Synthetic repertoires derived from convalescent COVID-19 patients enable discovery of SARS-CoV-2 neutralizing antibodies and a novel quaternary binding modality

Jule Goike*, Ching-Lin Hsieh*, Andrew Horton*, Elizabeth C. Gardner*, Foteini Bartzoka, Nianshuang Wang, Kamyab Javanmardi, Andrew Herbert, Shawn Abbassi, Rebecca Renberg, Michael J. Johanson, Jose A. Cardona, Thomas Segall-Shapiro, Ling Zhou, Ruth H. Nissly, Abhinay Gontu, Michelle Byrom, Andre C. Maranhao, Anna M. Battenhouse, Varun Gejji, Laura Soto-Sierra, Emma R. Foster, Susan L. Woodard, Zivko L. Nikolov, Jason Lavinder, Will N. Voss, Ankur Annapareddy, Gregory C. Ippolito, Andrew D. Ellington, Edward M. Marcotte, Ilya J. Finkelstein, Randall A. Hughes, James M. Musser, Suresh V. Kuchipudi, Vivek Kapur, George Georgiou, John M. Dye, Daniel R. Boutz†, Jason S. McLellan†, & Jimmy D. Gollihar† (* co-first authors) († co-corresponding) , BioRxiv (2021).
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The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has sparked concern over the continued effectiveness of existing therapeutic antibodies and vaccines. Hence, together with increased genomic surveillance, methods to rapidly develop and assess effective interventions are critically needed. Here we report the discovery of SARS-CoV-2 neutralizing antibodies isolated from COVID-19 patients using a high-throughput platform. Antibodies were identified from unpaired donor B-cell and serum repertoires using yeast surface display, proteomics, and public light chain screening. Cryo-EM and functional characterization of the antibodies identified N3-1, an antibody that binds avidly (Kd,app = 68 pM) to the receptor binding domain (RBD) of the spike protein and robustly neutralizes the virus in vitro. This antibody likely binds all three RBDs of the trimeric spike protein with a single IgG. Importantly, N3-1 equivalently binds spike proteins from emerging SARS-CoV-2 variants of concern, neutralizes UK variant B.1.1.7, and binds SARS-CoV spike with nanomolar affinity. Taken together, the strategies described herein will prove broadly applicable in interrogating adaptive immunity and developing rapid response biological countermeasures to emerging pathogens.