Definition

A humanized immunoglobulin G1 (IgG1)-based bispecific antibody directed against both the co-inhibitory molecule and immune checkpoint inhibitor T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) and poliovirus receptor-related immunoglobulin (PVRIG; PVR Related Immunoglobulin Domain Containing Protein; CD112R), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, the anti-TIGIT/anti-PVRIG bispecific antibody SIM0348 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 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. In addition, SIM0348 induces Fc-mediated killing of TIGIT-expressing immunosuppressive regulatory T cells (Tregs) and Tregs expressing TIGIT and PVRIG. TIGIT, a member of the immunoglobulin 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.