Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants
Science.
2021-07;
Lingshu Wang, Tongqing Zhou, Yi Zhang, Eun Sung Yang, Chaim A Schramm, Wei Shi, Amarendra Pegu, Olamide K Oloninyi, Amy Ransier, Samuel Darko, Sandeep R Narpala, Christian Hatcher, David R Martinez, Yaroslav Tsybovsky, Emily Phung, Olubukola M Abiona, Evan M Cale, Lauren A Chang, Kizzmekia S Corbett, Anthony T DiPiazza, Ingelise J Gordon, Kwanyee Leung, Tracy Liu, Rosemarie D Mason, Alexandra Nazzari, Laura Novik, Adam S Olia, Tyler Stephens, Christopher D Stringham, Chloe Adrienna Talana, I-Ting Teng, Danielle Wagner, Alicia T Widge, Baoshan Zhang, Mario Roederer, Julie E Ledgerwood, Tracy J Ruckwardt, Martin R Gaudinski, Ralph S Baric, Barney S Graham, Adrian B McDermott, Daniel C Douek, Peter D Kwong, John R Mascola, Nancy J Sullivan, John Misasi
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imilarly, variable lambda and kappa light chain sequences were human codon optimized, synthesized and cloned into CMV/R-based lambda or kappa chain expression vectors, as appropriate (Genscript). |
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The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μ g/mL; IC80 < 0.0006 to 0.0251 μ g/mL). 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 ... More
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μ g/mL; IC80 < 0.0006 to 0.0251 μ g/mL). 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 potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.
