Targeting CD47/SIRPα as a therapeutic strategy, where we are and where we are headed

Abstract

Immunotherapy using PD-1 and CTLA4 inhibitors to stimulate T cell immunity has achieved significant clinical success. However, only a portion of patients benefit from T cell-based immunotherapy. Macrophages, the most abundant type of innate immune cells in the body, play an important role in eliminating tumor cells and infectious microbes. The phagocytic check point protein CD47 inhibits the phagocytic activity of macrophages through binding to SIRPα expressed on macrophages. Blockade of the interaction between CD47 and SIRPα could restore phagocytic activity and eliminate tumor cells in vitro and in vivo. In this manuscript, we review the mechanism of action and development status of agents (antibodies targeting CD47 and SIRPα, SIRPα-Fc fusion proteins, and bi-specific antibodies) that block CD47/SIRPα interaction in preclinical studies and in the clinical setting. In addition, small molecules, mRNA, and CAR-T/M that target the CD47/SIRPα axis are also reviewed in this article.

Keywords: Bispecific antibody; CD47; Clinical development; Immunotherapy; Phagocytosis; SIRPα.

Fig. 1

Diagram of composition of CD47 and SIRPα protein. The upper panel is the SIRPα protein with signal region (1–30), Ig-like V-type (32–137), Ig-like C1-type1 (148–247), C1-type2 (254–348), transmembrane (helical, 374–394), and cytoplasmic region (365–504) with four short spacers for SH2-binding. The lower is the CD47 protein with signal region (1–18), extracellular domain (19–141), five transmembrane region (142–289, Helical 1 to Helical 5), and cytoplasmic region (290–323)

Fig. 2

Biology of CD47/SIRPα interaction. CD47 binds to SIRPα to transmit inhibitory signals to macrophages and to inhibit or lessen phagocytic activity through uncoupling of receptor binding and signal transduction. Therapeutic agents block the interaction between CD47 and SIRPα to remove the inhibitory signal and restore the phagocytic activity

Fig. 3

Mechanism of action of interruption of the CD47/SIRPα axis. Three mechanisms can be used to inhibit the CD47/SIRPα interaction. Phagocytosis (the most important mechanism of action): blocks the CD47/SIRPα interaction to remove inhibitory signals and promote phagocytosis of tumor cells; Antigen presentation: antiCD47 antibody connects tumor cells and SIRPα+ DCs to promote antigen presentation; Apoptosis: some antiCD47 antibodies could induce tumor cell poptosis

Fig. 4

Types of bis-specific molecules targeted CD47 and other molecules. Bispecific Ab-type 1: KIH format, targeted to CD47 (yellow) and other tumor associated antigens (CD19, CD20, and MSLN, blue); Bi-specific Ab-type 2: KIH format, targeted to CD47 (yellow) and immune checkpoint molecules (PD-1, CD40, and 41BB, green); Bi-specific Ab-type 3: SIRPα (cyan) fusion to N-terminus of H-chain of IgG (targeting tumor associated antigen, blue); Bi-specific Ab-type 4: ligand/receptor to modulate TME (GM-CSF, and VEGFR2, pink) fusion to the C-terminus of the H-chain of IgG (yellow); Bi-specific Ab-type 4: SIRPα fusion to the N-terminus of IgG-Fc and ligand/receptor to modulate TME (GM-CSF, VEGFR2, pink) fusion to the C-terminus