| Autor: |
Sebastian Casu, Federico Bertoglio, Kristian Daniel Ralph Roth, Maren Schubert, Peggy Riese, Stephan Steinke, André Frenzel, Yeonsu Kim, Margitta Scholz, Michael Hust, Hendrikus S.P. Garritsen, Allan Koch, Thomas Schirrmann, Maximilian Ruschig, Rico Ballmann, Stefan Dübel, Günter Roth, Dorina Schäckermann, Giulio Russo, Ulfert Rand, Thomas Klünemann, Marlies Becker, Gustavo Marçal Schmidt Garcia Moreira, Philipp Kuhn, Janin Korn, Philip Alexander Heine, Doris Meier, Luka Cicin-Sain, Nora Langreder, Esther Veronika Wenzel, Kathrin Eschke, Andreas Gerstner, Viola Fühner, Julia Adler, Andreas Hermann, Susanne Zock-Emmenthal, Leila Abasi, Joop van den Heuvel, Jakob Trimpert, Kai-Thomas Schneider, M. Zeeshan Chaudhry |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
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 a sub nM IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody was demonstrated in the Syrian hamster and in the hACE2 mice model using a silenced human IgG1 Fc part. The crystal structure of STE90-C11 Fab 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. The binding and inhibtion of STE90-C11 is not blocked by many known RBD mutations including N439K, L452R, E484K or L452R+E484Q (emerging B.1.617). 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.In BriefHuman antibodies were selected from convalescent COVID-19 patients using antibody phage display. The antibody STE90-C11 is neutralizing authentic SARS-CoV-2 virus in vitro and in vivo and the crystal structure of STE90-C11 in complex with SARS-CoV-2-RBD revealed that this antibody is binding in the RBD-ACE2 interface. S1 binding of STE90-C11 and inhibition of ACE2 binding is not blocked by many known RBD mutations. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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