ABSTRACT
As the coronavirus disease 2019 (COVID-19) pandemic continues, there is a strong need for highly potent monoclonal antibodies (mAbs) that are resistant against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VoCs). To date there have been four major variants (Alpha, Beta, Gamma, Delta) that have tested the efficacy of the vaccines and have led to some breakthrough infections amongst vaccinated populations. Here, we evaluate the potency of a previously described mAb J08 against these variants using cell-based assays and delve into the molecular details of the binding interaction using cryo-EM. We show that mAb J08 is unique because it has low nanomolar affinity against the VoCs, binds high on the receptor binding domain (RBD) ridge and is therefore unaffected by most mutations, and can bind in the RBD-up and -down conformations. These findings further validate the phase II/III human clinical trial underway using mAb J08 as a monoclonal therapy. One sentence summaryMonoclonal antibody J08 can potently neutralize wild-type SARS-CoV-2 and variants of concern by binding to the ridge of the receptor binding domain in up and down conformations and thereby avoid the effects of current escape mutations.