An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control

Jin-Gen Xu, Shi Chen, Yang He, Xi Zhu, Yanting Wang, Zhifeng Ye, Jin Chuan Zhou, Xuanhui Wu, Lei Zhang, Xiaochen Ren, Huifeng Jia, Haijia Yu, Xiaoyue Wei, Yujie Feng, Xiaofang Chen, Xiaopei Cui, Xianfei Pan, Shaojie Wang, Simin Xia, Hongjie Shang, Yueqing Pu, Wei Xu, Haidong Li, Qian Chen, Zeyu Chen, Manfu Wang, Xiaodong Yan, Hui Shi, Mingwei Li, Yisui Xia, Roberto Bellelli, Shunli Dong, Jun He, Jun Huang, Chen-Leng Cai, Xiangyang Zhu (), Yifan Zhan () and Li Wan ()
Additional contact information
Jin-Gen Xu: Chinese Academy of Scienes
Shi Chen: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yang He: Institute of Molecular and Cell Biology
Xi Zhu: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yanting Wang: Shanghai Huaota Biopharmaceutical Co. Ltd.
Zhifeng Ye: Chinese Academy of Scienes
Jin Chuan Zhou: University of Oxford
Xuanhui Wu: Chinese Academy of Scienes
Lei Zhang: Shanghai Huaota Biopharmaceutical Co. Ltd.
Xiaochen Ren: Shanghai Huaota Biopharmaceutical Co. Ltd.
Huifeng Jia: Shanghai Huaota Biopharmaceutical Co. Ltd.
Haijia Yu: Shanghai Huaota Biopharmaceutical Co. Ltd.
Xiaoyue Wei: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yujie Feng: Shanghai Huaota Biopharmaceutical Co. Ltd.
Xiaofang Chen: Shanghai Huaota Biopharmaceutical Co. Ltd.
Xiaopei Cui: Shanghai Huaota Biopharmaceutical Co. Ltd.
Xianfei Pan: Shanghai Huaota Biopharmaceutical Co. Ltd.
Shaojie Wang: Shanghai Huaota Biopharmaceutical Co. Ltd.
Simin Xia: Shanghai Huaota Biopharmaceutical Co. Ltd.
Hongjie Shang: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yueqing Pu: Shanghai Huaota Biopharmaceutical Co. Ltd.
Wei Xu: Shanghai Huaota Biopharmaceutical Co. Ltd.
Haidong Li: Yulin Normal University
Qian Chen: Shanghai Huaota Biopharmaceutical Co. Ltd.
Zeyu Chen: Biortus Biosciences Co. Ltd
Manfu Wang: Biortus Biosciences Co. Ltd
Xiaodong Yan: Biortus Biosciences Co. Ltd
Hui Shi: Biortus Biosciences Co. Ltd
Mingwei Li: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yisui Xia: Shenzhen University
Roberto Bellelli: Barbican
Shunli Dong: Huzhou Central Hospital
Jun He: Chinese Academy of Sciences
Jun Huang: Zhejiang University
Chen-Leng Cai: Chinese Academy of Sciences
Xiangyang Zhu: Shanghai Huaota Biopharmaceutical Co. Ltd.
Yifan Zhan: Shanghai Huaota Biopharmaceutical Co. Ltd.
Li Wan: Chinese Academy of Scienes

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-55207-9

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