Abstract

SARS-CoV-2 has been evolving into a large number of variants, including the highly pathogenic Delta variant, and the currently prevalent Omicron subvariants with extensive evasion capability, which raises an urgent need to develop new broad-spectrum neutralizing antibodies. Herein, we engineer two IgG-(scFv)2 form bispecific antibodies with overlapping epitopes (bsAb1) or non-overlapping epitopes (bsAb2). Both bsAbs are significantly superior to the parental monoclonal antibodies in terms of their antigen-binding and virus-neutralizing activities against all tested circulating SARS-CoV-2 variants including currently dominant JN.1. The bsAb1 can efficiently neutralize all variants insensitive to parental monoclonal antibodies or the cocktail with IC50 lower than 20 ng/mL, even slightly better than bsAb2. Furthermore, the cryo-EM structures of bsAb1 in complex with the Omicron spike protein revealed that bsAb1 with overlapping epitopes effectively locked the S protein, which accounts for its conserved neutralization against Omicron variants. The bispecific antibody strategy engineered from overlapping epitopes provides a novel solution for dealing with viral immune evasion.

Details

Title
A novel bispecific antibody targeting two overlapping epitopes in RBD improves neutralizing potency and breadth against SARS-CoV-2
Author
Sun, Hancong 1 ; Xia, Lingyun 2 ; Li, Jianhua 3 ; Zhang, Yuanyuan 2 ; Zhang, Guanying 1 ; Huang, Ping 1 ; Wang, Xingxing 3 ; Cui, Yue 1 ; Fang, Ting 1 ; Fan, Pengfei 1 ; Zhou, Qiang 2 ; Chi, Xiangyang 1 ; Yu, Changming 1 

 Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, People’s Republic of China 
 Center for Infectious Disease Research, Research Center for Industries of the Future, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Institute of Biology, Westlake Institute for Advanced Study, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, People’s Republic of China 
 Department of Microbiology, Zhejiang Provincial Center for Disease Control and Prevention, Key Laboratory of Public Health Detection and Etiological Research of Zhejiang Province, Hangzhou, Zhejiang Province, People’s Republic of China 
Publication year
2024
Publication date
Dec 2024
Publisher
Taylor & Francis Ltd.
e-ISSN
22221751
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3142112413
Copyright
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd. This work is licensed under the Creative Commons  Attribution – Non-Commercial License http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.