Progress of CD47 immune checkpoint blockade agents in anticancer therapy: a hematotoxic perspective

Abstract

CD47, a transmembrane protein, acts as a "do not eat me" signal that is overexpressed in many tumor cell types, thereby forming a signaling axis with its ligand signal regulatory protein alpha (SIRPα) and enabling the tumor cells to escape from macrophage-mediated phagocytosis. Several clinical trials with CD47 targeting agents are underway and have achieved impressive results preliminarily. However, hematotoxicity (particularly anemia) has emerged as the most common side effect that cannot be neglected. In the development of CD47 targeting agents, various methods have been used to mitigate this toxicity. In this review, we summarized five strategies used to alleviate CD47 blockade-induced hematotoxicity, as follows: change in the mode of administration; dual targeting bispecific antibodies of CD47; CD47 antibodies/SIRPα fusion proteins with negligible red blood cell binding; anti-SIRPα antibodies; and glutaminyl-peptide cyclotransferase like inhibitors. With these strategies, the development of CD47 targeting agents can be improved.

Keywords: Anemia; CD47/SIRPα; Immunotherapy; Macrophages; Phagocytosis checkpoint.

Fig. 1

Anti-CD47 antibodies induce hematotoxicity. A Anti-CD47 antibodies activate phagocytosis of RBCs by macrophages. B Anti-CD47 antibodies bind to different RBCs to cause RBC agglutination. Ab antibody, MΦ macrophage

Fig. 2

Strategies to diminish CD47 blockade induced hematotoxicity. A The priming low dose of CD47 antibody is administered to eliminate aged RBCs and lead to compensatory of reticulocytes. A higher maintenance dose is administered for better treatment. B Dual-targeting bispecific antibodies that target both tumor-associated antigen and CD47 can reduce RBCs binding while ensuring the binding to tumor cells. C CD47 antibodies/SIRPα fusion proteins with negligible RBC binding can reduce hematotoxicity. D Anti-SIRPα antibody does not eliminate RBCs while blocking the CD47/SIRPα pathway. E QPCTL inhibitors block the CD47/SIRPα pathway by altering the post-translational modification of CD47 and do not cause hematotoxicity. Ab antibody, MΦ macrophage, TAA tumor-associated antigen, Fp fusion protein, w/o pGlu without pyroglutamate modification