Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD

Cell Discovery

Yunji Liao¹  Hui Chen¹  Yang He²  ZongShang Xiang²  Yingying Guo²  Kempaiah Rayavara Kempaiah²  Qiang Zhou²  Lei Wang²  Haiyang Yin²  Jingjing Song²  Shusheng Wang²  Gang Li²  Ailin Wang²  Haoneng Tang³  Junjun Liu³  Zhenyu Wang⁴  Aleksandra Drelich⁴  Hang Ma⁴  Yunsong Chang⁴  Kaiyong Yang⁴  Ziqi Wang⁴  Yueqing Xie⁴  Bi-Hung Peng⁴  Jianwei Zhu⁴  Chien-Te K. Tseng⁴  Guangchun Liu⁴  Lingling Mu⁴  John Gilly⁵  Li Zhang⁵  Li Yang⁵  Yunsheng Yuan⁵  Yong Ke⁵  Yi Chen⁵  Haiqiu Huang⁵  Xiaodong Xiao⁵  Hua Jiang⁶  Xiaoju Zhang⁶  Mingyuan Wu⁶  Tianjiao Ji⁶  Lei Han⁶  Yuanyuan Zhang⁶  Zhangyi Song⁷  Yanlin Bian⁷  Hua Chen⁷  Wenbo Xu⁸  Huifang Zong⁸  Yali Yue⁸  Shuangli Zhu⁹  Jiawei Zhang^1,10  Baohong Zhang^1,10 

[1] Henan Provincial People’s Hospital, Department of Respiratory and Critical Care Medicine;School of Pharmacy, Shanghai Jiao Tong University;Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang, School of Life Sciences, Westlake University;Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, China;Jecho Biopharmaceuticals Co., Ltd.;Jecho Laboratories, Inc.;National Institute for Viral Disease Control and Prevention, China CDC;University of Texas, Medical Branch, Departments of Microbiology and Immunology;University of Texas, Medical Branch, Neurosciences, Cell Biology, and Anatomy;Zhengzhou University People’s Hospital;

DOI  :  10.1038/s41421-022-00381-7

来源: DOAJ

【 摘 要 】

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

【 授权许可】

Unknown