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.
Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
Cell Chem Biol. 2020 Sep 17;27(9):1181-1191.e7. doi: 10.1016/j.chembiol.2020.06.008. Epub 2020 Jul 7.
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.
中等大小的环肽是一类药物，可作为小分子化合物和大型生物分子的替代品。CD47-SIRPα 信号轴作为先天免疫检查点发挥作用，抑制吞噬细胞中的吞噬作用，并已被认为是癌症免疫治疗的有前途的靶点。然而，靶向该信号轴的环肽作为免疫治疗剂的潜力仍然未知。在这里，我们开发了一种由 15 个氨基酸组成的环肽，该环肽与小鼠 SIRPα 的细胞外结构域结合，并以变构方式有效地阻止其与 CD47 的相互作用。该肽在体外明显促进了抗体包被的肿瘤细胞被巨噬细胞吞噬，并增强了抗 CD20 或抗 gp75 抗体对肿瘤形成或转移的抑制作用。我们的结果表明，环肽对 CD47-SIRPα 相互作用的变构抑制可能是癌症免疫治疗的一种潜在方法。
