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

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

doi:10.1126/sciadv.abf5632

Juliette Fedry, Chunyan Wang + Show 9 more

Open Access

https://doi.org/10.1126/sciadv.abf5632

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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.

Highlights

The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) emerged from a zoonotic event in China, late 2019 [1]
We recently reported the potent human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV and SARS-CoV-2 at 1.3 and 3.8 nM, respectively, without competing with angiotensin converting enzyme 2 (ACE2) binding [52]
The sub-stochiometric binding observed for SARS2-S may partially explain our previous observations that 47D11 binds to the SARS-S with higher affinity than SARS2-S [52]

Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) emerged from a zoonotic event in China, late 2019 [1]. We recently reported the potent human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV and SARS-CoV-2 at 1.3 and 3.8 nM, respectively, without competing with ACE2 binding [52]. Upon incubation with 47D11, only the closed conformation of the SARS-CoV spike was observed, with stochiometric binding of 47D11 to each RBD (Figure 1A).

Results

Conclusion