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

Daniel Wrapp; Dorien De Vlieger; Kizzmekia S Corbett; Gretel M Torres; Nianshuang Wang; 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

doi:10.1016/j.cell.2020.04.031

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

Cell. 2020 May 28;181(5):1004-1015.e15. doi: 10.1016/j.cell.2020.04.031. Epub 2020 May 5.

Authors

Affiliations

¹ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
² VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
³ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
⁵ VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium.
⁶ Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.
⁷ Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany.
⁸ VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address: bert.schepens@vib-ugent.be.
⁹ VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address: xavier.saelens@vib-ugent.be.
¹⁰ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: jmclellan@austin.utexas.edu.

Abstract

Coronaviruses 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. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with 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 neutralizes 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.

Keywords: COVID-19; MERS; SARS; SARS-CoV-2; nanobody.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / isolation & purification*
Betacoronavirus / immunology*
COVID-19
Camelids, New World / immunology
Coronavirus Infections / therapy
Cross Reactions
Immunoglobulin G / chemistry
Immunoglobulin G / immunology
Models, Molecular
Pandemics
Pneumonia, Viral / therapy
Protein Domains
Receptors, Virus / chemistry
SARS-CoV-2
Single-Domain Antibodies / chemistry
Single-Domain Antibodies / immunology
Single-Domain Antibodies / isolation & purification*
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / immunology

Substances

Antibodies, Neutralizing
Immunoglobulin G
Receptors, Virus
Single-Domain Antibodies
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Grants and funding

R01 AI127521/AI/NIAID NIH HHS/United States