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Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections

Author

Listed:
  • Chao Zhang

    (University of Chinese Academy of Sciences)

  • Yifan Wang

    (University of Chinese Academy of Sciences)

  • Yuanfei Zhu

    (Fudan University)

  • Caixuan Liu

    (University of Chinese Academy of Sciences)

  • Chenjian Gu

    (Fudan University)

  • Shiqi Xu

    (University of Chinese Academy of Sciences)

  • Yalei Wang

    (University of Chinese Academy of Sciences)

  • Yu Zhou

    (University of Chinese Academy of Sciences)

  • Yanxing Wang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Wenyu Han

    (University of Chinese Academy of Sciences)

  • Xiaoyu Hong

    (University of Chinese Academy of Sciences)

  • Yong Yang

    (University of Chinese Academy of Sciences)

  • Xueyang Zhang

    (University of Chinese Academy of Sciences)

  • Tingfeng Wang

    (University of Chinese Academy of Sciences)

  • Cong Xu

    (University of Chinese Academy of Sciences)

  • Qin Hong

    (University of Chinese Academy of Sciences)

  • Shutian Wang

    (University of Chinese Academy of Sciences)

  • Qiaoyu Zhao

    (University of Chinese Academy of Sciences)

  • Weihua Qiao

    (University of Chinese Academy of Sciences)

  • Jinkai Zang

    (University of Chinese Academy of Sciences)

  • Liangliang Kong

    (The National Facility for Protein Science in Shanghai (NFPS))

  • Fangfang Wang

    (The National Facility for Protein Science in Shanghai (NFPS))

  • Haikun Wang

    (University of Chinese Academy of Sciences)

  • Di Qu

    (Fudan University
    BSL-3 Laboratory of Fudan University, School of Basic Medical Sciences, Shanghai Medical College, Fudan University)

  • Dimitri Lavillette

    (University of Chinese Academy of Sciences)

  • Hong Tang

    (University of Chinese Academy of Sciences)

  • Qiang Deng

    (Fudan University)

  • Youhua Xie

    (Fudan University)

  • Yao Cong

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Zhong Huang

    (University of Chinese Academy of Sciences)

Abstract

The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen–antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections.

Suggested Citation

  • Chao Zhang & Yifan Wang & Yuanfei Zhu & Caixuan Liu & Chenjian Gu & Shiqi Xu & Yalei Wang & Yu Zhou & Yanxing Wang & Wenyu Han & Xiaoyu Hong & Yong Yang & Xueyang Zhang & Tingfeng Wang & Cong Xu & Qin, 2021. "Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20465-w
    DOI: 10.1038/s41467-020-20465-w
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    Citations

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    Cited by:

    1. Shengjun Wang & Wei Ran & Lingyu Sun & Qingchi Fan & Yuanqi Zhao & Bowen Wang & Jinghong Yang & Yuqi He & Ying Wu & Yuanyuan Wang & Luoyi Chen & Arpaporn Chuchuay & Yuyu You & Xinhai Zhu & Xiaojuan Wa, 2024. "Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yifan Wang & Caixuan Liu & Chao Zhang & Yanxing Wang & Qin Hong & Shiqi Xu & Zuyang Li & Yong Yang & Zhong Huang & Yao Cong, 2022. "Structural basis for SARS-CoV-2 Delta variant recognition of ACE2 receptor and broadly neutralizing antibodies," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Lei Peng & Yingxia Hu & Madeleine C. Mankowski & Ping Ren & Rita E. Chen & Jin Wei & Min Zhao & Tongqing Li & Therese Tripler & Lupeng Ye & Ryan D. Chow & Zhenhao Fang & Chunxiang Wu & Matthew B. Dong, 2022. "Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Chao Zhang & Caixuan Liu & Jinping Shi & Yalei Wang & Cong Xu & Xiaohua Ye & Qingwei Liu & Xue Li & Weihua Qiao & Yannan Yin & Yao Cong & Zhong Huang, 2022. "Molecular mechanism of antibody neutralization of coxsackievirus A16," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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