SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies
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 protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 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 RBDs9. 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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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| Enthalten in: |
Nature - 588(2020), 7839 vom: 05. Dez., Seite 682-687 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Barnes, Christopher O [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.01.2021 Date Revised 02.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2020 Aug 30;:. - PMID 32869026 Citation Status MEDLINE |
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| doi: |
10.1038/s41586-020-2852-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316154946 |
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| 100 | 1 | |a Barnes, Christopher O |e verfasserin |4 aut | |
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| 500 | |a Date Revised 02.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2020 Aug 30;:. - PMID 32869026 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 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 RBDs9. 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Jette, Claudia A |e verfasserin |4 aut | |
| 700 | 1 | |a Abernathy, Morgan E |e verfasserin |4 aut | |
| 700 | 1 | |a Dam, Kim-Marie A |e verfasserin |4 aut | |
| 700 | 1 | |a Esswein, Shannon R |e verfasserin |4 aut | |
| 700 | 1 | |a Gristick, Harry B |e verfasserin |4 aut | |
| 700 | 1 | |a Malyutin, Andrey G |e verfasserin |4 aut | |
| 700 | 1 | |a Sharaf, Naima G |e verfasserin |4 aut | |
| 700 | 1 | |a Huey-Tubman, Kathryn E |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Yu E |e verfasserin |4 aut | |
| 700 | 1 | |a Robbiani, Davide F |e verfasserin |4 aut | |
| 700 | 1 | |a Nussenzweig, Michel C |e verfasserin |4 aut | |
| 700 | 1 | |a West, Anthony P |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Bjorkman, Pamela J |e verfasserin |4 aut | |
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