A pH-dependent anti-CD47 antibody that selectively targets solid tumors and improves therapeutic efficacy and safety

作者：Yulu Li, Juan Liu, Wei Chen, Wei Wang, Fang Yang, Ximing Liu, Sheng Yao, Kaixin Du, Miaomiao He, Xueyuan Lyu, Huiyu Li, Linlin Zhao, Zhizhong Wei, Fengchao Wang, Sanduo Zheng, Jianhua Sui · 发表于：Journal of Hematology & Oncology · 年份：2023 · DOI：10.1186/s13045-023-01399-4 · 被引用次数：31 · 研究领域：Phagocytosis and Immune Regulation、Monoclonal and Polyclonal Antibodies Research、Immunotherapy and Immune Responses

BACKGROUND: The antiphagocytic molecule CD47 is overexpressed in a wide variety of cancer cells, and antibodies targeting CD47 for cancer therapies are currently under intensive investigation. However, owing to the ubiquitous expression of CD47 on healthy cells, anti-CD47 therapies often achieve only weak therapeutic benefits and can induce severe side effects. Here, we report the generation of a pH-dependent anti-CD47 antibody (BC31M4) which selectively binds to tumors under the acidic solid tumor microenvironment. METHODS: BC31M4 was generated using antibody phage display and a pH-dependent selection strategy. The pH-dependent binding and blocking activities of BC31M4 were verified using in vitro assays, and the structural basis of the pH-dependent binding property was characterized. BC31M4's antitumor effect was confirmed by both phagocytosis assays and studies in xenograft models. The tumor selectivity, mechanism of action, PK properties, side effects, and therapeutic efficacy were further evaluated in humanized (hCD47 and its receptor hSIRPα) immunocompetent syngeneic mouse models. RESULTS: The crystal structure reveals that two histidines locate within the CDRs of the light chain directly contribute to the pH-dependent binding of BC31M4. BC31M4 promotes macrophage phagocytosis of tumor cells more potently at acidic-pH than at physiological-pH. Our hCD47/hSIRPα humanized syngeneic mouse model results demonstrated that BC31M4 selectively accumulates in tumors but not in n...