Novel sarbecovirus bispecific neutralizing antibodies with exceptional breadth and potency against currently circulating SARS-CoV-2 variants and sarbecoviruses

作者：Ying-Dan Wang, Meiqin Liu, Yaping Shen, Yunping Ma, Xiang Li, Yuanyuan Zhang, Mei Liu, Xing‐Lou Yang, Jun Chen, Renhong Yan, Die Luan, Yanqun Wang, Ying Chen, Qimin Wang, Haofeng Lin, Yaning Li, Kaiyue Wu, Tongyu Zhu, Jincun Zhao, Hongzhou Lu, Yumei Wen, Shibo Jiang, Fan Wu, Qiang Zhou, Zheng‐Li Shi, Jinghe Huang · 发表于：Cell Discovery · 年份：2022 · DOI：10.1038/s41421-022-00401-6 · 被引用次数：39 · 研究领域：SARS-CoV-2 and COVID-19 Research、Viral Infections and Immunology Research、Animal Virus Infections Studies

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both th...