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Background: TIGIT is a coinhibitory receptor that is highly expressed on tumor infiltrating lymphocytes (TILs), including effector and regulatory (Treg) CD4 + T cells, effector CD8 + T cells, and NK cells. Engagement of TIGIT with its cognate ligand PVR directly suppresses lymphocyte activation. TIGIT and PVR are broadly expressed in different types of solid tumors, suggesting that TIGIT-PVR signaling may be a dominant immune escape mechanism for cancer. Utilizing COM902, a therapeutic antibody targeting TIGIT, we demonstrate that co-blockade of TIGIT and a new checkpoint inhibitor, PVRIG, augments T cell responses in vitro and in vivo. Results: COM902 is a mouse/cyno cross-reactive fully human antibody that binds TIGIT with high affinity and specificity and disrupts the binding of TIGIT to PVR. This antibody binds to TIGIT on human CD8 + T cells with higher affinity than tested benchmark antibodies. In dissociated tumor samples, TIGIT expression was highest on TILs in endometrial, head and neck, kidney and lung tumors, and directly correlated with PVRIG expression. Except for breast tumors, PVR was moderately to highly expressed in all tumor types examined, while PVRL2 expression was highest in prostate, ovarian, liver and endometrial tumors. Combination of COM902 and COM701 resulted in enhanced CD3 + TIL activity in vitro. Furthermore, the combination of chimeric COM902 and anti-PVRIG resulted in significant CT26 tumor growth inhibition and enhanced overall survival, which was comparable to the combination of chimeric COM902 and anti-PD-L1. Conclusion: COM902 is a high affinity antagonistic TIGIT antibody, that is currently in preclinical development. Co-expression of TIGIT with PVRIG in TILs and their non-redundant inhibitory effects on T cell activation suggest a potential therapeutic advantage in clinical combinations targeting both pathways. Towards this end we are planning a trial that will eventually incorporate combinations of COM902 with the anti-PVRIG antibody, COM701. A. COM902 binds with high affinity to human TIGIT and cross reacts with cynomolgus monkey and mouse TIGIT. B. COM902 blocks the interaction between TIGIT and PVR in a dose-dependent manner. COM902, a Novel Therapeutic Antibody Targeting TIGIT Augments T Cell Function and the Activity of PVRIG Pathway Blockade In Vitro and In Vivo Kathryn Logronio 1 , Samir Qurashi 1 , Sarah Whelan 1 , Kyle Hansen 1 , Sandeep Kumar 1 , Ling Leung 1 , Hsin-Yuan Cheng 1 , Zoya Alteber 2 , Rupashree Sen 3 , Michele Doucet 3 , Mark White 1 , Spencer Liang 1 , Eran Ophir 2 , Sudipto Ganguly 3 , John Hunter 1 , Drew Pardoll 3 and Maya Kotturi 1 1 Compugen USA, Inc, South San Francisco CA, 2 Compugen Ltd, Holon Israel, 3 Bloomberg Kimmel Institute for Cancer Immunotherapy, John Hopkins University, Baltimore, MD ABSTRACT COMBINATION OF COM902 AND COM701 DEMONSRATES COMPARABLE OR GREATER POTENCY THAN ANTI-PD1 COM902: A HIGH AFFINITY, MOUSE/CYNO CROSS-REACTIVE TIGIT ANTAGONIST REDUCED TUMOR GROWTH IN PVRIG-/- AND TIGIT-/- MICE AND SYNERGISTIC TGI IN DOUBLE KO MICE IN B16-F10 MELANOMA CANCER MODEL COM902 INHIBITS TUMOR GROWTH & INCREASES SURVIVAL IN COMBINATION WITH ANTI-PVRIG OR ANTI-PDL1 IN CT26 COLON CANCER MODEL 0 2 4 6 8 0 2 4 6 8 10 CD8 PVRIG vs TIGIT TIGIT CD8 + T cell PVRIG CD8 + T cell r=0.6235 p<0.0001 0 2 4 6 8 0 50 100 150 200 CD8 PD-1 vs TIGIT TIGIT CD8 + T cell PD-1 CD8 + T cell r=0.6383 p<0.0001 0 50 100 150 200 0 2 4 6 8 10 CD8 PVRIG vs PD-1 PD-1 CD8 + T cell PVRIG CD8 + T cell r=0.5233 p<0.0001 0 2 4 6 0 2 4 6 8 CD4 PVRIG vs TIGIT TIGIT CD4 + T cell PVRIG CD4 + T cell r=0.5746 p<0.0001 0 2 4 6 0 10 20 30 CD4 PD-1 vs TIGIT TIGIT CD4 + T cell PD-1 CD4 + T cell r=0.6763 p<0.0001 0 10 20 30 0 2 4 6 8 CD4 PVRIG vs PD-1 PD-1 CD4 + T cell PVRIG CD4 + T cell r=0.5532 p<0.0001 A. TIGIT expression on CD8+, non-Treg CD4+, Treg CD4+ T cells, and NK cells is shown for indication. B. Correlation analysis of TIGIT, PVRIG, and PD1 expression on CD8+ and CD4+ T cells from dissociated tumors. TIGIT IS EXPRESSED ON LYMPHOCYTES IN THE TME IN CORRELATION TO PVRIG AND PD1 Tissue Type Total Samples % PVRL2 Low (score 1) % PVRL2 Moderate (score 2) % PVRL2 High (score 3) Prostate 21 71 19 10 Ovarian 10 80 10 10 Liver 10 60 40 0 Endometrial 14 71 21 0 Bladder 11 73 18 0 Head and Neck 24 54 13 0 Skin 8 75 0 0 Stomach 25 72 0 0 Colon 20 50 0 0 Breast 21 67 0 0 Pancreatic 11 73 0 0 Lung 17 47 0 0 Thyroid 10 30 0 0 Kidney 25 0 0 0 Brain 10 0 0 0 Tissue Type Total Samples % PVR Low (score 1) % PVR Moderate (score 2) % PVR High (score 3) Colon 20 0 5 95 Prostate 21 0 14 86 Liver 10 0 10 90 Skin 8 13 25 63 Stomach 9 33 11 56 Brain 10 30 10 60 Head and Neck 24 33 21 46 Bladder 11 18 27 55 Endometrial 14 0 50 50 Lung 19 37 26 37 Pancreatic 11 27 36 36 Thyroid 10 60 20 20 Ovarian 10 20 50 30 Kidney 25 32 40 28 Breast 19 84 11 5 The expression of PVR (A.) and PVRL2 (B.) in 16 different types of tumor tissues with n=10-20 patients per indication is shown. A polyclonal anti-PVRL2 antibody (HPA012759, Sigma-Aldrich) and a monoclonal anti-PVR antibody (Clone D8A5G, Cell Signaling Technology) were used. B. PVR AND PVRL2 ARE EXPRESSED IN MULTIPLE TUMOR TISSUES A. TIGIT AND PVRIG ARE PARALLEL, NON-REDUNDANT IMMUNE CHECKPOINTS IN THE PVR/NECTIN FAMILY COM902 HAVE SUPERIOR BINDING CAPACITY & SIMILAR OR GREATER FUNCTION COMPARED TO CLINICAL ANTI-TIGIT BMs Martinet & Smyth, Nat Rev Immunol, 2015 (modified) 7 10 14 17 0 1000 2000 3000 4000 Wild-type Days post-tumor implantation Tumor Volume (mm 3 ) 7 10 14 17 0 1000 2000 3000 4000 Pvrig -/- Days post-tumor implantation Tumor Volume (mm 3 ) 7 10 14 17 0 1000 2000 3000 4000 Days post-tumor implantation Tumor Volume (mm 3 ) Tigit -/- 7 10 14 17 0 1000 2000 3000 4000 Days post-tumor implantation Tumor Volume (mm 3 ) Pvrig -/- Tigit -/- 7 10 14 17 0 500 1000 1500 2000 2500 Days post-tumor implantation Mean Tumor Volume (mm 3 ) Wild-type Pvrig -/- Tigit -/- Pvrig -/- Tigit -/- p<0.03 p<0.01 0 10 20 30 0 20 40 60 80 100 Days post-tum o r im plantation Percent survival W ild Type P V R IG -/- T IG IT -/- P V R IG -/- T IG IT -/- A. B16-F10 tumor volume in PVRIG-/-, TIGIT-/- or PVRIG-/-TIGIT-/- double KO mice are represented as the mean volume ± SEM. B. Kaplan- Meier survival curves. C. Individual tumors measurements for each mouse P=0.0003 10 15 20 25 30 0 500 1000 1500 2000 Days Post Inoculation Tumor Volume (mm 3 ) Isotype mIgG1 -PD-L1 mIgG1 Chimeric COM902 Chimeric COM902 + -PD-L1 mIgG1 Vehicle (1x PBS) p = 0.0144 10 15 20 25 30 0 500 1000 1500 2000 Days Post Inoculation Tumor Volume (mm 3 ) p = 0.032 Vehicle (1x PBS) Isotype mIgG1 -PVRIG mIgG1 Chimeric COM902 Chimeric COM902 + -PVRIG mIgG1 0 10 20 30 0 20 40 60 80 100 Days post when TV >1500 mm 3 % Survival p = 0.012 70% 0 10 20 30 0 20 40 60 80 100 Days post when TV >1500 mm 3 % Survival p = 0.0092 80% A. Tumor volume for the chimeric COM902 (10 mg/kg ) & anti-PD-L1 (3 mg/kg ) combination, or the chimeric COM902 & anti-PVRIG (10 mg/kg ) combination are represented as the mean volume ± SEM. B. Kaplan-Meier survival curves for the monotherapy treatments and combinations (n=10). B. B.
