Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies.

BioRxiv : the Preprint Server for Biology
Christopher O BarnesPamela J Bjorkman


The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike 1-5 show therapeutic promise and are being evaluated clincally 6-8 . To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs 5 in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to up RBDs, (2) ACE2-blocking hNAbs that bind both up and down RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize up and down RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only up RBDs 9 . Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-...Continue Reading


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surface plasmon resonance

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