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

• Published in: Cell Vol. 181; no. 5; pp. 1004 - 1015.e15
• Main Authors: Wrapp, Daniel, De Vlieger, Dorien, Corbett, Kizzmekia S., Torres, Gretel M., Wang, Nianshuang, Van Breedam, Wander, Roose, Kenny, van Schie, Loes, Hoffmann, Markus, Pöhlmann, Stefan, Graham, Barney S., Callewaert, Nico, Schepens, Bert, Saelens, Xavier, McLellan, Jason S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.2020
• Subjects: Animals; antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - isolation & purification; Betacoronavirus - immunology; Camelidae; Camelids, New World - immunology; Coronavirus infections; Coronavirus Infections - therapy; COVID-19; cross reaction; Cross Reactions; crystal structure; epitopes; humans; immunoglobulin G; Immunoglobulin G - chemistry; Immunoglobulin G - immunology; llamas; membrane fusion; MERS; Middle East respiratory syndrome coronavirus; Models, Molecular; nanobody; neutralization; Pandemics; Pneumonia, Viral - therapy; Protein Domains; receptors; Receptors, Virus - chemistry; SARS; SARS-CoV-2; Single-Domain Antibodies - chemistry; Single-Domain Antibodies - immunology; Single-Domain Antibodies - isolation & purification; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; therapeutics; viruses; COVID-19; SARS; SARS-CoV-2; nanobody; MERS
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.04.031

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. [Display omitted] •VHHs isolated from a llama immunized with prefusion-stabilized coronavirus spikes•Structural characterization of VHHs reveals conserved mechanism of neutralization•SARS-CoV-1 S-directed VHH cross-reacts with SARS-CoV-2 S•Bivalent VHH neutralizes SARS-CoV-2 pseudoviruses Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identify neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further reveal how these antibodies bind spike proteins to prevent virus entry into cells.