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SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface

View ORCID ProfileFederico Bertoglio, Doris Meier, Nora Langreder, Stephan Steinke, View ORCID ProfileUlfert Rand, View ORCID ProfileLuca Simonelli, Philip Alexander Heine, Rico Ballmann, Kai-Thomas Schneider, Kristian Daniel Ralph Roth, Maximilian Ruschig, View ORCID ProfilePeggy Riese, Kathrin Eschke, Yeonsu Kim, Dorina Schäckermann, Mattia Pedotti, Philipp Kuhn, Susanne Zock-Emmenthal, Johannes Wöhrle, Marlies Becker, Martina Grasshoff, Esther Veronika Wenzel, Giulio Russo, Andrea Kröger, View ORCID ProfileLinda Brunotte, View ORCID ProfileStephan Ludwig, Viola Fühner, Stefan Daniel Krämer, View ORCID ProfileStefan Dübel, View ORCID ProfileLuca Varani, View ORCID ProfileGünter Roth, View ORCID ProfileLuka Čičin-Šain, View ORCID ProfileMaren Schubert, View ORCID ProfileMichael Hust
doi: https://doi.org/10.1101/2020.06.05.135921
Federico Bertoglio
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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  • ORCID record for Federico Bertoglio
Doris Meier
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Nora Langreder
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Stephan Steinke
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Ulfert Rand
2Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Luca Simonelli
3Istituto di Ricerca in Biomedicina (IRB), Universita’ della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland
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Philip Alexander Heine
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Rico Ballmann
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Kai-Thomas Schneider
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Kristian Daniel Ralph Roth
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Maximilian Ruschig
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Peggy Riese
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
2Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Kathrin Eschke
2Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Yeonsu Kim
2Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Dorina Schäckermann
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Mattia Pedotti
3Istituto di Ricerca in Biomedicina (IRB), Universita’ della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland
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Philipp Kuhn
4YUMAB GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Susanne Zock-Emmenthal
5Technische Universität Braunschweig, Institut für Genetik, Spielmannstr. 7, 38106 Braunschweig, Germany
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Johannes Wöhrle
6BioCopy GmbH, Elzstrasse 27, 79312 Emmendingen; Germany
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Marlies Becker
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Martina Grasshoff
7Helmholtz Centre for Infection Research, Research Group Innate Immunity and Infection, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Esther Veronika Wenzel
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Giulio Russo
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Andrea Kröger
7Helmholtz Centre for Infection Research, Research Group Innate Immunity and Infection, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Linda Brunotte
8Westfälische Wilhelms-Universität Münster, Institut für Virologie (IVM), Von-Esmarch-Strasse 56, 48149 Münster, Germany
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Stephan Ludwig
8Westfälische Wilhelms-Universität Münster, Institut für Virologie (IVM), Von-Esmarch-Strasse 56, 48149 Münster, Germany
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Viola Fühner
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Stefan Daniel Krämer
6BioCopy GmbH, Elzstrasse 27, 79312 Emmendingen; Germany
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Stefan Dübel
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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Luca Varani
3Istituto di Ricerca in Biomedicina (IRB), Universita’ della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland
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  • For correspondence: m.hust@tu-bs.de maren.schubert@tu-bs.de Luka.Cicin-Sain@helmholtz-hzi.de luca.varani@irb.usi.ch guenter.roth@biocopy.de
Günter Roth
6BioCopy GmbH, Elzstrasse 27, 79312 Emmendingen; Germany
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  • For correspondence: m.hust@tu-bs.de maren.schubert@tu-bs.de Luka.Cicin-Sain@helmholtz-hzi.de luca.varani@irb.usi.ch guenter.roth@biocopy.de
Luka Čičin-Šain
2Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstr. 7, 38124 Braunschweig, Germany
9Centre for Individualised Infection Medicine (CIIM), a joint venture of Helmholtz Centre for Infection Research and Medical School Hannover
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  • ORCID record for Luka Čičin-Šain
  • For correspondence: m.hust@tu-bs.de maren.schubert@tu-bs.de Luka.Cicin-Sain@helmholtz-hzi.de luca.varani@irb.usi.ch guenter.roth@biocopy.de
Maren Schubert
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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  • For correspondence: m.hust@tu-bs.de maren.schubert@tu-bs.de Luka.Cicin-Sain@helmholtz-hzi.de luca.varani@irb.usi.ch guenter.roth@biocopy.de
Michael Hust
1Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig
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  • For correspondence: m.hust@tu-bs.de maren.schubert@tu-bs.de Luka.Cicin-Sain@helmholtz-hzi.de luca.varani@irb.usi.ch guenter.roth@biocopy.de
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Abstract

COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a novel betacoronavirus discovered in December 2019 and closely related to the SARS coronavirus (CoV). Both viruses use the human ACE2 receptor for cell entry, recognizing it with the Receptor Binding Domain (RBD) of the S1 subunit of the viral spike (S) protein. The S2 domain mediates viral fusion with the host cell membrane. Experience with SARS and MERS coronavirus has shown that potent monoclonal neutralizing antibodies against the RBD can inhibit the interaction with the virus cellular receptor (ACE2 for SARS) and block the virus cell entry. Assuming that a similar strategy would be successful against SARS-CoV-2, we used phage display to select from the human naïve universal antibody gene libraries HAL9/10 anti SARS2 spike antibodies capable of inhibiting interaction with ACE2. 309 unique fully human antibodies against S1 were identified. 17 showed more than 75% inhibition of spike binding to cells expressing ACE2, assessed by flow cytometry and several antibodies showed even an 50% inhibition at a molar ratio of the antibody to spike protein or RBD of 1:1. Furthermore, these antibodies neutralized active SARS-Cov-2 virus infection of VeroE6 cells. All 17 were all able to bind the isolated RBD, four of them with sub-nanomolar EC50. Epitope analysis of the antibodies revealed that six bind at the RBD-ACE2 interface and two on the opposite side of the domain. Universal libraries from healthy donors offer the advantage that antibodies can be generated quickly and independent from the availability of material from recovered patients in a pandemic situation.

Competing Interest Statement

The authors declare a conflict of interest. The authors F.B., D.M., N.L., S.S., P.A.H., R.B., M.R., K.T.S., K.D.R.P., S.Z.E., M.B., E.V.W., Gi.R., V.F., S.T., M.S. and M.H. submitted a patent application on blocking antibodies against SARS-CoV-2.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface
Federico Bertoglio, Doris Meier, Nora Langreder, Stephan Steinke, Ulfert Rand, Luca Simonelli, Philip Alexander Heine, Rico Ballmann, Kai-Thomas Schneider, Kristian Daniel Ralph Roth, Maximilian Ruschig, Peggy Riese, Kathrin Eschke, Yeonsu Kim, Dorina Schäckermann, Mattia Pedotti, Philipp Kuhn, Susanne Zock-Emmenthal, Johannes Wöhrle, Marlies Becker, Martina Grasshoff, Esther Veronika Wenzel, Giulio Russo, Andrea Kröger, Linda Brunotte, Stephan Ludwig, Viola Fühner, Stefan Daniel Krämer, Stefan Dübel, Luca Varani, Günter Roth, Luka Čičin-Šain, Maren Schubert, Michael Hust
bioRxiv 2020.06.05.135921; doi: https://doi.org/10.1101/2020.06.05.135921
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SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface
Federico Bertoglio, Doris Meier, Nora Langreder, Stephan Steinke, Ulfert Rand, Luca Simonelli, Philip Alexander Heine, Rico Ballmann, Kai-Thomas Schneider, Kristian Daniel Ralph Roth, Maximilian Ruschig, Peggy Riese, Kathrin Eschke, Yeonsu Kim, Dorina Schäckermann, Mattia Pedotti, Philipp Kuhn, Susanne Zock-Emmenthal, Johannes Wöhrle, Marlies Becker, Martina Grasshoff, Esther Veronika Wenzel, Giulio Russo, Andrea Kröger, Linda Brunotte, Stephan Ludwig, Viola Fühner, Stefan Daniel Krämer, Stefan Dübel, Luca Varani, Günter Roth, Luka Čičin-Šain, Maren Schubert, Michael Hust
bioRxiv 2020.06.05.135921; doi: https://doi.org/10.1101/2020.06.05.135921

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