Signal Transduction and Targeted Therapy (Apr 2022)

A potent human monoclonal antibody with pan-neutralizing activities directly dislocates S trimer of SARS-CoV-2 through binding both up and down forms of RBD

  • Xiaofei Wang,
  • Ao Hu,
  • Xiangyu Chen,
  • Yixin Zhang,
  • Fei Yu,
  • Shuai Yue,
  • Arong Li,
  • Junsong Zhang,
  • Zhiwei Pan,
  • Yang Yang,
  • Yao Lin,
  • Leiqiong Gao,
  • Jing Zhou,
  • Jing Zhao,
  • Fang Li,
  • Yaling Shi,
  • Feng Huang,
  • Xiaofan Yang,
  • Yi Peng,
  • Luoyang Tu,
  • Huan Zhang,
  • Huanying Zheng,
  • Jun He,
  • Hui Zhang,
  • Lifan Xu,
  • Qizhao Huang,
  • Yongqun Zhu,
  • Kai Deng,
  • Lilin Ye

DOI
https://doi.org/10.1038/s41392-022-00954-8
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

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Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel coronavirus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.