anti-ILT4/anti-PD-L1 bispecific antibody SPX-303

A bispecific antibody directed against both the inhibitory immune checkpoint receptor immunoglobulin-like transcript 4 (ILT4; leukocyte immunoglobulin-like receptor subfamily B member 2; LILRB2; lymphocyte immunoglobulin-like receptor 2; LIR2; monocyte/macrophage immunoglobulin-like receptor 10; MIR-10; CD85d) and the immunosuppressive ligand programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274), with potential immune checkpoint inhibitory, immunostimulatory and antineoplastic activities. Upon administration, anti-ILT4/anti-PD-L1 bispecific antibody SPX-303 targets and binds to both ILT4 and PD-L1. The binding of SPX-303 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. This abrogates the immunosuppressive activities of ILT4 in the tumor microenvironment (TME), activates the expression of pro-inflammatory cytokines, including GM-CSF and tumor necrosis factor alpha (TNFalpha), and enhances a cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response. The binding of SPX-303 to PD-L1 prevents the binding to its receptor, programmed cell death protein 1 (PD-1, CD279), inhibits the PD-1/PD-L1-mediated signaling, and inhibits the PD-1/PD-L1-mediated downregulation of T-cell activation and proliferation. This restores and enhances a CTL-mediated immune response against tumor cells. PD-L1, which is overexpressed in many human cancer cell types, plays an important role in the downregulation of the immune system and 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.