Definition

An engineered fragment crystallizable (Fc) domain bispecific human immunoglobulin G1 (IgG1) monoclonal antibody directed against the human negative immunoregulatory checkpoint receptors programmed cell death protein 1 (PD-1; PDCD1; CD279) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4; CTLA-4), with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, volrustomig targets and binds to both PD-1 and CTLA4 expressed on tumor-infiltrating T lymphocytes (TILs), and inhibits the PD-1- and CTLA4-mediated downregulation of T-cell activation and proliferation. In addition, volrustomig is internalized and is able to degrade PD-1. This restores immune function and activates a sustained cytotoxic T-lymphocyte (CTL)-mediated immune response against tumor cells. Both PD-1 and CTLA4 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 PD1 and CTLA4 with volrustomig may enhance T-cell activation and proliferation more than the blockade of either immune checkpoint receptor alone. It may also decrease toxicity by avoiding the binding to CTLA-4-expressing T cells that are devoid of PD-1. The engineered Fc domain may reduce Fc effector function.