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


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.

SUBMITTER: Ma H 

PROVIDER: S-EPMC8847360 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Ma Hang H   Guo Yingying Y   Tang Haoneng H   Tseng Chien-Te K CK   Wang Lei L   Zong Huifang H   Wang Zhenyu Z   He Yang Y   Chang Yunsong Y   Wang Shusheng S   Huang Haiqiu H   Ke Yong Y   Yuan Yunsheng Y   Wu Mingyuan M   Zhang Yuanyuan Y   Drelich Aleksandra A   Kempaiah Kempaiah Rayavara KR   Peng Bi-Hung BH   Wang Ailin A   Yang Kaiyong K   Yin Haiyang H   Liu Junjun J   Yue Yali Y   Xu Wenbo W   Zhu Shuangli S   Ji Tianjiao T   Zhang Xiaoju X   Wang Ziqi Z   Li Gang G   Liu Guangchun G   Song Jingjing J   Mu Lingling L   Xiang ZongShang Z   Song Zhangyi Z   Chen Hua H   Bian Yanlin Y   Zhang Baohong B   Chen Hui H   Zhang Jiawei J   Liao Yunji Y   Zhang Li L   Yang Li L   Chen Yi Y   Gilly John J   Xiao Xiaodong X   Han Lei L   Jiang Hua H   Xie Yueqing Y   Zhou Qiang Q   Zhu Jianwei J  

Cell discovery 20220215 1


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 bind  ...[more]

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