产生一种有效的抗pd - l1 - cd47双特异性抗体,具有很强的治疗性和安全性,可用于癌症免疫治疗

Irene Tang, L. Schwimmer, Shenda Gu, Wei Wei Prior, Hieu Van Tran, Allan Chan, Anna McClain, C. Fraser, Chunyang Sun, M. Si, Guijiang Wang, Yunxia Zhao, Ning Zhang, Jiayu Fu, Mengxin Liu, Chuanzeng Cao, Shihao Chen
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摘要

细胞表面分子PD-L1和CD47是适应性和先天抗癌免疫的有效抑制剂。我们寻求产生一种安全、治疗性、双特异性的抗体,特异性靶向并阻断PD-L1和CD47的抑制活性。将具有良好抑制活性的新型抗pdl -1和抗cd47抗体人源化并构建成一种独特的双特异性抗体,用于临床应用。先前使用抗cd47抗体的临床前和临床研究表明,贫血和血小板减少是潜在的风险。QL401是一种PD-L1 x CD47双特异性抗体,旨在减少对红细胞的影响,同时在体外保持巨噬细胞的有效吞噬激活,并在体内延缓肿瘤生长。QL401由三个功能组件组成:PD-L1结合Fab臂、CD47结合scFv臂和人IgG4骨干。PD-L1结合臂提供肿瘤靶向和阻断PD-1来重新激活T细胞。CD47臂阻断SIRPα的结合,而IgG4 Fc保留Fc γ受体结合以提供吞噬信号。在临床前疗效研究中,QL401有效阻断SIRPα,以亚纳摩尔的效力促进肿瘤细胞的吞噬。在小鼠异种移植肿瘤模型中的体内疗效研究表明,QL401与单独或联合使用的PD-L1或CD47单克隆抗体相当或优于单克隆抗体。体外安全性评价显示,与CD47单克隆抗体相比,QL401对红细胞的结合和吞噬作用显著降低。此外,QL401不诱导血凝。在非人类灵长类动物中,QL401耐受性良好,高达100 mg/kg,红细胞或血小板未减少到正常范围以下。QL401目前正在进行人体I期安全性研究。
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Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy
Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.
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