anti-TIGIT antibody/TGFbeta-RII fusion protein AK130

A bifunctional fusion protein composed of a humanized Fc-mutant anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody fused to transforming growth factor beta (TGF-beta) receptor type II (TGFbetaRII), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration of anti-TIGIT antibody/TGFbeta-RII fusion protein AK130, the TGFbetaRII moiety targets, binds to and neutralizes TGF-beta while the anti-TIGIT antibody moiety simultaneously targets and binds to TIGIT expressed on various immune cells, particularly on tumor-infiltrating lymphocytes (TILs) and natural killer (NK) cells. The neutralization of TGF-beta prevents TGF-beta-mediated immunosuppressive signaling, thereby enhancing anti-tumor immunity in the tumor microenvironment (TME). The binding to TIGIT 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), and enhances the interaction of CD112 and CD155 with the costimulatory receptor CD226 (DNAX Accessory molecule-1; DNAM-1) expressed on immune cells, such as 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. TIGIT, a member of the Ig superfamily (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. TGF-beta, dysregulated in many types of cancer, plays a key role in immunosuppression in the TME and is involved in tumor cell proliferation and tumor progression. The mutations in the Fc region of the anti-TIGIT antibody moiety prevent antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and the resulting loss of lymphocytes.