Zhou Ying, Shen Haoran, Wu Min, Wang Jie, Wu Zhihai, Fu Fenggen, Liu Yang, Lu Jia, Yao Ying, Luo Nana, Zhou Shuaixiang, Tan Keai Sinn, Chen Bingliang, Wang Dongfang
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China.
Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China.
Int J Biol Macromol. 2023 Feb 28;229:158-167. doi: 10.1016/j.ijbiomac.2022.12.258. Epub 2022 Dec 29.
It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.
将胞外5'-核苷酸酶CD73作为靶点，与临床上已确立的免疫治疗靶点一起，为癌症患者带来协同有益的生存效果，这是一种引人入胜的方法。在本研究中，利用酵母展示平台开发了一种全人源、亚纳摩尔亲和力的CD73抗体IBI325。与Oleclumab相比，IBI325在hCD73亲和力方面相当，在细胞结合型和可溶性CD73酶抑制方面更有效，且未观察到钩状效应。相应地，IBI325逆转了单磷酸腺苷介导的免疫抑制，并观察到显著的T细胞增殖和细胞因子释放。此外，IBI325通过诱导γ干扰素分泌增强了T细胞回忆反应。在hPBMC重建的NOG小鼠模型和hCD73基因敲入小鼠模型中研究了IBI325的抗肿瘤疗效。结果，IBI325通过诱导肿瘤内免疫细胞扩增诱导了显著的肿瘤消退，并且IBI325与aPD-1的联合疗法在疗效上优于aCD73或aPD-1单药治疗。此外，CD73与IBI325的结合表位与先前报道的aCD73治疗药物不同。IBI325显示出可接受的药代动力学和足够的耐受性安全概况，以支持临床开发。总之，对具有完全CD73抑制作用的IBI325的药理学、药代动力学和毒性概况进行了表征，并报告了令人鼓舞的临床前结果。
