Definition

A symmetric immunoglobulin G (IgG)-like bispecific antibody targeting both the human cell surface antigen CD47 and the immunosuppressive ligand human programmed cell death-1 ligand 1 (PD-L1; cluster of differentiation 274; CD274), with potential immunostimulating, phagocytosis-inducing and antineoplastic activities. Upon administration, anti-PD-L1/anti-CD47 bispecific antibody BAT7104 targets and binds to both CD47 and PD-L1 expressed on tumor cells. The CD47 binding by BAT7104 blocks the interaction of CD47 with signal regulatory protein alpha (SIRPalpha), an inhibitory protein expressed on macrophages and dendritic cells (DCs), which prevents CD47/SIRPalpha-mediated signaling and abrogates the CD47/SIRPalpha-mediated inhibition of phagocytosis. This induces pro-phagocytic signaling mediated by the binding of calreticulin (CRT), specifically expressed on the surface of tumor cells, to low-density lipoprotein (LDL) receptor-related protein (LRP), expressed on macrophages, and results in macrophage activation and the specific phagocytosis of CD47-expressing tumor cells. The binding of BAT7104 to PD-L1 blocks its binding to and activation of its receptor programmed cell death 1 (PD-1; cluster of differentiation 279; CD279). This reverses T-cell inactivation caused by PD-1/PD-L1 signaling and enhances the cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response against PD-L1-expressing tumor cells. CD47, also called integrin-associated protein (IAP), is a tumor-associated antigen (TAA) widely expressed on normal, healthy cells, such as red blood cells and platelets, and overexpressed on the surface of a variety of cancer cells. Expression of CD47, and its interaction with SIRPalpha, leads to the inhibition of macrophage activation, which protects cancer cells from phagocytosis and allows cancer cells to proliferate. PD-L1 is overexpressed by many human cancer cell types. PD-L1 binding to PD-1 on T cells suppresses the immune system and results in immune evasion. PD-1, a transmembrane protein belonging to the immunoglobulin superfamily (IgSF) expressed on activated T-cells, is a negative regulator of the immune system that limits the expansion and survival of CD8-positive T cells. By co-targeting CD47 and PD-L1, BAT7104 may more selectively bind to tumor cells expressing both CD47 and PD-L1, reducing the side effects caused by the blockade of CD47 expressed on healthy hematopoietic stem cells (HSCs).