Definition

A recombinant fusion protein composed of an extracellular domain of human signal-regulatory protein alpha (SIRP-alpha; SIRPa; CD172a) linked to an Fc domain derived from human immunoglobulin G4 (IgG4), with potential immune checkpoint inhibitory, phagocytosis-inducing and antineoplastic activities. Upon administration, SIRP-alpha-Fc fusion protein HCB101 selectively targets and binds to CD47 expressed on tumor cells and blocks the interaction of CD47 with endogenous SIRPa, an inhibitory protein expressed on macrophages and dendritic cells (DCs), thereby preventing CD47/SIRPa-mediated signaling. This abrogates the CD47/SIRPa-mediated inhibition of macrophage activation, and 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), which is expressed on macrophages. This results in macrophage activation and the specific phagocytosis of tumor cells. Additionally, blocking CD47/SIRPa signaling activates an anti-tumor T-lymphocyte immune response and T-cell-mediated killing of tumor cells. CD47, also called integrin-associated protein (IAP), is a tumor-associated antigen (TAA) expressed on normal, healthy hematopoietic stem cells (HSC) and overexpressed on the surface of a variety of cancer cells. Expression of CD47, and its interaction with SIRPa, leads to the inhibition of macrophage activation and protects tumor cells from phagocytosis, thereby allowing these cells to proliferate and survive.