Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants
The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
| Errataetall: |
UpdateIn: Sci Transl Med. 2021 Oct 20;13(616):eabj5413. - PMID 34519517 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2021 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2021) vom: 01. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cho, Hyeseon [VerfasserIn] |
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Date Revised 11.02.2024 published: Electronic UpdateIn: Sci Transl Med. 2021 Oct 20;13(616):eabj5413. - PMID 34519517 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2021.04.01.437942 |
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| 500 | |a UpdateIn: Sci Transl Med. 2021 Oct 20;13(616):eabj5413. - PMID 34519517 | ||
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| 520 | |a The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Gonzales-Wartz, Kristina Kay |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Deli |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Peterson, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Janie |e verfasserin |4 aut | |
| 700 | 1 | |a Beutler, Nathan |e verfasserin |4 aut | |
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| 700 | 1 | |a Cong, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Postnikova, Elena |e verfasserin |4 aut | |
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| 700 | 1 | |a Shi, Wei |e verfasserin |4 aut | |
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| 700 | 1 | |a Cohen, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Ming |e verfasserin |4 aut | |
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