DataSheet_1_Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models.pdf

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)– and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor–mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.

肿瘤相关巨噬细胞（Tumor-associated macrophages, TAMs）在肿瘤微环境中大量富集，被视作癌症免疫治疗的潜在靶点。为在体内探究靶向人类TAMs的制剂的抗肿瘤效应，本研究构建了基于免疫缺陷小鼠的临床前肿瘤异种移植模型：该小鼠可表达多种人类细胞因子，并通过移植人类CD34+造血干祖细胞重建了人类免疫系统（下称HIS-MITRG小鼠）。HIS-MITRG小鼠可支持人类细胞系（Raji细胞）及患者来源的B细胞淋巴瘤的生长，同时可招募人类巨噬细胞浸润至肿瘤组织内。本研究考察了靶向人SIRPα的抗体SE12C3的潜在抗肿瘤活性——该抗体可抑制肿瘤细胞表面CD47与人类巨噬细胞表面SIRPα的结合，从而促进Fcγ受体介导的巨噬细胞对肿瘤细胞的吞噬作用。联合使用利妥昔单抗（靶向人CD20的抗体）与SE12C3，相较于利妥昔单抗单药治疗，可更显著地抑制HIS-MITRG小鼠体内的Raji肿瘤生长。这种增强的抗肿瘤效应依赖于人类巨噬细胞，其机制为增强了利妥昔单抗介导的巨噬细胞对淋巴瘤细胞的吞噬作用。利妥昔单抗与SE12C3联合治疗还可诱导人类TAMs向促炎表型重编程。此外，该联合治疗可完全阻断患者来源的弥漫大B细胞淋巴瘤在HIS-MITRG小鼠体内的生长。综上，本研究结果支持将HIS-MITRG小鼠作为靶向人类TAMs的潜在治疗策略（如靶向人SIRPα的抗体）的体内临床前评价模型。