Definition

A human monoclonal antibody targeting leukocyte surface antigen CD47, with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, anti-CD47 monoclonal antibody STI-6643 targets and binds to CD47 expressed on tumor cells, blocking the interaction of CD47 with signal regulatory protein alpha (SIRPa) expressed on phagocytic cells. This prevents CD47/SIRPa-mediated signaling and abrogates the CD47/SIRPa-mediated inhibition of macrophage activation and phagocytosis of cancer cells. This induces pro-phagocytic signaling mediated by the binding of calreticulin (CRT), which is specifically expressed on the surface of tumor cells, to low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1), which is expressed on macrophages, and results in macrophage activation and the specific phagocytosis of tumor cells. CD47, also called integrin-associated protein (IAP), is a tumor-associated antigen (TAA) expressed on normal, healthy hematopoietic stem cells (HSCs) but is overexpressed on the surface of a variety of cancer cells and contributes to poor prognosis. Expression of CD47, and its interaction with SIRPa, leads to the inhibition of macrophage activation and protects cancer cells from phagocytosis, thereby allowing cancer cells to proliferate. Compared to other anti-CD47 monoclonal antibodies, STI-6643 shows decreased binding to red blood cells (RBCs). This may prevent adverse effects such as anemia that can result from the blockade of CD47 expressed on RBCs. In addition, STI-6643 has a minimal effect on T-, B- or natural killer (NK) cell depletion which may further improve its efficacy by preserving infiltrating anti-tumor immune cells.