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Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies

Daniel Wrapp, Dorien De Vlieger, Kizzmekia S. Corbett, Gretel M. Torres, Wander Van Breedam, Kenny Roose, Loes van Schie, VIB-CMB COVID-19 Response Team, Markus Hoffmann, Stefan Pöhlmann, View ORCID ProfileBarney S. Graham, Nico Callewaert, Bert Schepens, Xavier Saelens, View ORCID ProfileJason S. McLellan
doi: https://doi.org/10.1101/2020.03.26.010165
Daniel Wrapp
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA 78712
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Dorien De Vlieger
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
4Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
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Kizzmekia S. Corbett
5Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA 20892
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Gretel M. Torres
6Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA 03756
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Wander Van Breedam
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
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Kenny Roose
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
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Loes van Schie
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
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Markus Hoffmann
7Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
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Stefan Pöhlmann
7Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
8Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany
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Barney S. Graham
5Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA 20892
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  • ORCID record for Barney S. Graham
Nico Callewaert
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
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Bert Schepens
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
4Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
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  • For correspondence: bert.schepens@vib-ugent.be xavier.saelens@vib-ugent.be jmclellan@austin.utexas.edu
Xavier Saelens
2VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium
3Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium
4Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
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  • For correspondence: bert.schepens@vib-ugent.be xavier.saelens@vib-ugent.be jmclellan@austin.utexas.edu
Jason S. McLellan
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA 78712
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  • ORCID record for Jason S. McLellan
  • For correspondence: bert.schepens@vib-ugent.be xavier.saelens@vib-ugent.be jmclellan@austin.utexas.edu
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ABSTRACT

The pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-1) and COVID-19 coronavirus (SARS-CoV-2) have all emerged into the human population with devastating consequences. These viruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics to combat these highly pathogenic coronaviruses. Here, we describe the isolation and characterization of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs are capable of potently neutralizing MERS-CoV or SARS-CoV-1 S pseudotyped viruses. The crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs block receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S, and demonstrate that this cross-reactive VHH is capable of neutralizing SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.

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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-ND 4.0 International license.
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Posted March 28, 2020.
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Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies
Daniel Wrapp, Dorien De Vlieger, Kizzmekia S. Corbett, Gretel M. Torres, Wander Van Breedam, Kenny Roose, Loes van Schie, VIB-CMB COVID-19 Response Team, Markus Hoffmann, Stefan Pöhlmann, Barney S. Graham, Nico Callewaert, Bert Schepens, Xavier Saelens, Jason S. McLellan
bioRxiv 2020.03.26.010165; doi: https://doi.org/10.1101/2020.03.26.010165
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Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies
Daniel Wrapp, Dorien De Vlieger, Kizzmekia S. Corbett, Gretel M. Torres, Wander Van Breedam, Kenny Roose, Loes van Schie, VIB-CMB COVID-19 Response Team, Markus Hoffmann, Stefan Pöhlmann, Barney S. Graham, Nico Callewaert, Bert Schepens, Xavier Saelens, Jason S. McLellan
bioRxiv 2020.03.26.010165; doi: https://doi.org/10.1101/2020.03.26.010165

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