Nature Communications (Dec 2024)
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,
- Li Wan
Affiliations
- Jin-Gen Xu
- Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes
- Shi Chen
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yang He
- Institute of Molecular and Cell Biology
- Xi Zhu
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yanting Wang
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Zhifeng Ye
- Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes
- Jin Chuan Zhou
- Department of Biochemistry, University of Oxford
- Xuanhui Wu
- Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes
- Lei Zhang
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Xiaochen Ren
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Huifeng Jia
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Haijia Yu
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Xiaoyue Wei
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yujie Feng
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Xiaofang Chen
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Xiaopei Cui
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Xianfei Pan
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Shaojie Wang
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Simin Xia
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Hongjie Shang
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yueqing Pu
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Wei Xu
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Haidong Li
- College of Biology and Pharmacy, Yulin Normal University
- Qian Chen
- Drug Discovery, 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
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yisui Xia
- Medical School, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University
- Roberto Bellelli
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Charterhouse Square, Barbican
- Shunli Dong
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital
- Jun He
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
- Jun Huang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University
- Chen-Leng Cai
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
- Xiangyang Zhu
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Yifan Zhan
- Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.
- Li Wan
- Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Scienes
- DOI
- https://doi.org/10.1038/s41467-024-55207-9
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
