Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy
Copyright © 2020 Elsevier Inc. All rights reserved..
Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:183 |
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| Enthalten in: |
Cell - 183(2020), 4 vom: 12. Nov., Seite 1013-1023.e13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Du, Shuo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.11.2020 Date Revised 10.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cell.2020.09.035 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315418184 |
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| 245 | 1 | 0 | |a Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy |
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| 500 | |a Date Completed 25.11.2020 | ||
| 500 | |a Date Revised 10.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Inc. All rights reserved. | ||
| 520 | |a Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Zhu, Qinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Pin |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Feifei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guopeng |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Xiaoxia |e verfasserin |4 aut | |
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| 700 | 1 | |a Deng, Wei |e verfasserin |4 aut | |
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| 700 | 1 | |a Nie, Jianhui |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yinghui |e verfasserin |4 aut | |
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| 700 | 1 | |a Liu, Ruixue |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Shuran |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Yisimayi, Ayijiang |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a He, Runsheng |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Yunlin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Wenjie |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Yali |e verfasserin |4 aut | |
| 700 | 1 | |a Qu, Yajin |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Chenggong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qisheng |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Ning |e verfasserin |4 aut | |
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