Discovery of Anti‐CD47 Peptides as Innate Immune Checkpoint Inhibitors

Cancer immunotherapy targeting adaptive immune cells has been attracting considerable interest due to its great success in treating multiple cancers. Recently, there is also increasing interest in agents that can stimulate innate immune cell activities. Immune checkpoint inhibitors targeting innate immune cells can block inhibitory interactions (“don't eat me” signals) between tumor cells and phagocytes. CD47 is a transmembrane protein overexpressed in various cancers and acts as a potent “do not eat me” signal that contributes to the immune evasion of cancer cells. Anti‐CD47 peptides that can bind to CD47 and block its interaction with signal regulatory protein alpha (SIRPα) are discovered using a novel phage display biopanning strategy. Anti‐CD47 peptides enhance the macrophage‐mediated phagocytosis of NCI‐H82 tumor cells in vitro. Unlike anti‐CD47 antibodies, these peptides do not induce the agglutination of red blood cells. Moreover, anti‐CD47 peptides exhibit high specificity for MC‐38 cancer cells expressing CD47. CMP‐22 peptide show the ability to increase the antitumor activity of doxorubicin and extends the survival of CT26 tumor‐bearing mice. The discovered anti‐CD47 peptides can be considered potential candidates for cancer immunotherapy by blocking the CD47/SIRPα interaction, especially in combination with chemotherapy, to elicit synergistic effects. CD47/SIRPα is an innate immune checkpoint pathway. Cancer cells overexpress CD47 on their surface. Through phage display biopanning, three anti‐CD47 peptides have been discovered that can block the binding of CD47 to SIRPα. This re‐activates macrophages to phagocytose cancer cells. The discovered anti‐CD47 peptides have the potential to be used as immune checkpoint inhibitors in combination with chemotherapy.