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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2021-12, Vol.70 (12), p.3525-3540
• Main Authors: Hansen, Kyle, Kumar, Sandeep, Logronio, Kathryn, Whelan, Sarah, Qurashi, Samir, Cheng, Hsin-Yuan, Drake, Andrew, Tang, Margaret, Wall, Patrick, Bernados, David, Leung, Ling, Ophir, Eran, Alteber, Zoya, Cojocaru, Gady, Galperin, Moran, Frenkel, Masha, White, Mark, Hunter, John, Liang, Spencer C., Kotturi, Maya F.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Antibodies, Monoclonal - immunology; B7-H1 Antigen - immunology; Cancer Research; CD155 antigen; CD226 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell Proliferation - physiology; CTLA-4 protein; Female; Humans; Immune checkpoint inhibitors; Immunoglobulin G; Immunoglobulin G - immunology; Immunology; Immunotherapy - methods; Jurkat Cells; Lymphocytes T; Macaca fascicularis; Macrophages; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Monoclonal antibodies; Oncology; Original; Original Article; PD-1 protein; PD-L1 protein; Receptors, Cell Surface - immunology; Receptors, Immunologic - immunology; Signal Transduction - immunology; Solid tumors; Tumor cells; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-021-02921-8

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.