Université d'UTRECHT, LAB. DE CRYO MICROSCOPIE“Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by human monoclonal antobody 47D11"
Science Advances, 02 Jun 2021:Vol. 7, no. 23, eabf5632, DOI: 10.1126/sciadv.abf5632Juliette Fedry, Daniel L Hurdiss, Chunyan Wang, Wentao Li, Gonzalo Obal, Ieva Drulyte, Wenjuan Du, Stuart C Howes, Frank JM van Kuppeveld, Friedrich Forster and Berend-Jan Bosch
CV:
Juliette Fedry, 31 years old, obtained her PhD at the Structural Virology Unit of Felix Rey at Pasteur Institute in Paris. She is currently a postdoctoral fellow at Utrecht University, in the Cryo-Electron Microscopy group headed by Prof. Friedrich Förster. She used her expertise in cryo-electron microscopy to decipher the molecular basis for neutralization of an antibody in preclinical development for SARS-CoV-2 treatment. This study reveals that the antibody targets a conserved region of the spike protein and is not affected by the emerging mutations, making it a promising therapeutic candidate in the fight against the new SARS-CoV-2 variants.
Summary of the article:
SARS-CoV-2 neutralizing antibodies elicited upon vaccination or viral infection mostly target the ACE2 binding region on the receptor binding domain (RBD) of the spike protein. This region is the most variable on the spike RBD, consistent with the fact that emerging variants fixed mutations in this part possibly reducing the efficiency of current vaccines and therapeutics. Therefore there is an urgent need for broadly neutralizing antibodies targeting less variable epitopes on the spike RBD. We previously identified a potent human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV without competing with ACE2 for spike binding, and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of trimeric SARS-CoV and SARS-CoV-2 spike ectodomains in complex with the 47D11 Fab. 47D11 binds specifically to the closed conformation of the receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a conserved and 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 that target epitopes only exposed in the RBD up conformation. Altogether, these results reveal a mutationally constrained epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or post-exposure therapy for COVID-19 emerging variants.
