A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations

Bertoglio, Federico; Fühner, Viola; Ruschig, Maximilian; Heine, Philip Alexander; Abassi, Leila; Klünemann, Thomas; Rand, Ulfert; Meier, Doris; Langreder, Nora; Steinke, Stephan; Ballmann, Rico; Schneider, Kai-Thomas; Roth, Kristian Daniel Ralph; Kuhn, Philipp; Riese, Peggy; Schäckermann, Dorina; Korn, Janin; Koch, Allan; Chaudhry, M. Zeeshan; Eschke, Kathrin; Kim, Yeonsu; Zock-Emmenthal, Susanne; Becker, Marlies; Scholz, Margitta; Moreira, Gustavo Marçal Schmidt Garcia; Wenzel, Esther Veronika; Russo, Giulio; Garritsen, Hendrikus S.P.; Casu, Sebastian; Gerstner, Andreas; Roth, Günter; Adler, Julia; Trimpert, Jakob; Hermann, Andreas; Schirrmann, Thomas; Dübel, Stefan; Frenzel, André; Van den Heuvel, Joop; Čičin-Šain, Luka; Schubert, Maren; Hust, Michael

The novel betacoronavirus SARS-CoV-2 causes a form of severe pneumonia disease, termed COVID-19. To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a sub nM IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the hACE2 mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11 derived human IgG1 with FcγR silenced Fc (COR-101) is currently undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.