Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy

Daisuke Hazama; Yizhen Yin; Yoji Murata; Makoto Matsuda; Takeshi Okamoto; Daisuke Tanaka; Naohiro Terasaka; Jinxuan Zhao; Mariko Sakamoto; Yuka Kakuchi; Yasuyuki Saito; Takenori Kotani; Yoshihiro Nishimura; Atsushi Nakagawa; Hiroaki Suga; Takashi Matozaki

doi:10.1016/j.chembiol.2020.06.008

Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy

Cell Chem Biol. 2020 Sep 17;27(9):1181-1191.e7. doi: 10.1016/j.chembiol.2020.06.008. Epub 2020 Jul 7.

Authors

Affiliations

¹ Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
² Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
³ Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Electronic address: ymurata@med.kobe-u.ac.jp.
⁴ Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
⁵ Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
⁶ Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
⁷ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: hsuga@chem.s.u-tokyo.ac.jp.
⁸ Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Electronic address: matozaki@med.kobe-u.ac.jp.

PMID: 32640189
DOI: 10.1016/j.chembiol.2020.06.008

Abstract

Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy.

Keywords: CD47; SIRPα; cancer; immunotherapy; innate immune checkpoint; macrocyclic peptide; macrophage; phagocytosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Animals
Antigens, CD20 / immunology
Antineoplastic Agents, Immunological / immunology
Antineoplastic Agents, Immunological / therapeutic use
CD47 Antigen / chemistry
CD47 Antigen / metabolism*
Cell Line, Tumor
Female
Humans
Immunotherapy
Macrophages / cytology
Macrophages / immunology
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Neoplasms / mortality
Neoplasms / pathology
Neoplasms / therapy
Peptides, Cyclic / chemistry
Peptides, Cyclic / metabolism*
Peptides, Cyclic / therapeutic use
Phagocytosis
Protein Binding
Receptors, Immunologic / chemistry
Receptors, Immunologic / metabolism*
Rituximab / immunology
Rituximab / therapeutic use
Survival Rate

Substances

Antigens, CD20
Antineoplastic Agents, Immunological
CD47 Antigen
Peptides, Cyclic
Ptpns1 protein, mouse
Receptors, Immunologic
Rituximab