Xu Jin-Gen, Chen Shi, He Yang, Zhu Xi, Wang Yanting, Ye Zhifeng, Zhou Jin Chuan, Wu Xuanhui, Zhang Lei, Ren Xiaochen, Jia Huifeng, Yu Haijia, Wei Xiaoyue, Feng Yujie, Chen Xiaofang, Cui Xiaopei, Pan Xianfei, Wang Shaojie, Xia Simin, Shang Hongjie, Pu Yueqing, Xu Wei, Li Haidong, Chen Qian, Chen Zeyu, Wang Manfu, Yan Xiaodong, Shi Hui, Li Mingwei, Xia Yisui, Bellelli Roberto, Dong Shunli, He Jun, Huang Jun, Cai Chen-Leng, Zhu Xiangyang, Zhan Yifan, Wan Li
Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes, Guangzhou, China.
Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, China.
Nat Commun. 2024 Dec 30;15(1):10872. doi: 10.1038/s41467-024-55207-9.
CD73, an ectoenzyme responsible for adenosine production, is often elevated in immuno-suppressive tumor environments. Inhibition of CD73 activity holds great promise as a therapeutic strategy for CD73-expressing cancers. In this study, we have developed a therapeutic anti-human CD73 antibody cocktail, HB0045. HB0045 is a 1:1 mixture of two humanized monoclonal IgG1 antibodies (mAbs), HB0038 and HB0039. The cocktail not only harnesses the advantages of its parental mAbs in enzyme inhibition but also shows a significantly greater capability of promoting T cell proliferation in vitro. Structural analyses show that HB0045 effectively locks the CD73 dimer in a "partially open" non-active conformation through a double lock mechanism. In various animal models of syngeneic and xenograft tumors, HB0045 inhibits tumor growth more potently than the single mAbs. Collectively, our findings provide functional and structural insights into the mechanism of a CD73-targeting antibody cocktail.
CD73是一种负责生成腺苷的胞外酶，在免疫抑制性肿瘤环境中常常上调。抑制CD73活性作为一种针对表达CD73的癌症的治疗策略具有很大的前景。在本研究中，我们开发了一种治疗性抗人CD73抗体鸡尾酒HB0045。HB0045是两种人源化单克隆IgG1抗体（mAb）HB0038和HB0039的1:1混合物。该鸡尾酒不仅利用了其亲本单克隆抗体在酶抑制方面的优势，而且在体外显示出显著更强的促进T细胞增殖的能力。结构分析表明，HB0045通过双锁机制有效地将CD73二聚体锁定在“部分开放”的非活性构象中。在同基因和异种移植肿瘤的各种动物模型中，HB0045比单克隆抗体更有效地抑制肿瘤生长。总体而言，我们的研究结果为靶向CD73的抗体鸡尾酒的作用机制提供了功能和结构方面的见解。
