3204 INCAGN01949: A Novel Anti-OX40 Agonist Antibody With...
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INCAGN01949: A Novel Anti-OX40 Agonist Antibody With the Potential to Enhance Tumor Specific T-cell Responsiveness, While Selectively Depleting Intratumoral Regulatory T Cells Abstract INCAGN01949 Demonstrates Affinity for OX40 and Recognizes Primary Activated T Cells Mechanism 1: OX40 Forward Signaling in T Cells INCAGN01949 Enhances IL-2 and Reduces IL-10 in Primary Treg:Teff Co-culture Assays OX40 (CD134, TNFRSF4) is a T cell costimulatory receptor that can potentiate T cell receptor (TCR) signaling during CD4 + and CD8 + T cell priming, effector cell differentiation and memory T cell recall responses. In preclinical mouse tumor models, surrogate anti-OX40 agonist antibodies have shown remarkable single agent anti-tumor efficacy, as well as the ability to combine effectively with other immunomodulatory antibodies and immune education strategies, such as therapeutic cancer vaccines. Agonistic antibodies targeting OX40 are predicted to counteract the immunosuppressive tumor microenvironment and promote tumor-specific T cell immunity via two primary mechanisms: 1) binding and activating OX40 signaling in tumor-specific effector and memory T cells, thereby enhancing their responsiveness to tumor-associated antigens, and 2) co-engaging Fcγ receptors expressed by tumor-associated effector cells, and facilitating the selective depletion of intratumoral regulatory T cells. INCAGN01949 is a fully human IgG1 monoclonal antibody identified using the Retrocyte Display™ platform and is being developed for the treatment of advanced malignancies. INCAGN01949 specifically binds to human and cynomolgus monkey OX40 with similar affinity. INCAGN01949 has been optimized to mediate receptor forward signaling under suboptimal TCR stimulatory conditions, leading to enhanced production of TNFα and IFNγ and decreased production of IL-10. INCAGN01949 achieves this functionality by virtue of its ability to facilitate OX40 clustering and downstream activation of the NFκB pathway in T cells across a broad range of antibody concentrations. Consistent with mouse preclinical tumor models, OX40 was found to be selectively overexpressed by intratumoral regulatory T cells in a range of human tumor types. Commensurate with its human IgG1 Fc region, INCAGN01949 was shown to effectively co-engage activating Fcγ receptors on immune effector cells, including natural killer cells and macrophages, to mediate ADCC and/or ADCP activities. Taken together, the biophysical and functional attributes of INCAGN01949 make it ideally suited for clinical development, both as a single agent and in combination with other immunomodulatory antibodies or immune education strategies. INCAGN01949 Mediates Dose-Dependent Signal Transduction in T Cells 3204 Ana Gonzalez, 1 Mariana Manrique, 1 Ekaterina Breous, 1,2 David Savitsky, 1 Jeremy Waight, 1 Randi Gombos, 1 Yuqi Liu, 1 Shiwen Lin, 1 Taha Merghoub, 3 Daniel Hirschhorn-Cymerman, 3 Gerd Ritter, 4 Jedd Wolchok, 3,4 Reid Huber, 5 Peggy Scherle, 5 Gregory Hollis, 5 Marc van Dijk, 1,2 Robert Stein, 1 and Nicholas S. Wilson 1 1 Agenus Inc,. Lexington MA; 2 4-Antibody AG, Basel, Switzerland; 3 Memorial Sloan Kettering Cancer Center, New York, NY; 4 The Ludwig Institute for Cancer Research, New York, NY; 5 Incyte Corporation, Wilmington, DE Presented at the American Association for Cancer Research Annual Meeting 2016 New Orleans, LA, USA • April 16–20, 2016 Mechanism 2: Intratumoral Depletion of Treg Cells INCAGN01949 Enhances Primary T Cell Function Across a Broad Concentration Range Paradigm: OX40 signaling in the context of TCR activation enhances effector T cell activation, cytokine production and survival, promoting memory T cell differentiation and reactivation Paradigm: Anti-OX40 antibodies promote anti-tumor immunity through selective depletion of intratumoral regulatory T cell (Treg) activity 1 A. INCAGN01949 does not bind to quiescent immune cells (flow cytometry). B. INCAGN01949 binds to stimulated (anti-CD3 antibody) T cells. C. Dose titration of INCAGN01949 binding to activated (anti-CD3 antibody) T cells. D. Affinity of INCAGN01949 by Bio-layer Interferometry. A. NFκB activation (relative light units [RLU]) by soluble INCAGN01949 or an isotype control antibody in OX40 reporter cells. B. NFκB activation by cross-linked INCAGN01949 or an isotype control antibody in OX40 reporter cells. A. Intracellular cytokine (IFNγ and TNFα) readout using flow cytometry post-anti-CD3 antibody stimulation and plate bound (complexed) INCAGN01949 or a matched isotype control stimulation. B. IL-2 secretion by human primary T cells in the presence of superantigen and INCAGN01949 IgG1, INCAGN01949 aglycosylated IgG1 (N297A), or isotype control. Human Treg cells (CD4 + CD25 high , CD127 − ) were activated with anti-CD2/anti-CD3/anti-CD28 beads for 48 h. Human T cells were isolated (MACs sorted by negative selection) and co-cultured with activated Treg cells (1 Teff:3 Treg) for 4 days in the presence of anti-CD2/anti-CD3/anti-CD28 beads, soluble or crosslinked (with a Fab'2 anti-human Fc) INCAGN01949 or an IgG1 isotype control. Culture supernatants were analyzed for (A) IL-2 and (B) IL-10 levels. CD14 + CD4 + T cells CD8 + T cells CD20 + B cells OX40 vs isotype control Non-stimulated Stimulated INCAGN01949 vs isotype control Human OX40 K a (1/Ms) 1.09×10 6 K d (1/s) 1.26×10 −4 K D (nM) 0.11 C D A B MFI Antibody concentration (µg/mL) 10,000 6000 0 0.0001 1 0.01 100 8000 4000 2000 INCAGN01949 IgG1 Isotype Isotype INCAGN01949 B A • INCAGN01949 IgG1 binds to human OX40 with an estimated affinity (K D ) of 0.11 nM and recognizes OX40 on activated human T cells in a dose dependent manner • INCAGN01949 IgG1 functions as an OX40 agonist antibody in human T cells, activating NFκB signaling and providing T cell costimulation in the context of suboptimal TCR activation • INCAGN01949 IgG1 prevents in vitro Treg cell suppression of T effector cells by inhibiting IL-10 production and results in enhanced IL-2 secretion • INCAGN01949 preferentially labeled activated human primary Tregs as compared to T effector cells, co-engaging FcγRIIIA and mediating its activation in reporter cell assays • • Scan code to download a copy of this poster or visit: http:// bit.ly/1SbFlqs Author Disclosures Ana Gonzalez, Mariana Manrique, Ekaterina Breous, David Savitsky, Jeremy Waight, Randi Gombos, Yuqi Liu, Shiwen Lin, Robert Stein, Marc van Dijk, Nicholas S. Wilson: Agenus Inc: Employment and Stock Ownership. Reid Huber, Peggy Scherle, Gregory Hollis: Incyte Corporation: Employment and Stock Ownership. Taha Merghoub, Daniel Hirschhorn-Cymerman, Gerd Ritter, Jedd Wolchok: Nothing to disclose. Acknowledgements The authors would like to thank Rebecca Woelfle for her assistance in preparing poster material and Joseph Connolly and Zhenyu Li for their help characterizing and producing INCAGN01949. Layout and printing support was provided by Evidence Scientific Solutions, Philadelphia, PA, funded by Incyte Corporation. Conclusions OX40 is Selectively Expressed by Intratumoral Regulatory T Cells From Multiple Tumor Types INCAGN01949-Dependent Signal Transduction in FcγRIIIA Reporter Cell Assay Requires IgG1 Isotype A. Activated human Treg cells versus T effector cell (Teff) OX40 expression by flow cytometry in 2 different donors. Delta mean fluorescence intensity (ΔMFI) was calculated by deducting the MFI IgG1 isotype values. B. A titration of INCAGN01949 was added to co-cultures of FcγRIIIA-expressing reporter cells, activated human Treg cells or T effector cells. The ΔRLU is shown. A. Representative histograms of OX40 expression from tumor-associated T effector cells (Teff) or Treg cells. B. OX40 expression across various tumor types. C. Tabulated summary of OX40 expression by tumor-associated T effector cells and Treg cells. A References 1. Smyth MJ, et al. Immunol Cell Biol. 2014;92:473–474. 2. Martinet L and Smyth M. Nat Rev Immunol. 2014;15:243–254. 3. Godfrey WR, et al. J Exp Med. 1994;180:757–762. 4. Bulliard Y, et al. J Exp Med. 2013;210:1685–1693. 5. Weinberg ID, et al. Immunol Rev. 2011;244:218–231. 6. Croft M. Ann Rev Imm. 2010;28:57–78. 7. Voo KS, et al. J Immunol. 2013;191:3641–3650. 8. Piconese S, et al. J Exp Med. 2008;205:825–839. 9. Bulliard Y, et al. Immunol Cell Biol. 2013;92:475–480. 10. Nimmerjahn F and Ravetch JV. Curr Opin Immunol. 2007;19:239–245. Note: − = negative/no expression, + = weak expression, ++ = moderate expression, +++ = moderate-to-high expression, ++++ = high expression. CRC, colorectal carcinoma; NSCLC, non-small cell lung carcinoma; RCC, renal cell carcinoma. Indication Samples (n) CD4 + T cells Treg cells NSCLC 4 +/− ++++ Endometrial 2 +/− ++++ Colorectal 2 − + Breast 2 − ++ Ovarian 1 − +++ Renal 1 − + CD8 + or CD4 + T cells Treg cells Endometrial Cancer OX40 vs isotype control B OX40 + T cell (IHC) C A B A B Activated Treg, T effector cells or OX40-overexpressing cells FcRγIIIA NFAT reporter cell line Effector Activation CD28 OX40 Costimulation Memory Generation Clonal Expansion Effector Contraction Reactivation OX40 Costimulation Naïve Memory NK CELL T REG INCAGN01949 FcRs T REG MACROPHAGE INCAGN01949 FcRs NK cell Regulatory T cell Neutrophil Macrophage TUMOR ADCP Regulatory T cell depletion and effector T cell costimulation ADCC INCAGN01949 Preferentially Binds to Treg Cells and Induces FcγRIIIA Receptor–Dependent Signaling A. Schematic for the FcγRIIIA reporter based cell assay. B. A titration of INCAGN01949 on an IgG1 or IgG4 backbone were added to co-cultures of FcγRIIIA-expressing reporter cells and OX40 + recombinant cells. The delta response light units ([ΔRLU] isotype control values deducted) is shown. RLU Antibody concentration (μg/mL) 12,000 8000 0 0.01 0.1 1 10 10,000 6000 2000 4000 RLU Antibody concentration (μg/mL) 12,000 8000 0 0.01 0.1 1 10 10,000 6000 2000 4000 B A B A % CD8 + IFNγ + TNFα + T cells Antibody concentration (μg/mL) 30 20 0 0.001 0.1 0.01 100 25 15 5 10 10 1 IL-2 (pg/mL) Antibody concentration (μg/mL) 2500 1500 0 0.001 0.1 0.01 100 2000 1000 10 500 1 IgG1 Isotype INCAGN01949 IgG1 Isotype INCAGN01949 IgG1 Isotype INCAGN01949 IgG1 Isotype control INCAGN01949 IgG1 INCAGN01949 IgG1 N297A 0.1 0.01 1 Antibody Concentration (μg/mL) ΔRLU 15,000 10,000 0 Treg cells Teff 100 0.001 5000 10 Donor 1 Donor 2 20,000 10,000 0 5000 Treg cells Teff ΔMFI 15,000 1 Antibody Concentration (μg/mL) ΔRLU 10,000 7500 5000 0 INCAGN01949 IgG4 INCAGN01949 IgG1 10 0.1 2500 Soluble Crosslinked (αhulgG, Fab'2) IL-2 (ng/mL) 1000 500 0 750 250 Soluble Crosslinked (αhulgG, Fab'2) IL-10 (ng/mL) 350 200 0 250 100 300 150 50 70,000 60,000 50,000 40,000 30,000 20,000 0 Ovarian (Stage IIC) NSCLC (Stage II) OX40 (number) Teff Treg cells 10,000 RCC (Stage III) Endo (Stage IB) CRC (Stage IIIB) INCAGN01949 OX40 FcγRIIIA NFAT pathway Luciferase Samples from multiple tumor types (ovarian cancer, colorectal carcinoma, endometrial carcinoma, renal cell carcinoma, and non-small cell lung carcinoma) demonstrate an enrichment in OX40 high intratumoral regulatory T cells INCAGN01949 IgG1 functions as effective agonist of the OX40 pathway, and may have the potential in patients to enhance T cell responsiveness to weakly immunogenic tumor- associated antigens, while attenuating the immune suppressive function of intratumoral populations of regulatory T cells. Taken together, these preclinical data support the clinical development of INCAGN01949
Transcript of 3204 INCAGN01949: A Novel Anti-OX40 Agonist Antibody With...
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INCAGN01949: A Novel Anti-OX40 Agonist Antibody With the Potential to Enhance Tumor Specific T-cell Responsiveness, While Selectively Depleting Intratumoral Regulatory T Cells
Abstract INCAGN01949 Demonstrates Affinity for OX40 and Recognizes Primary Activated T Cells
Mechanism 1: OX40 Forward Signaling in T Cells
INCAGN01949 Enhances IL-2 and Reduces IL-10 in Primary Treg:Teff Co-culture Assays
OX40 (CD134, TNFRSF4) is a T cell costimulatory receptor that can potentiate T cell receptor (TCR) signaling duringCD4+ and CD8+ T cell priming, effector cell differentiation and memory T cell recall responses. In preclinical mouse tumormodels, surrogate anti-OX40 agonist antibodies have shown remarkable single agent anti-tumor efficacy, as well as theability to combine effectively with other immunomodulatory antibodies and immune education strategies, such astherapeutic cancer vaccines. Agonistic antibodies targeting OX40 are predicted to counteract the immunosuppressivetumor microenvironment and promote tumor-specific T cell immunity via two primary mechanisms: 1) binding andactivating OX40 signaling in tumor-specific effector and memory T cells, thereby enhancing their responsiveness totumor-associated antigens, and 2) co-engaging Fcγ receptors expressed by tumor-associated effector cells, andfacilitating the selective depletion of intratumoral regulatory T cells.
INCAGN01949 is a fully human IgG1 monoclonal antibody identified using the Retrocyte Display™ platform and is beingdeveloped for the treatment of advanced malignancies. INCAGN01949 specifically binds to human and cynomolgusmonkey OX40 with similar affinity. INCAGN01949 has been optimized to mediate receptor forward signaling undersuboptimal TCR stimulatory conditions, leading to enhanced production of TNFα and IFNγ and decreased production ofIL-10. INCAGN01949 achieves this functionality by virtue of its ability to facilitate OX40 clustering and downstreamactivation of the NFκB pathway in T cells across a broad range of antibody concentrations. Consistent with mousepreclinical tumor models, OX40 was found to be selectively overexpressed by intratumoral regulatory T cells in a range ofhuman tumor types. Commensurate with its human IgG1 Fc region, INCAGN01949 was shown to effectively co-engageactivating Fcγ receptors on immune effector cells, including natural killer cells and macrophages, to mediate ADCC and/orADCP activities. Taken together, the biophysical and functional attributes of INCAGN01949 make it ideally suited forclinical development, both as a single agent and in combination with other immunomodulatory antibodies or immuneeducation strategies.
INCAGN01949 Mediates Dose-Dependent Signal Transduction in T Cells
3204Ana Gonzalez,1 Mariana Manrique,1 Ekaterina Breous,1,2 David Savitsky,1 Jeremy Waight,1 Randi Gombos,1 Yuqi Liu,1 Shiwen Lin,1 Taha Merghoub,3 Daniel Hirschhorn-Cymerman,3Gerd Ritter,4 Jedd Wolchok,3,4 Reid Huber,5 Peggy Scherle,5 Gregory Hollis,5 Marc van Dijk,1,2 Robert Stein,1 and Nicholas S. Wilson1
1Agenus Inc,. Lexington MA; 24-Antibody AG, Basel, Switzerland; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4The Ludwig Institute for Cancer Research, New York, NY; 5Incyte Corporation, Wilmington, DE
Presented at theAmerican Association for Cancer Research Annual Meeting 2016New Orleans, LA, USA • April 16–20, 2016
Mechanism 2: Intratumoral Depletion of Treg Cells INCAGN01949 Enhances Primary T Cell Function Across a Broad Concentration Range
Paradigm: OX40 signaling in the context of TCR activation enhances effector T cell activation, cytokine production and survival, promoting memory T cell differentiation and reactivation
Paradigm: Anti-OX40 antibodies promote anti-tumor immunity through selective depletion of intratumoral regulatory T cell (Treg) activity1
A. INCAGN01949 does not bind to quiescent immune cells (flow cytometry).B. INCAGN01949 binds to stimulated (anti-CD3 antibody) T cells.C. Dose titration of INCAGN01949 binding to activated (anti-CD3 antibody) T cells.D. Affinity of INCAGN01949 by Bio-layer Interferometry.
A. NFκB activation (relative light units [RLU]) by soluble INCAGN01949 or an isotype control antibody in OX40 reporter cells.B. NFκB activation by cross-linked INCAGN01949 or an isotype control antibody in OX40 reporter cells.
A. Intracellular cytokine (IFNγ and TNFα) readout using flow cytometry post-anti-CD3 antibody stimulation and platebound (complexed) INCAGN01949 or a matched isotype control stimulation.
B. IL-2 secretion by human primary T cells in the presence of superantigen and INCAGN01949 IgG1, INCAGN01949aglycosylated IgG1 (N297A), or isotype control.
Human Treg cells (CD4+ CD25high, CD127−) were activated with anti-CD2/anti-CD3/anti-CD28 beads for 48 h. Human T cells were isolated (MACs sorted by negative selection) and co-cultured with activated Treg cells (1 Teff:3 Treg) for 4 days in the presence of anti-CD2/anti-CD3/anti-CD28 beads, soluble or crosslinked (with a Fab'2 anti-human Fc) INCAGN01949 or an IgG1 isotype control. Culture supernatants were analyzed for (A) IL-2 and (B) IL-10 levels.
CD14+ CD4+T cells
CD8+T cells
CD20+B cells
OX40 vs isotype control
Non-stimulated Stimulated
INCAGN01949 vs isotype controlHuman OX40
Ka (1/Ms) 1.09×106
Kd (1/s) 1.26×10−4
KD (nM) 0.11
C
D
A
B
MFI
Antibody concentration (µg/mL)
10,000
6000
00.0001 10.01 100
8000
4000
2000
INCAGN01949
IgG1 Isotype
Isotype
INCAGN01949
BA
• INCAGN01949 IgG1 binds to human OX40 with an estimated affinity (KD) of 0.11 nM andrecognizes OX40 on activated human T cells in a dose dependent manner
• INCAGN01949 IgG1 functions as an OX40 agonist antibody in human T cells, activatingNFκB signaling and providing T cell costimulation in the context of suboptimal TCRactivation
• INCAGN01949 IgG1 prevents in vitro Treg cell suppression of T effector cells by inhibitingIL-10 production and results in enhanced IL-2 secretion
• INCAGN01949 preferentially labeled activated human primary Tregs as compared toT effector cells, co-engaging FcγRIIIA and mediating its activation in reporter cell assays
•
•
Scan code to download acopy of this poster or visit:
http://bit.ly/1SbFlqs
Author DisclosuresAna Gonzalez, Mariana Manrique, Ekaterina Breous, David Savitsky, Jeremy Waight, Randi Gombos, Yuqi Liu, Shiwen Lin, Robert Stein, Marc van Dijk, Nicholas S. Wilson: Agenus Inc: Employment and Stock Ownership. Reid Huber, Peggy Scherle, Gregory Hollis: Incyte Corporation: Employment and Stock Ownership. Taha Merghoub, Daniel Hirschhorn-Cymerman, Gerd Ritter, Jedd Wolchok: Nothing to disclose.
AcknowledgementsThe authors would like to thank Rebecca Woelfle for her assistance in preparing poster material and Joseph Connolly and Zhenyu Li for their help characterizing and producing INCAGN01949.Layout and printing support was provided by Evidence Scientific Solutions, Philadelphia, PA, funded by Incyte Corporation.
Conclusions
OX40 is Selectively Expressed by IntratumoralRegulatory T Cells From Multiple Tumor Types
INCAGN01949-Dependent Signal Transduction in FcγRIIIA Reporter Cell Assay Requires IgG1 Isotype
A. Activated human Treg cells versus T effector cell (Teff) OX40 expression by flow cytometry in 2 different donors. Deltamean fluorescence intensity (ΔMFI) was calculated by deducting the MFI IgG1 isotype values.
B. A titration of INCAGN01949 was added to co-cultures of FcγRIIIA-expressing reporter cells, activated human Tregcells or T effector cells. The ΔRLU is shown.
A. Representative histograms of OX40expression from tumor-associated T effectorcells (Teff) or Treg cells.
B. OX40 expression across various tumor types.C. Tabulated summary of OX40 expression by
tumor-associated T effector cells and Tregcells.
A
References 1. Smyth MJ, et al. Immunol Cell Biol. 2014;92:473–474.2. Martinet L and Smyth M. Nat Rev Immunol. 2014;15:243–254.3. Godfrey WR, et al. J Exp Med. 1994;180:757–762.4. Bulliard Y, et al. J Exp Med. 2013;210:1685–1693.5. Weinberg ID, et al. Immunol Rev. 2011;244:218–231.
6. Croft M. Ann Rev Imm. 2010;28:57–78.7. Voo KS, et al. J Immunol. 2013;191:3641–3650.8. Piconese S, et al. J Exp Med. 2008;205:825–839.9. Bulliard Y, et al. Immunol Cell Biol. 2013;92:475–480.10. Nimmerjahn F and Ravetch JV. Curr Opin Immunol. 2007;19:239–245.
Note: − = negative/no expression, + = weak expression, ++ = moderate expression, +++ = moderate-to-high expression, ++++ = high expression.CRC, colorectal carcinoma; NSCLC, non-small cell lung carcinoma; RCC, renal cell carcinoma.
Indication Samples (n) CD4+ T cells Treg cells
NSCLC 4 +/− ++++
Endometrial 2 +/− ++++
Colorectal 2 − +
Breast 2 − ++
Ovarian 1 − +++
Renal 1 − +
CD8+ or CD4+T cells
Treg cells
Endometrial Cancer
OX40 vs isotype control
B OX40+ T cell (IHC)
C
A B
A B
Activated Treg, T effector cells or
OX40-overexpressing cellsFcRγIIIA NFAT reporter cell line
Effector
ActivationCD28
OX40Costimulation
Memory Generation
ClonalExpansion
Effector Contraction Reactivation
OX40Costimulation
Naïve
Memory
NK CELL
TREG
INCAGN01949FcRs
TREG
MACROPHAGE
INCAGN01949FcRs
NK cellRegulatory T cell
NeutrophilMacrophage
TUMORADCP
Regulatory T cell depletion and effector T cell
costimulation
ADCC
INCAGN01949 Preferentially Binds to Treg Cells and Induces FcγRIIIA Receptor–Dependent Signaling
A. Schematic for the FcγRIIIA reporter based cell assay.B. A titration of INCAGN01949 on an IgG1 or IgG4 backbone were added to co-cultures of FcγRIIIA-expressing reporter
cells and OX40+ recombinant cells. The delta response light units ([ΔRLU] isotype control values deducted) is shown.
RL
U
Antibody concentration (µg/mL)
12,000
8000
0
0.01 0.1 1 10
10,000
6000
2000
4000
RL
U
Antibody concentration (µg/mL)
12,000
8000
0
0.01 0.1 1 10
10,000
6000
2000
4000
BA
BA
% C
D8
+IF
Nγ
+T
NFα
+T
cell
s
Antibody concentration (µg/mL)
30
20
00.001 0.10.01 100
25
15
5
10
10
1
IL-2
(p
g/m
L)
Antibody concentration (µg/mL)
2500
1500
0
0.001 0.10.01 100
2000
1000
10
500
1
IgG1 Isotype
INCAGN01949
IgG1 Isotype
INCAGN01949
IgG1 Isotype
INCAGN01949
IgG1 Isotype control
INCAGN01949 IgG1
INCAGN01949 IgG1 N297A
0.10.01 1
Antibody Concentration (μg/mL)
ΔR
LU
15,000
10,000
0
Treg cells
Teff
1000.001
5000
10
Donor 1 Donor 2
20,000
10,000
0
5000
Treg cells
Teff
ΔM
FI
15,000
1
Antibody Concentration (μg/mL)
ΔR
LU
10,000
7500
5000
0
INCAGN01949 IgG4
INCAGN01949 IgG1
100.1
2500
Soluble Crosslinked(αhulgG, Fab'2)
IL-2
(n
g/m
L)
1000
500
0
750
250
Soluble Crosslinked(αhulgG, Fab'2)
IL-1
0 (
ng
/mL
)
350
200
0
250
100
300
150
50
70,000
60,000
50,000
40,000
30,000
20,000
0
Ovarian
(Stage IIC)
NSCLC
(Stage II)
OX
40 (
nu
mb
er)
Teff
Treg cells
10,000
RCC
(Stage III)
Endo
(Stage IB)
CRC
(Stage IIIB)
INCAGN01949
OX40
FcγRIIIA
NFATpathway
Luciferase
Samples from multiple tumor types (ovarian cancer, colorectal carcinoma, endometrialcarcinoma, renal cell carcinoma, and non-small cell lung carcinoma) demonstrate anenrichment in OX40high intratumoral regulatory T cellsINCAGN01949 IgG1 functions as effective agonist of the OX40 pathway, and may havethe potential in patients to enhance T cell responsiveness to weakly immunogenic tumor-associated antigens, while attenuating the immune suppressive function of intratumoralpopulations of regulatory T cells. Taken together, these preclinical data support theclinical development of INCAGN01949
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