anti-PD-1/anti-ILT4 bispecific antibody CDX-585

A humanized, dual antagonist immunoglobulin G1 kappa (IgG1K) monoclonal antibody directed against the inhibitory immune checkpoint receptors programmed cell death protein 1 (PD-1; PDCD1; CD279) and ILT4 (immunoglobulin-like transcript 4; leukocyte immunoglobulin-like receptor subfamily B member 2; LILRB2; lymphocyte immunoglobulin-like receptor 2; LIR2; monocyte/macrophage immunoglobulin-like receptor 10; MIR-10; CD85d), with potential immunomodulating and antineoplastic activities. Upon administration, anti-PD-1/anti-ILT4 bispecific antibody CDX-585 targets and binds to both PD-1 and ILT4. The binding of CDX-585 to PD-1 prevents the activation of PD-1 by its ligands, programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274) and/or 2 (PD-L2). 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 CDX-585 to ILT4 prevents activation by its ligands, including the major histocompatibility complex class I (MHC I) molecules human leukocyte antigen (HLA)-A, HLA-B, HLA-C and HLA-G, and inhibits ILT4-mediated signaling. Dual checkpoint blockade of PD-1 and ILT4 may enhance T-cell activation, activate expression of pro-inflammatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNFalpha), and augment cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune responses 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 PD-L1 or PD-L2; it plays an important role in tumor evasion from host immunity. ILT4, a transmembrane protein and inhibitory member of the immunoglobulin-like transcript (ILT) family of proteins, is expressed primarily by myeloid cells, including monocytes, macrophages, dendritic cells (DCs) and granulocytes, and certain tumor cells; it also plays a role in tumor evasion.