The Broadly Neutralizing DEV_K57 Antibody, Isolated from a Convalescent Patient, in Complex with the SARS-CoV-2 RBD

The continuous evolution of SARS-CoV-2 necessitates broadly neutralizing antibodies for robust therapeutics. In this study, we isolated 1824 single B cells from a COVID-19 convalescent donor and obtained 91 pairs of nucleotide sequences potentially encoding VH/VL domains. From this library, we generated and evaluated a panel of 38 recombinant monoclonal antibodies. Among this panel, we identified DEV_K57 as a broadly neutralizing human IgG1 antibody targeting the SARS-CoV-2 RBD. DEV_K57 exhibited in vitro neutralization breadth against diverse variants, demonstrating subnanomolar IC50 values. This in vitro efficacy was translated in vivo. In a Syrian hamster model of SARS-CoV-2 Delta infection, DEV_K57 significantly reduced viral RNA and infectious titers in both the upper and lower respiratory tracts, conferring a favorable safety profile with minimal histopathological damage. To elucidate its mechanism, we performed comprehensive biophysical and structural analyses. Biolayer interferometry revealed a high picomolar binding affinity to the RBD Delta. Furthermore, size-exclusion chromatography coupled with small-angle X-ray scattering and computational modeling uncovered a unique, stable dimeric architecture of the DEV_K57 Fab-RBD complex in solution, with a binding interface distinct from previously characterized structures. These findings underscore the value of rapid antibody isolation for pandemic preparedness against future emerging biological threats.