Definition

A bispecific antibody targeting the co-inhibitory receptor lymphocyte-activation gene 3 protein (LAG-3; LAG3; CD223) 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, anti-LAG-3/TIGIT bispecific antibody ZGGS15 targets, binds to and blocks LAG-3 expressed by tumor infiltrating lymphocytes (TILs), thereby preventing the interaction between LAG-3 and major histocompatibility complex class II (MHC II) molecules on the surface of antigen-presenting cells (APCs) and tumor cells. This prevents the negative regulation of T-cell activity that occurs via LAG-3-MHC II binding and enhances a cytotoxic T-lymphocyte (CTL)-mediated immune response against tumor cells, leading to a reduction in tumor growth. In addition, ZGGS15 simultaneously targets and binds to TIGIT expressed on various immune cells, particularly on TILs, thereby preventing 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 further exert a T-cell-mediated immune response against cancer cells. LAG-3, a member of the immunoglobulin superfamily (IgSF), negatively regulates both the proliferation and activation of T cells. Its expression on TILs is associated with tumor-mediated immune suppression. TIGIT, a member of the 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.