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

<div class='caption-title'>47D11 has differing conformational selectivity for the SARS-CoV and SARS-CoV-2 spike.</div>
<div class='caption-title'>47D11 binds specifically to the RBD in down conformation and prevents their full compaction.</div>
<div class='caption-title'>The 47D11 epitope comprises a mutationally constrained hydrophobic pocket that is normally shielded by glycan N343.</div>
Fedry J, Hurdiss DL, Wang C, Li W, Obal G, Drulyte I, Du W, Howes SC, van Kuppeveld FJM, Förster F, Bosch BJ
OpenAccess logo Sci Adv 7 (2021)
Cited: 36 times
EuropePMC logo PMID: 33958322

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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