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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.
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Details
1 Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, People’s Republic of China
2 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
3 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