Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

Wang, Lingshu; Zhou, Tongqing; Zhang, Yi; Yang, Eun Sung; Schramm, Chaim A; Shi, Wei; Pegu, Amarendra; Oloniniyi, Olamide K; Henry, Amy R; Darko, Samuel; Narpala, Sandeep R; Hatcher, Christian; Martinez, David R; Tsybovsky, Yaroslav; Phung, Emily; Abiona, Olubukola M; Antia, Avan; Cale, Evan M; Chang, Lauren A; Choe, Misook; Corbett, Kizzmekia S; Davis, Rachel L; DiPiazza, Anthony T; Gordon, Ingelise J; Hait, Sabrina Helmold; Hermanus, Tandile; Kgagudi, Prudence; Laboune, Farida; Leung, Kwanyee; Liu, Tracy; Mason, Rosemarie D; Nazzari, Alexandra F; Novik, Laura; O039,; Connell, Sarah; Dell, Sijy; Olia, Adam S; Schmidt, Stephen D; Stephens, Tyler; Stringham, Christopher D; Talana, Chloe Adrienna; Teng, I-Ting; Wagner, Danielle A; Widge, Alicia T; Zhang, Baoshan; Roederer, Mario; Ledgerwood, Julie E; Ruckwardt, Tracy J; Gaudinski, Martin R; Moore, Penny L; Doria-Rose, Nicole A

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.