Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Juliette Fedry; Daniel L Hurdiss; Chunyan Wang; Wentao Li; Gonzalo Obal; Ieva Drulyte; Wenjuan Du; Stuart C Howes; Frank J M van Kuppeveld; Friedrich Förster; Berend-Jan Bosch

doi:10.1126/sciadv.abf5632

Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Juliette Fedry, Daniel L Hurdiss, Chunyan Wang, Wentao Li, Gonzalo Obal, Ieva Drulyte, Wenjuan Du, Stuart C Howes, Frank J M van Kuppeveld, Friedrich Förster, Berend-Jan Bosch

Utrecht University, University Medical Center Utrecht

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The emergence of SARS-CoV-2 antibody escape mutations highlights the urgent need for broadly neutralizing therapeutics. We previously identified a human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of both trimeric spike ectodomains in complex with the 47D11 Fab. 47D11 binds to the closed receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies targeting the exposed receptor-binding motif. Together, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or postexposure therapy for COVID-19.

Original language	English
Article number	eabf5632
Pages (from-to)	1-11
Number of pages	11
Journal	Science advances
Volume	7
Issue number	23
Early online date	6 May 2021
DOIs	https://doi.org/10.1126/sciadv.abf5632
Publication status	Published - Jun 2021

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Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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title = "Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11",

abstract = "The emergence of SARS-CoV-2 antibody escape mutations highlights the urgent need for broadly neutralizing therapeutics. We previously identified a human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of both trimeric spike ectodomains in complex with the 47D11 Fab. 47D11 binds to the closed receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies targeting the exposed receptor-binding motif. Together, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or postexposure therapy for COVID-19.",

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AU - Obal, Gonzalo

AU - Drulyte, Ieva

AU - Du, Wenjuan

AU - Howes, Stuart C

AU - van Kuppeveld, Frank J M

AU - Förster, Friedrich

AU - Bosch, Berend-Jan

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Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

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