Definition

A bispecific antibody directed against the human negative immunoregulatory checkpoint receptor programmed cell death protein 1 (PD-1; PD1; PDCD1; CD279) and human transforming growth factor beta (TGF-beta) receptor II (TGFbRII), with potential immune checkpoint modulating and antineoplastic activities. Upon administration, anti-PD-1/anti-TGFbRII bispecific antibody INCA33890 targets and binds to both PD-1 and TGFbRII and prevents the activation of PD-1 and TGF-beta-mediated signaling pathways in the tumor microenvironment (TME). The binding of INCA33890 to PD-1 prevents the activation of PD-1 by its ligands, programmed cell death-1 ligand 1 (PD-L1; CD274) and/or 2 (PD-L2; CD273). This abrogates T-cell inhibition, activates antigen-specific T lymphocytes and enhances cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis, which may lead to a reduction in tumor growth. The binding of INCA33890 to TGFbRII prevents the binding of TGF-beta to TGFbRII, thereby preventing the activation of the TGF-beta-mediated signaling pathway. This abrogates TGF-beta-mediated immunosuppression in the TME, increases natural killer (NK) cell and CTL activities, and inhibits tumor cell proliferation in susceptible tumor cells. PD-1, an inhibitory receptor belonging to the immunoglobulin superfamily (IgSF), is expressed on activated T lymphocytes; it functions as an immune checkpoint that negatively regulates T-cell activation and effector function when activated by its ligands and plays an important role in tumor evasion from host immunity. TGF-beta, a pro-inflammatory mediator, is upregulated in certain types of cancers and is involved in cancer cell proliferation, tumor progression, migration and invasion, and the suppression of the immune response.