Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies

作者：Ying-Dan Wang, Xiang Zhang, Yunping Ma, Yanqun Wang, Wuqiang Zhan, Qinwen Zheng, Meng Zhang, Ping Ji, Mei Liu, Qianying Liu, Tingting Sun, Tongyu Zhu, Yu‐Mei Wen, Lei Sun, Jincun Zhao, Fan Wu, Zhenguo Chen, Jinghe Huang · 发表于：Cell Discovery · 年份：2022 · DOI：10.1038/s41421-022-00463-6 · 被引用次数：34 · 研究领域：SARS-CoV-2 and COVID-19 Research、Monoclonal and Polyclonal Antibodies Research、Nanowire Synthesis and Applications

Abstract The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC 50 ) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC 50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to ...