Zeng Dadi, Sun Qiang, Chen Ang, Fan Jiangfeng, Yang Xiaopeng, Xu Lei, Du Peng, Qiu Weiyi, Zhang Weicai, Wang Shuang, Sun Zhiwei
Beijing Institute of Biotechnology, Fengtai District, Beijing 100071, China.
Oncotarget. 2016 Dec 13;7(50):83040-83050. doi: 10.18632/oncotarget.13349.
CD47/SIRPα interaction serves as an immune checkpoint for macrophage-mediated phagocytosis. Mouse anti-CD47 blocking antibodies had demonstrated potent efficacy in the treatment of both leukemic and solid tumors in preclinical experimentations, and therefore had moved forward rapidly into clinical trials. However, a fully human blocking antibody, which meets clinical purpose better, has not been reported for CD47 up to date. In this study, we reported the isolation of a fully human anti-CD47 blocking antibody, ZF1, from a phage display library. ZF1 displayed high specificity and affinity for CD47 protein, which were comparable to those for humanized anti-CD47 blocking antibody B6H12. Importantly, ZF1 treatment could induce robust, or even stronger than B6H12, phagocytosis of leukemic cancer cells by macrophage in vitro, and protect BALB/c nude mice from cancer killing by engrafted leukemic cells (CCRF and U937) to a similar extent as B6H12 did. Thus, these data provide primary early pre-clinical support for the development of ZF1 as a fully human blocking antibody to treat human leukemia by targeting CD47 molecule.
CD47/SIRPα 相互作用作为巨噬细胞介导的吞噬作用的免疫检查点。小鼠抗CD47阻断抗体在临床前实验中已证明对白血病和实体瘤治疗具有强效疗效，因此已迅速进入临床试验阶段。然而，截至目前，尚未报道过一种更符合临床需求的全人源阻断抗体。在本研究中，我们报道了从噬菌体展示文库中分离出一种全人源抗CD47阻断抗体ZF1。ZF1对CD47蛋白表现出高特异性和亲和力，与人性化抗CD47阻断抗体B6H12相当。重要的是，ZF1处理可在体外诱导巨噬细胞对白血病癌细胞进行强大的吞噬作用，甚至比B6H12更强，并且在保护BALB/c裸鼠免受移植白血病细胞（CCRF和U937）杀伤方面与B6H12具有相似的效果。因此，这些数据为将ZF1开发为通过靶向CD47分子治疗人类白血病的全人源阻断抗体提供了初步的临床前早期支持。
