%0 Journal Article
%T A novel bispecific antibody targeting two overlapping epitopes in RBD improves neutralizing potency and breadth against SARS-CoV-2.
%A Sun H
%A Xia L
%A Li J
%A Zhang Y
%A Zhang G
%A Huang P
%A Wang X
%A Cui Y
%A Fang T
%A Fan P
%A Zhou Q
%A Chi X
%A Yu C
%J Emerg Microbes Infect
%V 0
%N 0
%D 2024 Jul 2
%M 38953857
%F 19.568
%R 10.1080/22221751.2024.2373307
%X ABSTRACTSARS-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.