Abstract 683: Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect

Abstract

Abstract Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. Immune checkpoint inhibitors, such as monoclonal antibodies (mAbs) to CTLA-4, PD-1, and PD-L1, have provided clinical benefit in patients with a variety of types of cancer, and a growing number of agents targeting immune checkpoints are in preclinical and clinical development. SIRPα is a transmembrane protein that is abundant in myeloid cells, such as macrophages and dendritic cells. SIRPα interacts with another transmembrane protein CD47 through their ectodomains, and they constitute the cell-cell communication system (the CD47-SIRPα system). We previously demonstrated that the interaction of SIRPα on macrophages with CD47 on tumor cells prevented the phagocytosis of tumor cells by macrophages. In contrast, blockage by anti-SIRPα antibodies of the CD47-SIRPα interaction enhanced the phagocytic activity of macrophages against antibody-opsonized tumor cells, suggesting that the CD47-SIRPα axis acts as an immune checkpoint pathway involved in tumor escape from immunosurveillance. Here, by the use of random nonstandard peptide integrated discovery (RaPID) system, we have identified novel macrocyclic peptides that bind to the extracellular domain of SIRPα with high affinity. These SIRPα-binding macrocyclic peptides inhibited the CD47-SIRPα interaction. Moreover, one of the SIRPα-binding macrocycles promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro and enhanced the antitumor effect of mAbs against tumor antigens in xenograft or syngeneic mouse models of cancer. Our results thus suggest that macrocyclic peptides against SIRPα hold promise as a novel tool for cancer immunotherapy. Citation Format: Daisuke Hazama, Yoji Murata, Takeshi Okamoto, Daisuke Tanaka, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Takashi Matozaki. Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 683.