An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control
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 antibod...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55207-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jin-Gen Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c80b86df9b5c4cbc87b4fbba1cc82c9e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c80b86df9b5c4cbc87b4fbba1cc82c9e2025-01-05T12:35:11ZengNature PortfolioNature Communications2041-17232024-12-0115111710.1038/s41467-024-55207-9An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor controlJin-Gen Xu0Shi Chen1Yang He2Xi Zhu3Yanting Wang4Zhifeng Ye5Jin Chuan Zhou6Xuanhui Wu7Lei Zhang8Xiaochen Ren9Huifeng Jia10Haijia Yu11Xiaoyue Wei12Yujie Feng13Xiaofang Chen14Xiaopei Cui15Xianfei Pan16Shaojie Wang17Simin Xia18Hongjie Shang19Yueqing Pu20Wei Xu21Haidong Li22Qian Chen23Zeyu Chen24Manfu Wang25Xiaodong Yan26Hui Shi27Mingwei Li28Yisui Xia29Roberto Bellelli30Shunli Dong31Jun He32Jun Huang33Chen-Leng Cai34Xiangyang Zhu35Yifan Zhan36Li Wan37Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of ScienesDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Institute of Molecular and Cell BiologyDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of ScienesDepartment of Biochemistry, University of OxfordKey Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of ScienesDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.College of Biology and Pharmacy, Yulin Normal UniversityDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Biortus Biosciences Co. LtdBiortus Biosciences Co. LtdBiortus Biosciences Co. LtdBiortus Biosciences Co. LtdDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Medical School, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen UniversityCentre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Charterhouse Square, BarbicanHuzhou Key Laboratory of Molecular Medicine, Huzhou Central HospitalGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe 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 UniversityGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesDrug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd.Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of ScienesAbstract 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.https://doi.org/10.1038/s41467-024-55207-9 |
| spellingShingle | 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 An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control Nature Communications |
| title | An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control |
| title_full | An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control |
| title_fullStr | An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control |
| title_full_unstemmed | An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control |
| title_short | An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control |
| title_sort | antibody cocktail targeting two different cd73 epitopes enhances enzyme inhibition and tumor control |
| url | https://doi.org/10.1038/s41467-024-55207-9 |
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