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

Sci Adv. 2021 Jun 2;7(23):eabf5632. doi: 10.1126/sciadv.abf5632. Print 2021 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal* / chemistry
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Neutralizing* / chemistry
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Viral* / chemistry
  • Antibodies, Viral* / immunology
  • Humans
  • SARS Virus* / chemistry
  • SARS Virus* / immunology
  • SARS-CoV-2* / chemistry
  • SARS-CoV-2* / immunology
  • Structure-Activity Relationship

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral