SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

• Published in: Nature (London) Vol. 588; no. 7839; pp. 682 - 687
• Main Authors: Barnes, Christopher O., Jette, Claudia A., Abernathy, Morgan E., Dam, Kim-Marie A., Esswein, Shannon R., Gristick, Harry B., Malyutin, Andrey G., Sharaf, Naima G., Huey-Tubman, Kathryn E., Lee, Yu E., Robbiani, Davide F., Nussenzweig, Michel C., West, Anthony P., Bjorkman, Pamela J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-12-2020; Nature Publishing Group
• Subjects: 101/1; 101/28; 631/250/2152/2153/1291; 631/326/596/4130; 631/535/1258/1259; 82/103; 82/80; 82/83; ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - metabolism; Angiotensin-Converting Enzyme 2 - ultrastructure; Antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - therapeutic use; Antibodies, Neutralizing - ultrastructure; Antigens; Avidity; Binding sites; Binding Sites - genetics; Binding Sites - immunology; Blocking; Cell Line; Conformation; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 Drug Treatment; Cryoelectron Microscopy; Epitope mapping; Evaluation; Glycoproteins; Humanities and Social Sciences; Humans; Hydrophobicity; Immune response; Locking; Mapping; Models, Molecular; multidisciplinary; Mutation; N-glycans; Neutralization; Neutralizing; Pandemics; Physiological aspects; Polysaccharides; Receptors, Coronavirus - chemistry; Receptors, Coronavirus - metabolism; Receptors, Coronavirus - ultrastructure; SARS-CoV-2 - chemistry; SARS-CoV-2 - immunology; SARS-CoV-2 - metabolism; SARS-CoV-2 - ultrastructure; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - ultrastructure; Spikes; Structure; Trimers; Viral antibodies; Viral diseases; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-2852-1

The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein
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–
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show promise therapeutically and are being evaluated clinically
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–
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. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies
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in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the
VH3-53
gene segment with short CDRH3 loops that block ACE2 and bind only to ‘up’ RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and ‘down’ RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs
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. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived
N
-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
Eight structures of human neutralizing antibodies that target the SARS-CoV-2 spike receptor-binding domain are reported and classified into four categories, suggesting combinations for clinical use.