Definition

A 1:1 fixed dose combination formulation composed of the two monoclonal antibodies AI-025, a monoclonal antibody directed against the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279), and gotistobart, a pH-sensitive immunoglobulin (Ig) G1 monoclonal antibody directed against the human T-cell-expressed receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4; CTLA-4; CD152), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration of anti-PD-1 antibody AI-025/anti-CTLA-4 antibody ONC-392 combination formulation AI-061, AI-025 targets, binds to and inhibits PD-1 and ONC-392 targets, binds to and inhibits CTLA-4. This inhibits the PD-1- and CTLA-4-mediated downregulation of T-cell activation and proliferation. This restores immune function and activates a cytotoxic T-lymphocyte (CTL)-mediated immune response against tumor cells. Both PD-1 and CTLA-4 are selectively expressed on TILs in the tumor microenvironment (TME) and negatively regulate the activation and effector functions of T cells. They play key roles in the downregulation of the immune system and tumor evasion from host immunity. Dual checkpoint blockade of PD-1 and CTLA-4 enhances T cell activation and proliferation more than the blockade of either immune checkpoint receptor alone. 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; cluster of differentiation 274; CD274) or 2 (PD-L2; CD273); it plays an important role in tumor evasion from host immunity. CTLA-4, an inhibitory receptor and member of the immunoglobulin superfamily (IgSF), plays a key role in the downregulation of the immune system.