported

37 (822)23 (622)14 (378)8 (178)

34 (739)23 (676)11 (324)12 (260)

13

Prior therapiesNIVO3+IPI1

(n = 45)NIVO1+IPI3

(n = 46)

Prior therapy n ()PlatinumBevacizumab

39 (867)24 (533)

42 (913)25 (543)

Prior radiotherapy n () 38 (844) 39 (848)

Prior systemic therapy in the RM setting n ()0ge1

19 (422)26 (578)

24 (522)22 (478)

Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity daggerAssessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T et alAppl Immunohistochem Mol Morphol 201523541-549)AJCC American Joint Committee on Cancer

Prior systemic therapy (PST) in the recurrentmetastatic (RM) setting

CheckMate 358

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

14

Change from Baseline in Target Lesion SizeCheckMate 358

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100

minus75

minus50minus25

0

255075

Patient

Max

imum

cha

nge

from

ba

selin

e in

targ

et le

sion

s (

)

100

minus100minus75minus50minus25

0255075

Patient

NIVO3+IPI1 NIVO1+IPI3

No PST for RM diseasePST for RM disease

Bars with asterisks represent confirmed responses (complete or partial response) PST prior systemic therapy

No PST for RM diseasePST for RM disease

ORR 231 (90ndash436) PST for RM disease ORR 364 (172ndash593) PST for RM disease

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

15

Complete Response to Treatment withNivolumab + Ipilimumab

42-year-old woman with recurrent stage IIA (with lung metastases) HPV positive SCC of the cervix ECOG PS 1 tumor cell PD-L1 lt1

Base

line

95

mo

2 m

o

CD4

CD8

Biopsy (wk 7) showing extensive infiltration of CD8 cells with a high CD8CD4 ratio

All images provided by Dr Naumann Levine Cancer Institute Atrium Health Charlotte NC USAHDRB high dose rate brachytherapy SCC squamous cell carcinoma WPRT whole pelvic radiotherapy

Before CheckMate 358bull First diagnosed with localized disease January 2016bull Prior therapies

ndash WPRT + cisplatin ndash HDRB completed April 2016ndash Carboplatin + paclitaxel + bevacizumab completed January 2017

ndash Documented disease progression

CheckMate 358bull Treated with NIVO3+IPI1bull Complete response time to response 77 mobull Biopsy at wk 7 showed only necrosisbull Stopped treatment after 2 yearsbull No evidence of disease as of August 2019

(7 mo post-treatment completion)

CheckMate 358

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

16

CheckMate 358 Safety Summary

bull No new safety signalsbull Higher incidence of TRAEs and treatment-related SAEs leading to

treatment discontinuation in NIVO1+IPI3 compared with NIVO3+IPI1bull No treatment-related deaths

SAE serious adverse event TRAE treatment-related adverse event

Event n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4

TRAEs 36 (800) 13 (289) 38 (826) 17 (370)

Treatment-related SAEs 12 (267) 8 (178) 16 (348) 10 (217)

TRAEs leading to treatment discontinuation 6 (133) 2 (44) 9 (196) 6 (130)

Treatment-related SAEs leading to treatment discontinuation 2 (44) 1 (22) 5 (109) 5 (109)

CheckMate 358

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

17

CheckMate 358 TRAEs with Incidence ge5

bull Higher incidence of treatment-related gastrointestinal events in NIVO1+IPI3 compared with NIVO3+IPI1 this could be due to higher ipilimumab dose

bull Of the 6 patients with grade 3ndash4 treatment-related gastrointestinal events colitis was reported in 4 patients and diarrhea nausea vomiting and gastritis were reported in 1 patient each

TRAEs with incidence lt5 included the following SOCs blood cardiac ear eye infections injury psychiatric renal reproductive systembreast and vascular SOC system organ class

TRAEs by SOC n ()

NIVO3+IPI1(n = 45)

NIVO1+IPI3(n = 46)

Any grade Grade 3ndash4 Any grade Grade 3ndash4Generaladministration site 17 (378) 0 20 (435) 0

Gastrointestinal 16 (356) 4 (89) 26 (565) 6 (130)

Skin 16 (356) 0 16 (348) 2 (43)

Laboratory investigations 15 (333) 5 (111) 17 (370) 9 (196)

Endocrine 13 (289) 2 (44) 20 (435) 0

Pulmonary 6 (133) 1 (22) 6 (130) 1 (22)

Metabolism 5 (111) 1 (22) 5 (109) 0

Nervous system 4 (89) 0 6 (130) 0

Musculoskeletal 2 (44) 1 (22) 9 (196) 0

Hepatobiliary 2 (44) 2 (44) 3 (65) 2 (43)

CheckMate 358

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

18

Why CTLA-4 and PD-1 have Best-in-Class Potential

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

19

CTLA-4 Improves PD-1 Responses amp Durability in Multiple Tumors

2-3x improved ORR with CTLA4 in certain tumors

34

45

37

36

21

28

12

20

19

12

12

7

5

5

58

57

45

41

38

36

31

31

28

23

21

20

16

10

Previously treated MSI-H CRC

1L Melanoma

1L NSCLC (ge50 PD-L1)

1L RCC

2L+ Bladder cancer

1L NSCLC (ge1 PD-L1)

Ovarian cancer

2L+ Hepatocellular cancer

Mesothelioma

Cervical cancer

2L+ SCLC

2L+ Gastric esophageal cancer

Sarcoma

Prostate cancer (mCRPC)

PD1 ORR

PD1CTLA4 ORR

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

20

CRs amp PRs show durability gt70wks

Agenus data C-700-01 interim analysis data cut off 16 Oct 2019 Estimates for efficacy set (n=42) ndash all patients with measurable disease at baseline dosed as of 15 Jul 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

Balstilimab (anti-PD-1) Alone is Active and Durable in 2L Cervical Cancer (119 ORR1 CR 4 PRs) Independent Reads

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

21Agenus data C-550-01 interim analysis data cut off 12 Jul 2019 with 1 Nov 2019 update on patients with response Estimates for efficacy set (n=34) ndash all patients with measurable disease at baseline dosed as of 31 Mar 2019 Notes Plot shows all patients with on-study tumor assessments at the time of interim analysis including patients without measurable disease AGEN1884 and AGEN2034 are being evaluated in 2L cervical cancer and undisclosed tumors Recepta Biopharma SA has exclusive rights to AGEN1884 and AGEN2034 in Brazil and five other South American countries

CRs amp PRs show durability gt50wks

Balstilimab (anti-PD-1) + Zalifrelimab (anti-CTLA-4) may be a Best-in-Class Option in 2L Cervical Cancer (206 ORR 3 CR 4PR) Independent Reads

Balstilimab 3mgkg Q2WZalifrelimab 1mgkg Q6W

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

22

Sponsor Agent of Patients

ORR CR PR Related AEs (Grade 3+)

Agenus Balstilimab 42 143 24 119 91

Merck Pembrolizumab 98 122 31 92 122

Agenus Balstilimab + Zalifrelimab

34 265 118 147 146

BMS Ipilimumab + Nivolumab

26 231 38 192 289

Seattle Genetics Genmab

Tisotumab vedotin 55 22 2 20 56

Iovance LN-145 27 444 111 333 963

Data from pre-planned interim analysis Sponsor reported as Treatment-Emergent Adverse Events Chung HC et al 2019 Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer Results From the Phase II KEYNOTE-158 Study J Clin Oncol 37(17)1470-1478 Data presented for full population (no biomarker restrictions for comparison)

Balstilimab (anti-PD-1) plus zalifrelimab (anti-CTLA-4) may be the most promising amp clinically advanced off-the-shelf treatment option with an acceptable safety profile

Addition to original presentation UPDATED DATA APR2020

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

23

Agenus CTLA-4 amp PD-1 Potential Best-in-Class Option for 2L Cervical Cancer

Agenus data C-550-01 Interim analysis data cut off 12 July 2019 n=34 efficacy set (patients with measurable disease at baseline) Agenus data C-700-01 Interim analysis data cut off 16 Oct 2019 n=42 efficacy set (patients with measurable disease at baseline) 1Naumann RW et al Annals of Oncology (2019) 30 (suppl_5) v851-v934 2Chung HC et al J Clin Oncol 2019 Jun 1037(17)1470-1478

Corrected Slide

Sponsor Treatment of

PatientsComplete Response

Partial Response

Overall Response Rate

Combination of PD-1 and CTLA-4

Agenus Balstilimab + Zalifrelimab 34 88 118 206

BMS Ipilimumab + Nivolumab1 26 38 192 231

PD-1 Monotherapy

Agenus Balstilimab 42 24 95 119

Merck Pembrolizumab2 98 26 117 143

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

24On treatment AEs AEs occurring after study treatment initiation and within 3090 days of study drug discontinuationC-550-01 Interim analysis data cur 12 July 2019C-700-01 interim analysis data cut 16 October 2019

Clinical Benefit with Tolerability in 2L Cervical Cancer Studies with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4)

Balstilimab+Zalifrelimab

(N=41)

Balstilimab(N=44)

Serious on-treatment AEs n () [AEs] 15 (366) [24] 22 (500) [44]

Grade 3+ on-treatment Adverse Events n () [AEs] 18 (439) [36] 25 (568) [84]

Any on-treatment AEs leading to discontinuation 1 (24) [1] 2 (45) [2]

Immune-related on-treatment by investigator n ()n () [AEs] 18 (439) [47] 10 (227) [16]

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

25

1 Recurrent cervical cancer is an area of high unmet need2 Accelerated approval from small single arm clinical trials is established as a

pathway to the clinic3 Anti PD-L1 has activity (ORR) between 10-15

a) Including Balstilimab4 Adding anti CTLA-4 to anti PD-L1 increases clinical activity with acceptable

safety a) Including Zalifrelimab to Balstilimab

5 I believe that accelerated approval of Balstilimab alone and Balstilimab + Zalifrelimab in those with PST for RM cervical cancer is likely

Conclusions

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

26

Anna Wijatyk MDHead of Clinical Development

WE AIM TO HAVE CANCER PATIENTS LIVING LONGER AND

BETTER

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

27

On Track to Deliver 2 BLAs Balstilimab amp Zalifrelimab

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

28

Balstilimab (PD-1) Monotherapy Complete Response CasePatient 1 ndash Continuing on treatment since May 2018

Baseline On-treatmentTarget lesions mediastinal lns 36 mm CR from cycle 6 on

Non-t lesions none

Related AEs G2 mucosal inflammation G1 maculo-popular rash G1 lichen planus

Demographics 64 yo White

Primary tumor FIGO-IIIa SCC

Prior treatment carbotax in 2016

Screening Cycle 36 ndash CR0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Independent review

T

umor

size

Weeks

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

29

Combination Balstilimab (PD-1) amp Zalifrelimab (CTLA-4) Complete Response (Overall 3 CRs 4 PRs)

Screening

Week 27 ndash CR from week 6-on

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40

T

umor

size

Weeks

Baseline On-treatmentTarget lesions Vaginal stump 47 mm

inguinal ln 19 mmCR on wk 6

Non-target lesions none -

Related AEs G2 hypothyroidism

Demographics 57 yo white

Primary tumor FIGO-IIIB SCC nonkeratinizing

Prior treatment Hysterectomy and CRT in 2015 1st line carbotax in 2018

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

30

2 Interim AnalysesPivotal Trial Analysis

Underway

25 Countries120 Sites

8 Studies Open

Clinical Development and Operations

~300 Patients Treated

54 Agenus Team Members

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

31

Balstilimab Balstilimab + Zalifrelimab

AGEN1181AGEN1223AGEN2373

Deliver Clinical Data on Multiple Discoveries

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

32

IND Cleared Sites Activated Patients Dosed

New Discoveries to Patients with Path-breaking Speed

Industry Standard 168 days

Agenus timelines - 65 Days

Speed to clinic speed to patients speed to market

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

33

Jennifer Buell PhDPresident and COO

Agenus

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

34

Agenus Discoveries In The Clinic

Option programs w GILD

Agenus PartnersCommercial QS-21 (SHINGRIX)1

Pivotal(Planned BLA 2020)

Balstilimab (PD-1) Balstilimab + Zalifrelimab

(CTLA-4)

Phase 12AGEN1181

AGEN1223AGEN2373

GS-1423MK-4830

INCAGN1876INCAGN1949INCAGN2390INCAGN2385

More detailed information available in Agenus SEC and 10k filings1 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

35

Dr Charles DrakeMD PhDbull Professor of Medicinebull Co-Director Cancer Immunotherapy Programsbull Co-Leader Tumor Biology and Microenvironmentbull Faculty Director ndash Human Immune Monitoring Corebull Division Director ndash GU Oncology

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

36

Regulatory T Cells (Treg)Are Prevalent in the Tumor Microenvironment

CD8 T cellTumour cell

MHC

PD-L1- - -

PD-L2PD-1- - -

Tumourantigen

TCR

PD-1

+++

PD-L1 expression on tumor cells OR

Myeloid cells SEND a negative signal

CD8 T cellTumour cellMHC

TCR

+++

Suppressive Factors

Regulatory CD4 T Cell

(FoxP3+)

-- - --

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

37

Targeted Treg Depletion Treats Cold Tumors(in mice)

Klages K et al Cancer Research 2010

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

38

High Risk PC

Arm AAndrogen Deprivation Therapy(ADT)

Arm BADT Plus Vaccine

Surgery on day 28 (+-3)

Safety Tolerability

T Cell infiltration of prostate gland

Profile the Tumor Microenvironment Post-Treatment

Randomize

n=16 n=16

Charles Drake Emmanuel Antonarakis Ashley Ross Ted Schaeffer Alan Partin

Can a Cancer Vaccine Make A Cold Tumor HotGVAX Vaccine in Prostate Cancer

Endpoints

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

39

In Human Prostate CancerIncreased CD8 Infiltration is Balanced by Treg InfluxAdaptive Treg Resistance

UntreatedControlN = 13

AndrogenDeprivation

TherapyN=15

AndrogenDeprivation

PLUS VaccineN=13

CD8+ T cell density(mean 95CI)

96 (72ndash120) 205 (121ndash289) 263 (129ndash397)

Treg celldensity(mean 95CI)

29 (21ndash36) 59 (34ndash85) 78 (48ndash107)

CD8+ Tregratio(mean 95CI)

37 (29ndash46)

40 (27ndash53) 39 (22ndash57)

Obradovic Dallos Drake et al in review

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

40

CD45

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Fold

cha

nge

rela

tive

to P

re-C

CD4

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

CD8a

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

Ptprc(CD45)

Cd4 Cd8a

Eomes Tbx21(T-bet)

Foxp3

Tbx21 (Tbet)

Pre-C

Post-C

D7

C-Res

istan

t10-1

100

101

102

FoxP3

Pre-C

Post-C

D7

C-Res

istan

t100

101

102

103

EOMES

Pre-C

Post-C D

7

C-Res

istan

t100

101

102

103

Fold

cha

nge

rela

tive

to P

re-C

153 CD4+ T 23 CD8+ T108 NK cells69 B cells68 MAC150 DC432 Other

Pre-C

237 Treg

CD4+ T

119 CD4+ T 22 CD8+ T57 NK cells66 B cells337 MAC89 DC310 Other

C-Resistant

134 Treg

CD4+ T

106 CD4+ T21 CD8+ T172 NK cells25 B cells114 MAC105 DC457 Other

Post-C D7

395 Treg

CD4+ T

Shen and Drake Prostate Cancer Neoplastic Disease 2017

In Murine Prostate CancerIncreased CD8 Infiltration is Balanced by Treg Influx

Adaptive Treg Resistance

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

41

pm

e F

PK

M C

TL

A4

Ex

pre

ss

ion

PBMC N

aive C

D4

PBMC A

ctivate

d CD4

PBMC T

reg

TIL T

reg

PBMC N

aive C

D8

PBMC A

ctivate

d CD8

PBMC A

g Experie

nced CD8

TIL A

g Experie

nced CD8

0

250

500

750

1000

1250

Nirschl T and Drake CIn Preparation

CTLA-4 Is Highly Expressed on The TregThat Infiltrate Cancer

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

42

A Depleting Anti-CTLA-4 (IgG2a)Cures a Fraction of Mice with Prostate Cancer

00 10 20 30 40 50 60 70

0

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix + αPD-1

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (ND)

0

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Degarelix + αCTLA-4 (D)

167

0 10 20 30 40 50 60 700

500

1000

1500

2000

Days after degarelix

Tum

or v

olum

e (m

m3 )

Degarelix

0

Shen and Drake Prostate Cancer Neoplastic Disease 2017

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

43

Radiation TherapyDrives

Adaptive TregResistance

Muroyama Ghasemzadeh Drake Cancer Immunology Research 2017

Contro

lRT

Contro

lRT

Contro

lRT

0

10

20

30

40

50

B16 RENCA MC38

C

D4+

Fox

p3+C

D4+

cells

Contro

lRT

Contro

lRT

Contro

lRT

0

200

400

600

800

B16 RENCA MC38

MF

I of

Fox

p3

Control

RT

B16F10 RENCA MC38

0 102 103 104 105

0102

103

104

105

156

0 102 103 104 105

0102

103

104

105

317

0 102 103 104 105

0102

103

104

105

227

0 102 103 104 105

0102

103

104

105

418

0 102 103 104 105

0102

103

104

105

230

0 102 103 104 105

0102

103

104

105

500

Foxp

3

CD4

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

44

A Depleting aCTLA-4Plus Radiation

Cures The MajorityOf Treated Animals

Marisciano Drake et al Clinical Cancer Res 2018

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

45

100 of RT + aCTLA-4 Cured Mice Show Long-Term Protection

Not the Case for RT + aPD-1

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

46

Selected aCTLA-4 Agents in the Clinic

46

Ipilimumab Tremilimumab BMS 928218 MK 1308

IgG Isotype IgG1 IgG2 AfucosylatedIgG1

Not Reported

TregDepletion

+- No Not Reported Not Reported

Grade III IVIRAE

asymp25 asymp15 Not Reported Not Reported

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

47

bull High Affinity for CTLA-4

bull Fc Optimized to Enhance Depletion

bull Enhanced T Cell Activation

bull Promote T Cell Memory

bull Reasonable Tolerability

Optimized aCTLA-4 Product Profile

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

48

The Fc Engineered ldquoDLErdquo Scaffold1 Enhances Binding to Human FcgRIIIa2 Bind to both the ff and vv FcgRIIIa Variants

Waight JD et al Cancer Cell 2018

IgG1 aCTLA-4 Fc Engineered aCTLA-4

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

49

Enhanced Treg Depletion with AGEN1181

Source Agenus Data

Parental IgG1

Isotype Control

AGEN1181

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

50

Enhanced T Cell Activation with AGEN1181

Source Agenus Data

Increased FcgRIIIa Binding (hIgG1-DLE)

WT FcgRIIIa Binding (hIgG1)

Absent FcgRIIIa Binding (hIgG1-N297A)

Waight JD et al Cancer Cell 2018

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

51

Superior Combination Activity with PD-1 BlockadeIn comparison to first-generation anti-CTLA-4

51

Source Agenus dataWaight et al Cancer Cell 2018

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

52

Early Clinical Activity with AGEN1181

bull Ongoing Dose-Escalation Trial

bull Combination with Agenusrsquo aPD-1 balstilimab initiated in Dec 2019

bull 20 patients treated to date on monotherapy and in combination with balstilimab

bull 1 CR and disease stabilization in majority of response evaluable patients

bull Based on AGEN1181rsquos MOA expect to target 3 times the population who benefit from Ipilimumab (Yervoyreg)

52

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

53

bull 73 yo Female with Endometrial Carcinoma (Uterine)

ndash Initial Diagnosis 04-Nov-2015 Stage IIndash Prior treatment

bull TABHSO with Lymphadenectomy bull Carboplatin Taxol HDR Vaginal Cuff Radiationbull Pembrolizumab bull Incyte 107 (PI3K Inhibitor)bull 5FU Cisplatin Palliative Radiation

bull Metastatic progression lymph node + sigmoid colon

bull AGEN1181 Treatment ndash After Dose 2 ndash symptom resolved (per investigator)ndash After Dose 4 ndash CONFIRMED CR

Metastatic Endometrial CancerConfirmed Complete Response

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

54

A complete response to CTLA-4 monotherapy (AGEN1181) is noteworthy in solid tumors

Ipilimumab Monotherapy

bull Most CRs in solid tumors are in melanoma

bull All CRs in solid tumors were at dosed at 3 or 10 mgkg

bull With gt1000 patients 4 CRs reported across all solid tumors outside of melanoma

AGEN1181 Monotherapy

bull Stable disease in solid tumors outside of melanoma (endometrial ampullary ovarian)

bull CRSD were at low doses 1 mgkg or less

bull 2 out of first 3 patients treated with1mgkg dose demonstrate clinical benefit (1 CR 1 SD)

bull AGEN1181 shows surprising early activity for an aCTLA-4 antibody

1 CR (1mgkg) amp 2 SD durable (01 and 1mgkg) seen with AGEN1181

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

55

bull AGEN1181 is an Fc Enhanced Anti-CTLA-4

bull Well-documented enhanced in vitro activity (Waight et al)

bull Potential for Enhanced Clinical Activity vs IgG1 (Ipilimumab)In combination with anti-PD-1In combination with Radiation TherapyIn combination with other Anti-Cancer Therapies

Summary Forward Looking

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

56

Dr Tyler CurielMD MPH FACP

bull Daisy M Skinner Presidentrsquos Chair in Cancer Immunology Research

bull Professor of Medicine and Microbiology Immunology amp Medical Genetics

bull University of Texas Health San Antonio TX

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

57

A Deeper Look

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

58

Endometrial Cancer Patient Complete Response

bull BRCA (-)bull MSI stablebull PD-L1 (-)bull FcγRIIIA FF phenotype

PATIENT UNLIKELY TO RESPOND TO IMMUNE THERAPY

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

59

AGEN1181 Selectively Expands an IFN-Responsive Memory CD8+ T Cell Population in vitro

AGEN1181AGEN1884analog Isotype

Changes in CD8+ memory T cellsResting memory T cells identified Enriched for AGEN1181

Resting Memory T cells 1

Resting Memory T cells 2

CD8 cytotoxic T cells

CD8 γδNK-like T cells

Proliferating cells

Dendritic cells

Source Agenus data

1 K-means clustering amp UMAP visualizationCombined AGEN1181 AGEN1884 analog

isotype

2 Conditional cell type differences

3 Key insight AGEN1181 selectively expands an IFN type 1 responding

memory T cell

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

60

AGEN Discovery Response to ipilimumab + nivolumab correlates with expansion of gamma delta (γδ) T cells in melanoma patients

γδ T cells

bull Intratumoral CD45+ cells isolated from melanoma patients receiving ipilimumab + nivolumab

bull Single cells were sequenced using Smart-seq2

bull AGEN analysis drives new mechanistic insight

All other clusters

Identify γδ T cell populationCo-express γδ TCRs NK receptors amp cytolytic markers

0

002

004

006

008

01

012

pre post pre post

γ

δT

cells

Pre Post Post

Non-responders Responders

Pre

Key insight γδ T cell population is expanded in ipi + nivo responders

Normalized expression

-10 20

Data source Sade-Feldman et al Cell 2018Data analysis Agenus

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

61

Next-Generation Benefit AGEN1181 enhances the γδ T cell response in vitro relative to 1st generation CTLA-4

0

168

284

0

05

1

15

2

25

3

ISOTY

PE 3M

AGEN1884

AGEN1181

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

AGEN

1181

isoty

peAG

EN18

84 an

alog

AGEN

1181

AGEN

1181

isoty

peAG

EN18

84 an

alog

All other clusters

Identify γδ T cell populationComparable to intratumoral population

Key insight AGEN1181 (i) selectively expands and (ii) may increase cytotoxic potential of γδ T cells in vitro

γ

δT

cells

to

tal C

D8+

IFNG

NKp301

FcεRIγ1

i Frequency of γδ T cells

AGEN

1181

isoty

pe

AGEN

1181

AGEN

1884

analo

g

Normalized expression

-10 10

Normalized expression

-10 201Activated NK cell receptor markersCorreia et al PNAS 2018

ii Selected activation markers

Intrat

umora

l γδ

In vit

ro γδ

Source Agenus data

62

bull Uncovered potential cellular mechanisms underlying enhanced T cell responses to next generation CTLA-4 in pre-clinical studiesbull Next generation CTLA-4 benefit on memory-like T cell subsetbull Next generation CTLA-4 benefit on γδ T cell subset

bull Next experiments will expand observations to patients on AGEN1181

Conclusions

63

Next Steps

1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction

2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble

factors or direct signals)

64

Dhan Chand PhDHead of Drug Discovery

OUR NEXT WAVEOF INNOVATION

66

CD73-adenosine and TGFβ are Major Contributors to Therapeutic

Resistance

67

AGEN Solution A Bi-functional Tumor Conditioning Agent

GS-1423 is potentially a first-in-class bi-functional antibody

TGFb-Trap

CD73 binding region

GS linker

Phase I initiatedQ2 2019

(licensed to Gilead)

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

63

Next Steps

1 Make better killersbull AGEN1181 (conventional T cells gamma delta T cells)bull CAR iNKTbull Epitope prediction

2 Soften the battlefieldbull AGEN1181 (reduce regulatory T cells)bull Bi-specific molecules (eg reduce myeloid cell effects soluble

factors or direct signals)

64

Dhan Chand PhDHead of Drug Discovery

OUR NEXT WAVEOF INNOVATION

66

CD73-adenosine and TGFβ are Major Contributors to Therapeutic

Resistance

67

AGEN Solution A Bi-functional Tumor Conditioning Agent

GS-1423 is potentially a first-in-class bi-functional antibody

TGFb-Trap

CD73 binding region

GS linker

Phase I initiatedQ2 2019

(licensed to Gilead)

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

64

Dhan Chand PhDHead of Drug Discovery

OUR NEXT WAVEOF INNOVATION

66

CD73-adenosine and TGFβ are Major Contributors to Therapeutic

Resistance

67

AGEN Solution A Bi-functional Tumor Conditioning Agent

GS-1423 is potentially a first-in-class bi-functional antibody

TGFb-Trap

CD73 binding region

GS linker

Phase I initiatedQ2 2019

(licensed to Gilead)

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

66

CD73-adenosine and TGFβ are Major Contributors to Therapeutic

Resistance

67

AGEN Solution A Bi-functional Tumor Conditioning Agent

GS-1423 is potentially a first-in-class bi-functional antibody

TGFb-Trap

CD73 binding region

GS linker

Phase I initiatedQ2 2019

(licensed to Gilead)

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

67

AGEN Solution A Bi-functional Tumor Conditioning Agent

GS-1423 is potentially a first-in-class bi-functional antibody

TGFb-Trap

CD73 binding region

GS linker

Phase I initiatedQ2 2019

(licensed to Gilead)

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

68

GS-1423 Enhances Tumor Cell Killing Alone and in Combination with anti-PD-1 in a Suppressive Tumor Microenvironment

0 20 40 60 800

20

40

60

80

Time (hours)

T

umor

Cel

l Killi

ng

IsotypeGS-1423anti-PD-1GS-1423 + anti-PD-1

Phase I initiated Q2 2019

GS-1423 is licensed to Gilead by Agenus

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

69

Regulatory T Cells are a Potent Suppressive Barrier to Effective Anti-

tumor Immune Responses

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

70

AGEN Solution Bispecific Antibody Designed for Selective Intratumoral Treg Depletion and T Cell Co-stimulation

AGEN1223 ndash first-in-class bispecific tobull Selectively deplete intratumoral Tregsbull Enhance T cell effector functionbull Improve safety

Fc-optimized ldquoback-endrdquo

Target Y

Phase I initiatedDecember 2019

Target X

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

71

AGEN1223 Offers Dual Mechanism of TME Conditioning and Effector T Cell Stimulation Enhanced Treg depletion compared to mAbs or combination of mAbs

0 2 4 60

1 0

2 0

3 0

4 0

5 0

Treg

H o u rs

AD

CC

ac

tiv

ity

A G E N 1 2 2 3

A n ti-G IT R (IN C A G N 0 1 8 7 6 )

A n ti-G IT R (M K 4 1 6 6 )

A n ti-G IT R (T R X -5 1 8 )

A n ti-O X 4 0 (IN C A G N 0 1 9 4 9 )

A n ti-O X 4 0 (A G E N 2 0 4 9 )

A n ti-O X 4 0 (P F -0 4 5 1 8 6 0 0 )

A n ti-O X 4 0 (G S K 3 1 7 4 9 9 8 )

C o m b in a t io n (IN C A G N 0 1 8 7 6 x A G E N 2 0 4 9 )

AGEN1223

Target X (competitor mAbs)Target Y (competitor mAbs)Combination of mAbs

0 2 4 6

50

40

30

20

10

0

Hours

A

DCC

activ

ity

Phase I initiated December 2019

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

72

Tumor-associated Macrophages Adopt a Suppressive Phenotype and Attenuate Antitumor Immunity

SHP-12

ITIMs

PhagocytosisM1 pro-inflammatory phenotype

Inhibitoryreceptor

Ligand expressed broadly across tumor types

Tumor Macrophage

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

73

AGEN Solution Ligand-blocking Antagonist Antibody Designed to Repolarize and Enhance Function of Tams

Ligand

SHP-12

ITIMs

AGEN1531

PhagocytosisM1 pro-inflammatory phenotype

AGEN1531 is a potential first-in-class antagonist antibody designed tobull Repolarize tumor-associated macrophages

towards an M1 pro-inflammatory statebull Restore effector functions of intratumoral

T amp NK cellsbull Overcome dendritic cell tolerogenicity

Inhibitoryreceptor

Tumor

Macrophage

IND Projected 2020

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

74

AGEN1531 Antagonizes a Key Immunosuppressive Interface

-3 -2 -1 0 1 2

0

200000

400000

600000

Antibody (log microgmL)

RLU

AGEN1531

Isotype

AGEN1531 relieves target-mediated inhibition of FcγR signalling

AGEN1531 converts macrophages from immune suppressing to tumor fighting

M

1 m

acro

phag

es

AGEN1531

Isotyp

e con

trol

M1-enri

ched

contr

ol

M2-enri

ched

contr

ol0

20

40

60

80

IND Projected 2020

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

75

Patient Progression on Anti-PD-1 Driven by Secondary Immune

Checkpoints

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

76

AGEN Solution Dual Functioning Bispecific that Biases a Major T amp NK Cell Immunoregulatory Interaction Towards Activation

AGEN1777 is a potential first-in-class dual antagonist bispecific

APC

T NK cellCo-stimulatory

receptorLigand

Tumor cell

AGEN1777

FcγR

Ligand

Enhanced co-stimulatory signaling

Inhibitory receptors

IND Projected 2020

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

77

AGEN1777 Controls Tumors in a Mouse Colon Tumor Model

10 20 30 40 500

500

1000

1500

2000

AGEN1777 Bispecific(mouse surrogate)

Days post implantation

Tum

or v

olum

e (m

m3 ) CR 1315

10 20 30 40 500

500

1000

1500

2000

Isotype Control(Bispecific)

Days post implantation

Tum

or v

olum

e (m

m3 )

10 20 30 40 500

500

1000

1500

2000

anti-PD-1(mAb)

Days post implantationTu

mor

vol

ume

(mm

3 ) CR 215

IND Projected 2020Source Agenus data

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

78

Data Accepted forPresentation at AACR 2020

(Abstract 922)

Novel Combinations AddressTherapeutic Resistance

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

79

Our next disruptors exemplify innovation and smart design

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

80

Dr Mark ExleyPhDbull Affiliate Harvard Medical Schoolbull Professorship University of Manchesterbull Founder of NKT Therapeutics

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

81

Tumor cell

Cytotoxicity

NK cell

IL-12

IFNɣ

iNKT cell

IL-12

Cytotoxicity

GzmBFasL

TAM or APC

IFNɣActivation

Mark Exley PhDPrincipal

INVARIANT NKT CELLS BOOST

IMMUNE RESPONSE NATURALLY

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

82

Tumor cell

Cytotoxicity

GzmBFasL

IFNɣ

iNKT cell

IL-12

Tumor associated

macrophages

Tumor cell

Cytotoxicity

NK or T cell

IL-12

IFNɣActivation

Invariant Natural Killer T (iNKT) CellsOrchestrators of the immune system

iNKTsbull Suppress GvHD (no gene editing)bull Home to tumor sitebull Massive expansion capacity gt40000

fold (1 healthy donor ~ 1000 doses)

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

83

bull 1H2020 Safety with iNKT in Multiple Myeloma CLLSLL iNHL (FL MZL) and DLBCL

bull 2H2020 Safety and efficacy of iNKT and CPIs (ie AGEN1181 AGEN2034) in solid tumors

Some cancers over-express CD1d

iNKTs May be Effective in Solid and Hematologic Tumors

Allogeneic iNKTs expected to enter clinic

as mono and CPI combinations in 2020

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

84

Julie DeSanderHead of Business Development

SMART COLLABORATIONS

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

85

Agenus Notable Strategic Partnerships~$25B in potential milestones amp royalties $525M already received

$1725Mreceived1

$145Mreceived2

$9Mreceived

$190Mreceived

More detailed information available in Agenus SEC and 10k filings1 Including $30M in equity investment2 Including $95M in equity investments3 Eligible for two milestones ($15 Million and $25 Million) based on Shingrix meeting certain commercial sales targets metrics by 2024 and 2026

$10Mreceived

Eligiblebull $200M milestonesbull Royalties

Eligiblebull $85M milestonesbull Royalties

Eligiblebull $40M milestones3

Eligiblebull $17Bn milestonesbull Royalties

Eligiblebull $450M milestonesbull Royalties

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

86

2020 Partnering Strategy

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations

In-licensing

Ex-US Partnerships

Clinical Collaborations

Platform Collaborations

Research Collaborations In-licensing

87

QampA

87

QampA