anti-TIGIT/anti-PVRIG bispecific antibody PM1009

A bispecific antibody composed of a human immunoglobulin G1 (IgG1) monoclonal antibody directed against the co-inhibitory molecule and immune checkpoint inhibitor T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) with a single chain variable fragment (scFv) targeting poliovirus receptor-related immunoglobulin (PVRIG; PVR Related Immunoglobulin Domain Containing Protein; CD112R) fused to the c-terminus, with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, the anti-TIGIT/anti-PVRIG bispecific antibody PM1009 simultaneously targets, binds to and inhibits TIGIT and PVRIG and their downstream signaling pathways. Inhibition of TIGIT expressed on various immune cells, particularly on tumor-infiltrating lymphocytes (TILs), prevents the interaction of TIGIT with its ligands CD112 (nectin-2; poliovirus receptor related-2; PRR2; PVRL2) and CD155 (poliovirus receptor; PVR; nectin-like protein 5; NECL-5). This enhances the interaction of CD112 and CD155 with the costimulatory receptor CD226 (DNAX Accessory molecule-1; DNAM-1), which is expressed on immune cells, such as natural killer (NK) cells and CD8+ T cells. This leads to CD226 dimerization and CD226-mediated signaling and activates the immune system to exert a T-cell-mediated immune response against cancer cells. Inhibition of PVRIG expressed on cytotoxic T-lymphocytes (CTLs) and NK cells within the tumor microenvironment (TME) blocks the interaction of PVRIG with its ligand nectin cell adhesion molecule 2 (poliovirus receptor-related 2; PVRL2; CD112), which is overexpressed on a variety of tumor cell types. This abrogates the PVRIG-mediated inhibition of T-lymphocyte and NK cell activation. This activates CTLs and NK cells, enhances anti-tumor responses and immune-mediated tumor cell killing, and inhibits tumor cell proliferation. TIGIT, a member of the Ig super family (IgSF) and an immune inhibitory receptor, plays a key role in the suppression of T-cell proliferation and activation; it is involved in tumor cell immune evasion, and the inhibition of antiviral immune responses. PVRIG, a member of the B7/CD28 family and an immune checkpoint receptor, negatively regulates the activation of various immune cells upon activation and plays a key role in immunosuppression.