Accelerat ed Product Developm ent for Phase I/ II Clin ical Evaluat ion – Balancing Science, Tim e and Cost

Industry Perspective

Forward Look ing St at em ent

This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical fact are statements that could be forward-looking statements. You can identify these forward-looking statements through our use of words such as “may,” “will,” “can,” “anticipate,” “assume,” “should,” “indicate,” “would,” “believe,” “contemplate,” “expect,” “seek,” “estimate,” “continue,” “plan,” “point to,” “project,” “predict,” “could,” “intend,” “target,” “potential” and other similar words and expressions of the future. These forward-looking statements are subject to risks and uncertainties that may cause actual future experience and results to differ materially from those discussed in these forward-looking statements. Important factors that might cause such a difference include, but are not limited to, the timing, cost and uncertainty of obtaining regulatory approvals for product candidates; our ability to develop and commercialize products before competitors that are superior to the alternatives developed by such competitors; the validity of our patents and our ability to avoid intellectual property lit igation, which can be costly and divert management time and attention; the risks relating to the integration of the businesses of Kolltan and Celldex; and the other factors listed under “Risk Factors” in our filings with the SEC, including Forms 10-K, 10-Q and 8-K.

Celldex does not undertake any obligation to release publicly any revisions to such forward-looking statement to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

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Celldex Philosophy

Developing Targeted Therapeutics for Patients With Devastating Diseases

Unlock ing t he Power of t he Im m une Syst em t o Treat Devast at ing DiseasesDeep pipeline of ant ibodies, ant ibody-drug conjugat es and ot her prot ein-based t herapeut ics • Glem bat um um ab vedot in (ADC targeting gpNMB)

– METRIC registration study in metastatic TNBC: enrollment completion targeted for Sept. 2017– Phase 2 single-agent study in checkpoint-refractory metastatic melanoma; primary ORR

endpoint met; added expansion cohorts in combo with varlilumab (data fall 2017) and in combo with checkpoint inhibitors

• Var l i lum ab (binds and activates CD27) collaboration with BMS; Opdivo (nivolumab) combo now in Phase 2 — well tolerated in Phase 1 dose-escalation with early signs of clinical activity

• CDX-0158 (inhibits KIT) in ongoing Phase 1 study for refractory GIST and KIT-positive tumors; preclinical data support clinical evaluation in combination with other IO agents, such as varlilumab

• CDX-3379 (unique ErbB3 inhibitor) completed Phase 1 and demonstrated clear clinical activity, including stable disease and durable responses; Phase 2 study planning underway

• CDX-014 (ADC targeting TIM-1) entered Phase 1 in renal cell carcinoma in July 2016

• Several ongoing and planned third-party sponsored studies (including Glemba in SCLC and uveal melanoma) and a broad investigator initiated research program to further explore our pipeline

• Access to state of the art technology for ongoing development of novel immunotherapies

Exper ienced im m uno-oncology t eam ; involved in t he developm ent of Yervoy® and Opdivo®

Yervoy ® and Opdivo® are a registered trademarks of Bristol-Myers Squibb.4

Pipeline, Celldex Sponsored St udies

Drug Candidat e and Indicat ion Target Preclin ical Phase 1 Phase 2 Phase 3

Glem bat um um ab vedot inTriple negative breast cancer

gpNMB

Glem bat um um ab vedot inMetastatic melanoma

gpNMB

Var li lum abHead and neck, ovarian, colorectal and renal cell carcinomas, and GBM

CD27

CDX-0158Gastrointestinal stromal tumors (GIST)and other KIT-positive tumors

KIT

CDX-3379Multiple solid tumors

ErbB3

CDX-014Renal cell carcinoma

TIM-1

monotherapy ongoing; combo planned

+ nivolumab (BMS collaboration)

in combo regimens

monotherapy ongoing; combo planned

METRIC (registrational study)

(3 arms: monotherapy complete; + varli &+ checkpoint inhibitor ongoing)

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Pipeline, Third-Par t y Sponsored St udies*

Drug Candidat e and Indicat ion Target Preclin ical Phase 1 Phase 2 Phase 3

Glem bat um um ab vedot inUveal melanomaSponsor : NCI (CRADA)

gpNMB

Glem bat um um ab vedot inSquamous cell lung cancerSponsor : PrECOG, LLC

gpNMB

CDX-1401 / CDX-301Multiple solid tumorsSponsor : CITN

NY-ESO-1

Flt3L

* In addition to the studies listed above, Celldex also has an Investigator Initiated Research (IIR) program with seven studies ongoing with our investigational agents and additional studies currently under consideration.

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Preclin ical Program s

• Fully human antibody targeted to CD40

• Data at SITC, ASH 2016

• Potent agonist activity and a safety profile that allows systemic dosing at levels that provide good tissue and tumor penetration in preclinical models

• IND planned in 2017

CDX-1140

• Comprised of the targets Tyro3, AXL and MerTK

• Potential applications in oncology, inflammation, and infectious disease

• Developing antibodies and assays to select drug candidates for development

TAM Program

• Developing a bispecific antibody program that combines different immune targeting antibodies

• Update later in 2017

Bispecif ic Ant ibodies

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How do we accelerat e Phase I/ II product developm ent and m anage m anufact ur ing r isks, balancing product qualit y, t im e and cost ?

Celldex Approach• Clearly define project objectives

– Proof of concept– Defined and justified development path

• In-house capabilit ies– Cell line development– Process development– Analytical development & product characterization– Preclinical R&D– Early phase manufacturing

• Understanding product demand and dosage requirements– Defines requirements for cell line productivity and manufacturing scale

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Present at ion Out l ine

Cell l ine developm ent

Process developm ent

Analyt ical suppor t

Form ulat ion developm ent

Manufact ur ing

Preclin ical R&D

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Cell Line Developm ent

Balancing Product Quality, Cost, & Timelines

Cell Line Developm ent

Celldex Cell Bank ing Guidelines• Early or late stage development

– Proof of concept– Pivotal study

• Expression level requirements– Projected product demand (dosage and patient population)

• Utilize commercially available expression systems such as GS-CHO or CHOZN

References• Poin ts to Conside r in the Production and Testing of New Drugs and Biologics Produced by Recom binant DNA

Technology (1985)• Supplem ent to the Poin ts to Conside r in the Production and Testing of New Drugs and Biologics Produced by

Recom binant DNA Technology: Nucle ic Acid Characte riza tion and Gene tic Stab ility (1992)• Poin ts to Conside r in the Characte riza tion of Ce ll Lines Used to Produce Biologics (1993)• Poin ts to Conside r in the Manufacture and Testing of Monoclona l Antibody Products for Hum an Use (1997)• ICH Q5A (R1): Vira l Sa fe ty Eva lua tion of Biotechnology Products Derived from Ce ll Lines of Hum an or Anim al Origin• ICH Q5B: Qua lity of Biotechnologica l Products: Ana lysis of the Expression Construct in Ce lls Used for Production of

r-DNA Derived Prote in Products• ICH Q5D: Deriva tion and Characte riza tion of Ce ll Substra tes Used for Production of Biotechnologica l/Biologica l

Products

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Research Cell Bank (RCB) Cr it er ia

RCBs should be generat ed f rom :• Early Stage RCB - Cell lines that have gone through at least one round of

limiting dilution cloning or other method such as FACS cell sorting• Late Stage RCB - Cell lines that have gone through at least two rounds of

limiting dilution cloning or other method if it can be validated to ensure greater than 95% probability of clonality

A lead and back-up RCB clone should be select ed based on:• Early Stage RCB - Growth and productivity, at least in fed-batch shake

flask studies• Late Stage RCB - Growth and productivity in bench-scale bioreactors as

well as cell line stability and genetic characterization

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Mast er Cell Bank (MCB) Cr it er ia

Ear ly St age MCB• In order to reduce timelines, a first generation RCB and MCB may be

subject to minimal development and testing on the way to Phase I clinical studies.

Lat e st age MCB• In order to improve productivity, increase probability of clonality, and

ensure cell line stability, a second (or later) RCB and MCB may need to be established.

• As a starting point in developing the second (or later) generation cell line, one could use:– The MCB of the first (or previous) generation cell line,– A different cell pool or clone than the one selected during initial cell line

development, or – A completely new transfection which could be done using the same or

different cell line development platform (host cell line and expression vector).

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Genet ic Charact er izat ion

Genet ic charact er izat ion st udies on:• Early stage MCBs are not required, unless a later stage MCB is not

generated for a project going into late stage clinical development.• Late stage MCBs from which WCBs will be generated are required.

These studies should be done prior to the initiation of Phase II/ III pivotal clinical studies.

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Genet ic Charact er izat ion

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Ce ll Ba n k Sta ge Sou th e rn qPCR Ge n e Copy

cDNA Se qu e n cin g North e rn

RCB(4-6 clones) Late X

RCB(Lead & Back-up) Late X X X

MCB* Late X X X X

WCB* X X

EPCBFrom late stage MCB

or WCBX X X X

Cell line stabilit y*From late stage MCB

or WCBX X X X

Process Developm ent

Balancing Product Quality, Cost & Timelines

Plat form Process

Cell Cult ure• Seed Train Expansion (Shake Flasks, WAVE Bioreactor, 50L and 250L Single Use Bioreactor)• Production Culture in Either 250L or 1000L Single Use BioreactorHarvest• Harvest and Clarification (Millipore POD Depth Filtration)Pur if icat ion and Virus Inact ivat ion• Protein A Chromatography• Low pH Virus Inactivation• pH Adjustment (Neutralization)• Anion Exchange Membrane Chromatography• Sartoclear P Depth filtration• Cation Exchange Chromatography• Nanofiltration Virus Clearance • Concentration and DiafiltrationForm ulat ion• Adjust Protein Concentration• Add (Polysorbate 80) (Excipient)• 0.22 μm Filtra tion in to Appropria te ly Sized Bags or Bottle s

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Int egrat ed Manufact ur ing & Developm ent Process Flow

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Process Development

Cell Line Development &

Cell Banking

Analytical Development

Manufacturing

Feedback loop Feedback loop

Case St udy: HIV m Ab Process Developm ent

• Top subclones (RCBs) were used to develop the upstream cell culture process.

• Cell culture and mAb production were assessed in shake flasks, wave bioreactors and 3L bioreactors. Cell line stability studies were initiated.

• Temperature shifts, pH shifts, nutrient feeds, nutrient utilization were investigated to achieve maximum product titer (10-15 bioreactors per mAb).

• Bioreactor harvests were used as feed-streams to evaluate primary recovery filter sizing using depth filtration and for the development of the purification process.– Column capacities, membrane areas, nanofilter defined.– Purity assessed; aggregation, solubility and HCP clearance – Small scale stability initiated. – Purified material provided to AD/QC for assay qualification.

• USP and DSP confirmed with MCB.

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Analyt ical

Balancing Product Quality, Cost & Timelines

Analyt ical Capabil i t ies (1)

Biophysical Charact er izat ion• Circular Dichroism Spect roscopy

– Determination and assessment of tertiary and secondary structure• Dynam ic Light Scat t er ing

– Assessment of aggregation and higher order structure.• Dif ferent ial Scanning Calor im et ry

– Assessment of thermal conformational stability • Isot herm al Chem ical Denat urat ion (UnChained Labs “The Hunk”)

– Assessment of chemical conformational stability– Probing protein fine structure and conformation by intrinsic tryptophan

fluorescence– Formulation development and investigative support

• Diode Ar ray UV Spect roscopy– Assesses protein fine tertiary structure in the second derivative

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Analyt ical Capabil i t ies (2)

St ruct ural Charact er izat ion• Mass Spect rom et ry (Agilent 6530 Q-ToF)

– Intact Mass Determination– Peptide Mapping with sequence coverage by MS/MS

• Determination of sites of deamidation, oxidation, glycosylation as well as any other post translational modifications.

– N-Terminal Peptide Sequencing– Determination of site of conjugation in ADCs– Determination of disulphide connectivity and free thiol content

• Size Het erogeneit y– Absolute Molar Mass

• Wyatt Dawn Heleos II Multi Angle Laser Light Scattering (MALLS) Detector• Wyatt Optilab T-rEX refractive index detector• Wyatt online Quasi Elastic Light Scattering detector (QELS)

– SEC-HPLC with UV detection• Prot ein Quant it at ion

– Solo VPE– DAD spectrophotometer

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Analyt ical Capabil i t ies (3)

St ruct ural Charact er izat ion (cont ’d)• Am ino Acid Analysis (AAA)

– Compositional and quantitative AAA for the confirmation of composition as well for extinction coefficient determination

• Carbohydrat e Analysis– Quantitative sialic acid analysis– Quantitative monosaccharide analysis– Charge profiling of released oligosaccharides by charge (AEX)– Normal phase profiling of released oligosaccharides by normal phase HPLC

• Deam idat ion– IsoQuant

• Elect rophoresis– Capillary electrophoresis– Capillary iso-electric focusing ICE280 / Maurice (Protein Simple)– Standard gel electrophoresis as well as Western Blotting of transferred proteins

is also routinely run for assessments of purity, identity as well as comparability

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Analyt ical Suppor t of Process Developm ent and Ear ly Phase Manufact ur ing

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Process Development

Analytical Development

Manufacturing

Process Residuals Analysis• Residual Protein A• Residual Host Cell Protein• Residual Insulin• Residual methotrexate• Residual methionine sulphoximine

Developm ent and Qualif icat ion of Rout ine Met hodologies• In-Process Product Concentration (Solo VPE)• Size Exclusion Chromatography• Capillary iso-Electric Focusing• Reducing and Non-reducing SDS-PAGE• ELISA for functional binding and identity

Form ulat ion Developm ent

Balancing Product Quality, Cost & Timelines

Form ulat ion Developm ent

Balancing speed t o cl in ic w it h r isk t hat form ulat ion is not adequat e st able t o suppor t st orage under t he desired condit ion• Typically we have performed minimal formulation development for early

phase products, but our requirements and expectations are evolving based on our experience

• Drug substance– ≤ -65° vs. 2-8°C storage

• Sm alle r ba tch sizes – frozen is accep tab le• Large r ba tch sizes – frozen p roduct becom es a m ajor logistica l cha llenge , so 2-8°C

storage becom es a necessity

– Standard p ractice assum es tha t ea rly phase d rug substance will be stored frozen while rea l tim e stab ility da ta is collected on re frige ra ted m ate ria l

• Drug product– 2-8°C storage is p re fe rred– Frozen d rug p roduct is accep tab le for p roof of concep t

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Manufact ur ing

Balancing Product Quality, Cost & Timelines

Manufact ur ing

In House Capabil i t y = Flexibil i t y and Speed• Utilize disposable technology, e.g., Single Use Bioreactors (SUBs)• Utilize com m ercia lly ava ilab le m edia , e.g., CD-CHO with various feeds• Scale d irectly from 3L b ioreactors in p rocess deve lopm ent to 250L or

1000L sca le in p roduction ; do not pe rform engineering runs (reduce tim e and cost)

• Phase appropria te cGMP• Reprocessing flexib ility – project can proceed with scheduling tha t’s in

our con tro l

Invest m ent in EU com pliance• Clin ica l deve lopm ent speed• Avoid prem ature ou tsourcing to CMO

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Fall River Manufact ur ing Facil i t y1000L, 250L, and 50L SUBs

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1000L SUB Harvest ut i l izing t he Mil l ipore POD clar if icat ion syst em w it h single use m em branes

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In Conclusion

Clear ly def ine project object ives• Proof of concept• Defined and justified development path

In house capabil i t ies• Cell line development• Process development• Analytical development & product characterization• Preclinical R&D• Early phase manufacturing

Underst anding product dem and and dosage requirem ent s• Defines requirements for cell line productivity and manufacturing scale

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Acknow ledgem ent sAnt ibody Developm ent Team (Ham pt on, NJ) Manufact ur ing Team (Fall River , MA)

L. Vitale C. FerioliJ. Widger K. JohnsonC. Patterson A. HarkinsA. Crocker J. RayT. O’Neill A. Nichols

V. GeldartProcess Developm ent Team (Needham , MA) L. Fox

R. Hammond J. SequeiraE. Barrett K. RichardD. McCormack R. BilewaskiK. SherlockC. Swarce Preclinical Team (Needham , MA)E. Crawford L. ThomasC. Leite A. BaronasY. Chhung K. Borrelli

J. BoyerAnalyt ical Developm ent (Fall River , MA) E. Do

J. Womble E. ForsbergS. Renn-Bingham L. GergelI. Papayannopoulos M. GrealishC. Omeoga C. PilsmakerK. Edwards M. Rocheleau

Qualit y Cont rol (Fall River , MA) Qualit y Assurance (Fall River , MA)Amy Munroe Kathleen DeemerCarrie Domozick Dan ComstockFatima Seuffert Matt DeMeloMelissa Majkut Mary Jane DoldJoyce Sousa Brian RowanLinda Arruda Vince VitaleHana Rihani Documentation team; Maria Van Saun, Nancy Leskiw

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