ABSTRACT
An essential step for SARS-CoV-2 infection is the attachment to the host cell receptor by its Spike receptor-binding domain (RBD). Most of the existing RBD-targeting neutralizing antibodies block the receptor-binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non-RBM-targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a KD of 5.6 nM, neutralizes SARS-CoV-2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross-reactivity against SARS-CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted "ideal" vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20-binding but confers little or no resistance to neutralization. Finally, in vitro mode-of-action characterization and negative-stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS-CoV-2 Spike for the development of potential antiviral drugs.
Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Humans , Spike Glycoprotein, CoronavirusABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide severe coronavirus disease 2019 (COVID-19) pandemic since December 2019. There is a great demand for effective therapies for the prevention and treatment of COVID-19. Developing therapeutic neutralizing antibodies (NAbs), which could block viral infection, is such a promising approach, as NAbs have been successfully applied to the treatment of other viral infections. The recent advances of antibody technology have greatly accelerated the discovery of SARS-CoV-2 NAbs, and many of which are now actively tested in clinical trials. Here, we review the approaches applied for SARS-CoV-2 NAb development, and discuss the emerging technologies underlining the antibody discovery. We further summarize the common features of these antibodies including the shared neutralizing epitopes and sequence features.