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

Cell Discovery

Qiang Zhou¹  Yuanyuan Zhang¹  Yingying Guo¹  Yunji Liao²  Mingyuan Wu²  Junjun Liu²  Jiawei Zhang²  Yali Yue²  Yanlin Bian²  Huifang Zong²  Baohong Zhang²  Haiyang Yin²  Haoneng Tang²  Hui Chen²  Yong Ke²  Lei Wang²  Yunsheng Yuan²  Hang Ma²  Jianwei Zhu³  Yang He⁴  Zhenyu Wang⁴  Guangchun Liu⁴  ZongShang Xiang⁴  Lingling Mu⁴  Jingjing Song⁴  Gang Li⁴  Yunsong Chang⁴  Lei Han⁵  Hua Jiang⁶  John Gilly⁶  Xiaodong Xiao⁶  Ailin Wang⁷  Hua Chen⁷  Kaiyong Yang⁷  Shusheng Wang⁷  Li Zhang⁷  Yueqing Xie⁷  Zhangyi Song⁷  Haiqiu Huang⁷  Shuangli Zhu⁸  Wenbo Xu⁸  Tianjiao Ji⁸  Aleksandra Drelich⁹  Kempaiah Rayavara Kempaiah⁹  Chien-Te K. Tseng^1,10  Bi-Hung Peng^1,11  Yi Chen^1,12  Xiaoju Zhang^1,13  Li Yang^1,13  Ziqi Wang^1,13 

[1] 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, Hangzhou, Zhejiang, China;Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China;Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China;Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China;Jecho Biopharmaceuticals Co., Ltd., Tianjin, China;Jecho Laboratories, Inc., Frederick, MD, USA;Jecho Institute, Co., Ltd., Shanghai, China;Jecho Biopharmaceuticals Co., Ltd., Tianjin, China;Jecho Biopharmaceuticals Co., Ltd., Tianjin, China;Jecho Institute, Co., Ltd., Shanghai, China;Jecho Biopharmaceuticals Co., Ltd., Tianjin, China;Jecho Laboratories, Inc., Frederick, MD, USA;Jecho Laboratories, Inc., Frederick, MD, USA;National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China;University of Texas, Medical Branch, Departments of Microbiology and Immunology, Galveston, TX, USA;University of Texas, Medical Branch, Departments of Microbiology and Immunology, Galveston, TX, USA;University of Texas, Medical Branch, Neurosciences, Cell Biology, and Anatomy, Galveston, TX, USA;University of Texas, Medical Branch, Pathology, Galveston, TX, USA;University of Texas, Medical Branch, Center for Biodefense and Emerging Disease, Galveston, TX, USA;University of Texas, Medical Branch, Neurosciences, Cell Biology, and Anatomy, Galveston, TX, USA;Zhengzhou University People’s Hospital; Henan Provincial People’s Hospital, Clinical Research Service Center, Zhengzhou, Henan, China;Zhengzhou University People’s Hospital; Henan Provincial People’s Hospital, Department of Respiratory and Critical Care Medicine, Zhengzhou, Henan, China;

DOI  :  10.1038/s41421-022-00381-7

来源: Springer

【 摘 要 】

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】

CC BY