An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control
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.
Authors
- Li Wan (ORCID: https://orcid.org/0009-0007-7676-3337)
- Yisui Xia (ORCID: https://orcid.org/0000-0002-5576-2147)
- Zeyu Chen (ORCID: https://orcid.org/0009-0007-7376-1934)
- Simin Xia
- Manfu Wang (ORCID: https://orcid.org/0000-0002-2221-1082)
- Huifeng Jia
- Jun He (ORCID: https://orcid.org/0000-0003-0270-9729)
- Hui Shi (ORCID: https://orcid.org/0000-0002-2027-723X)
- Wei Xu (ORCID: https://orcid.org/0000-0001-9544-762X)
- Chen‐Leng Cai (ORCID: https://orcid.org/0000-0001-6900-4737)
- Haijia Yu
- Xi Zhu
- Zhifeng Ye
- Yifan Zhan (ORCID: https://orcid.org/0000-0001-6974-0486)
- Roberto Bellelli (ORCID: https://orcid.org/0000-0002-2062-7113)
- Yang He (ORCID: https://orcid.org/0000-0002-7460-5649)
- Xiaopei Cui (ORCID: https://orcid.org/0000-0002-9724-6175)
- Xiaodong Yan (ORCID: https://orcid.org/0000-0002-0774-9140)
- Jun Huang (ORCID: https://orcid.org/0000-0002-7837-653X)
- Xuanhui Wu (ORCID: https://orcid.org/0000-0003-4623-1907)
- Shi Chen (ORCID: https://orcid.org/0000-0002-5860-2616)
- Shunli Dong (ORCID: https://orcid.org/0000-0002-0980-3876)
- Jin-Gen Xu
- Huifang Shang (ORCID: https://orcid.org/0000-0003-0947-1151)
- Mingwei Li
- Qian Chen (ORCID: https://orcid.org/0000-0002-1487-5479)
- Lei Zhang (ORCID: https://orcid.org/0000-0002-5726-7449)
- Haidong Li (ORCID: https://orcid.org/0000-0002-4427-7920)
- Yanting Wang (ORCID: https://orcid.org/0000-0002-0961-6958)
- Xiaofang Chen (ORCID: https://orcid.org/0000-0001-8406-4762)
- Shaojie Wang (ORCID: https://orcid.org/0000-0002-4251-8874)
- Xiaochen Ren
- Jinchuan Zhou (ORCID: https://orcid.org/0000-0001-5716-5170)
- Xiaoyue Wei (ORCID: https://orcid.org/0000-0003-3168-4970)
- Xiangyang Zhu (ORCID: https://orcid.org/0000-0001-9574-6072)
- Pan Xianfei
- Y. N. Pu (ORCID: https://orcid.org/0009-0004-6272-3543)
- Yujie Feng (ORCID: https://orcid.org/0009-0009-5682-3720)
Institutions
- Shenzhen University (CN)
- Chinese Academy of Sciences (CN)
- Yulin Normal University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- University of Oxford (GB)
- Biortus (China) (CN)
- Huzhou Central Hospital (CN)
- Hua Medicine (China) (CN)
- Institute of Molecular and Cell Biology (SG)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-55207-9
- Citations
- 8
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 3.23
Funders
- Shanghai Rising-Star Program
- Medical Research Council
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences