A SARS-CoV-2 Neutralizing Antibody Selected from COVID-19 Patients by Phage Display is Binding to the ACE2-RBD Interface and is Tolerant to Known RBD Mutations
The novel betacoranavirus SARS-CoV-2 causes a form of severe pneumonia disease, termed COVID-19 (coronavirus disease 2019). Recombinant human antibodies are proven potent neutralizers of viruses and can block the interaction of viral surface proteins with their host receptors. To develop 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 S1 subunit of the viral spike (S) protein were selected by phage display. The selected antibodies were produced in the scFv-Fc format and 30 showed more than 80% inhibition of spike (S1-S2) binding to cells expressing ACE2, assessed by flow cytometry screening assay. The majority of these inhibiting antibodies are derived from the VH3-66 V-gene. The antibody STE90-C11 showed an IC50 of 0.56 nM in a plaque-based live SARS-CoV-2 neutralization assay. The crystal structure of STE90-C11 in complex with SARS-CoV-2-RBD was solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. In contrast to other published anti-SARS-CoV-2 antibodies, the binding of STE90-C11 is not blocked by known RBD mutations, endowing our antibody with higher intrinsic resistance to those possible escape mutants.
Funding: We kindly acknowledge the financial support of MWK Niedersachsen (14-76103-184CORONA-2/20) for antibody generation. We also acknowledge support of the European Union for the ATAC (“antibody therapy against corona”, Horizon 2020 number 101003650) consortium.
Conflict of Interest: The authors declare a conflict of interest. F.B., D.M.,N.L., S.S., P.A.H., R.B., M.R., K.T.S.,K.D.R.R., S.Z.-E., M.B., V.F., S.T.,M.S. and M.H. are inventors on a patent application on blocking antibodies against SARS-CoV-2. A.H., A.F. and T.S. are officers of CORAT Therapeutics GmbH, a company founded by YUMAB GmbH for the clinical and regulatory development of STE90-C11 (COR-101). A.F., T.S., S.D. and M.H. are shareholders of YUMAB GmbH.
Ethical Approval: Approval number, FV-2020-02. Approved by the TU Braunschweig Institute for Psychology.
Bertoglio, Federico and Fühner, Viola and Ruschig, Maximilian and Heine, Philip Alexander and Rand, Ulfert and Klünemann, Thomas and Meier, Doris and Langreder, Nora and Steinke, Stephan and Ballmann, Rico and Schneider, Kai-Thomas and Roth, Kristian Danial Ralph and Kuhn, Philipp and Riese, Peggy and Schäckermann, Dorina and Korn, Janin and Koch, Allan and Zock-Emmenthal, Susanne and Becker, Marlies and Scholz, Margitta and Moreira, Gustavo Marçal Schmidt Garcia and Wenzel, Esther Veronika and Russo, Giulio and Garritsen, Hendrikus S.P. and Casu, Sebastian and Gerstner, Andreas and Roth, Günter and Hermann, Andreas and Schirrmann, Thomas and Dübel, Stefan and Frenzel, André and Van den Heuvel, Joop and Cicin-Sain, Luka and Schubert, Maren and Hust, Michael, A SARS-CoV-2 Neutralizing Antibody Selected from COVID-19 Patients by Phage Display is Binding to the ACE2-RBD Interface and is Tolerant to Known RBD Mutations. Available at SSRN: https://ssrn.com/abstract=3754550 or http://dx.doi.org/10.2139/ssrn.3754550
This version of the paper has not been formally peer reviewed.
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