Definition

A bispecific antibody directed against the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) and the co-inhibitory molecule and immune checkpoint inhibitor T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, the anti-PD-1/anti-TIGIT bispecific antibody IBI321 simultaneously targets, binds to and inhibits PD-1 and TIGIT and their downstream signaling pathways. Inhibition of PD-1-mediated signaling may restore immune function through the activation of T cells and T-cell-mediated immune responses. 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. PD-1, a transmembrane protein in the immunoglobulin superfamily (IgSF) expressed on T cells, functions as an immune checkpoint that negatively regulates T-cell activation and effector function when activated by its ligands programmed cell death-1 ligand 1 (PD-L1) or 2 (PD-L2); it plays an important role in tumor evasion from host immunity. 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.