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COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade

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Abstract

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.

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References

  1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–723. https://doi.org/10.1016/j.cell.2017.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Whelan S, Ophir E, Kotturi MF et al (2019) PVRIG and PVRL2 are induced in cancer and inhibit CD8 + T-cell function. Cancer Immunol Res 7:257–268. https://doi.org/10.1158/2326-6066.CIR-18-0442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stanietsky N, Simic H, Arapovic J et al (2009) The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 106:17858–17863. https://doi.org/10.1073/pnas.0903474106

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yu X, Harden K, Gonzalez LC et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10:48–57. https://doi.org/10.1038/ni.1674

    Article  CAS  PubMed  Google Scholar 

  5. Shibuya A, Campbell D, Hannum C et al (1996) DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4:573–581. https://doi.org/10.1016/S1074-7613(00)70060-4

    Article  CAS  PubMed  Google Scholar 

  6. Shibuya K, Lanier LL, Phillips JH et al (1999) Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11:615–623. https://doi.org/10.1016/S1074-7613(00)80136-3

    Article  CAS  PubMed  Google Scholar 

  7. Chiang EY, de Almeida PE, de Almeida Nagata DE et al (2020) CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses. Eur J Immunol 50:891–902. https://doi.org/10.1002/eji.201948405

    Article  CAS  PubMed  Google Scholar 

  8. Zhu Y, Paniccia A, Schulick AC et al (2016) Identification of CD112R as a novel checkpoint for human T cells. J Exp Med 213:167–176. https://doi.org/10.1084/jem.20150785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vaena D, Patnaik A, Hamilton E et al (2019) Abstract CT168: Phase I study of COM701 (a novel checkpoint inhibitor of PVRIG) in patients with advanced solid tumors. Cancer Res. https://doi.org/10.1158/1538-7445.AM2019-CT168

    Article  Google Scholar 

  10. Johnston RJ, Comps-Agrar L, Hackney J et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8 + T cell effector function. Cancer Cell 26:923–937. https://doi.org/10.1016/j.ccell.2014.10.018

    Article  CAS  PubMed  Google Scholar 

  11. Chauvin J, Pagliano O, Fourcade J et al (2015) TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients. J Clin Invest 125:2046–2058. https://doi.org/10.1172/JCI80445

    Article  PubMed  PubMed Central  Google Scholar 

  12. Harjunpää H, Guillerey C (2020) TIGIT as an emerging immune checkpoint. Clin Exp Immunol 200:108–119. https://doi.org/10.1111/cei.13407

    Article  PubMed  Google Scholar 

  13. Alteber Z, Kotturi MF, Whelan S et al (2021) Therapeutic targeting of checkpoint receptors within the DNAM-1 axis. Cancer Discov, Accepted

    Google Scholar 

  14. Golan T, Bauer TM, Golan T, et al (2018) Phase 1 dose‐finding study of the anti–TIGIT antibody MK‐7684 as monotherapy and in combination with pembrolizumab in patients with advanced solid. 33rd annual meeting and pre-conference programs of the society for immunotherapy of cancer (SITC 2018). J Immunother Cancer (SITC 2018). J Immunother Cancer 6:115 Abstract O25

  15. Sharma S, Ulahannan S, Mettu NB, et al (2018) Initial results from a phase 1a/b study of Etigilimab (OMP-313M32), an anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody in advanced solid tumours. 33rd annual meeting and pre-conference programs of the society for immunotherapy of cancer (SITC 2018). J Immunother Cancer 6(Suppl 1) Abstract P289

  16. Bendell JC, Bedard P, Bang Y-J et al (2020) Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Cancer Res. https://doi.org/10.1158/1538-7445.AM2020-CT302

    Article  Google Scholar 

  17. Rodriguez-Abreu D, Johnson ML, Hussein MA et al (2020) Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 38:9503–9503. https://doi.org/10.1200/jco.2020.38.15_suppl.9503

    Article  Google Scholar 

  18. Finnefrock AC, Fu T-M, Freed DC, et al (2012) PD-1 Binding Proteins. U.S. Patent No. 8,168,757

  19. Murter B, Pan X, Ophir E et al (2019) Mouse PVRIg has CD8 + T cell-specific coinhibitory functions and dampens antitumor immunity. Cancer Immunol Res 7:244–256. https://doi.org/10.1158/2326-6066.CIR-18-0460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Savas P, Virassamy B, Ye C et al (2018) Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med 24:986–993. https://doi.org/10.1038/s41591-018-0078-7

    Article  CAS  PubMed  Google Scholar 

  21. Sun Y, Luo J, Chen Y et al (2020) Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma). Int Immunopharmacol 80:106198. https://doi.org/10.1016/j.intimp.2020.106198

    Article  CAS  PubMed  Google Scholar 

  22. Liu W, Putnam AL, Xu-yu Z et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711. https://doi.org/10.1084/jem.20060772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Farhood B, Najafi M, Mortezaee K (2019) CD8 + cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 234:8509–8521. https://doi.org/10.1002/jcp.27782

    Article  CAS  PubMed  Google Scholar 

  24. Miller BC, Sen DR, Al AR et al (2019) Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 20:326–336. https://doi.org/10.1038/s41590-019-0312-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schietinger A, Philip M, Krisnawan VE et al (2016) Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated article tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45:389–401. https://doi.org/10.1016/j.immuni.2016.07.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Philip M, Schietinger A (2019) ScienceDirect heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections. Curr Opin Immunol 58:98–103. https://doi.org/10.1016/j.coi.2019.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Speiser DE, Ho P, Verdeil G (2016) Regulatory circuits of T cell function in cancer. Nat Rev Immunol 16:599–611. https://doi.org/10.1038/nri.2016.80

    Article  CAS  PubMed  Google Scholar 

  28. Yost KE, Satpathy AT, Wells DK et al (2019) Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med 25:1251–1259. https://doi.org/10.1038/s41591-019-0522-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fourcade J, Sun Z, Chauvin JM et al (2018) CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI insight 3:1–13. https://doi.org/10.1172/jci.insight.121157

    Article  Google Scholar 

  30. Nishiwada S, Sho M, Yasuda S et al (2015) Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res 35:2287–2297

    CAS  PubMed  Google Scholar 

  31. Stamm H, Oliveira-ferrer L, Grossjohann E et al (2019) Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer. Oncoimmunology 8:e1674605. https://doi.org/10.1080/2162402X.2019.1674605

    Article  PubMed  PubMed Central  Google Scholar 

  32. Leipold D, Prabhu S (2019) Pharmacokinetic and pharmacodynamic considerations in the design of therapeutic antibodies. Clin Transl Sci 12:130–139. https://doi.org/10.1111/cts.12597

    Article  CAS  PubMed  Google Scholar 

  33. Kurtulus S, Sakuishi K, Ngiow S et al (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 1:1–10. https://doi.org/10.1172/JCI81187DS1

    Article  Google Scholar 

  34. Chihara N, Madi A, Kondo T et al (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558:454–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Han JH, Cai M, Grein J et al (2020) Effective anti-tumor response by TIGIT blockade associated with FcγR engagement and myeloid cell activation. Front Immunol 11:1–14. https://doi.org/10.3389/fimmu.2020.573405

    Article  CAS  Google Scholar 

  36. Nimmerjahn F, Ravetch JV (2008) Fcγ receptors as regulators of immune responses. Nat Rev Immunol 8:34–47. https://doi.org/10.1038/nri2206

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

KH, SK, KL, SW, SQ, HYC, AD, MT, PW, DB, LL, EO, ZA, GC, MG, MF, MW, JH, SL and MK received salary from Compugen Ltd at the time of this study.

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Authors and Affiliations

  1. Compugen USA, Inc, South San Francisco, CA, USA

    Kyle Hansen, Sandeep Kumar, Kathryn Logronio, Sarah Whelan, Samir Qurashi, Hsin-Yuan Cheng, Andrew Drake, Margaret Tang, Patrick Wall, David Bernados, Ling Leung, Mark White, John Hunter, Spencer C. Liang & Maya F. Kotturi

  2. Compugen Ltd, Azrieli Center, 26 Harokmim St. Bldg D, 5885849, Holon, Israel

    Eran Ophir, Zoya Alteber, Gady Cojocaru, Moran Galperin & Masha Frenkel

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  1. Kyle Hansen
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Correspondence to Eran Ophir.

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Hansen, K., Kumar, S., Logronio, K. et al. COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade. Cancer Immunol Immunother 70, 3525–3540 (2021). https://doi.org/10.1007/s00262-021-02921-8

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