Structural insights of a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody

Torres, Jonathan L.; Ozorowski, Gabriel; Andreano, Emanuele; Liu, Hejun; Copps, Jeffrey; Piccini, Giulia; Donnici, Lorena; Conti, Matteo; Planchais, Cyril; Planas, Delphine; Manganaro, Noemi; Pantano, Elisa; Paciello, Ida; Pileri, Piero; Bruel, Timothée; Montomoli, Emanuele; Mouquet, Hugo; Schwartz, Olivier; Sala, Claudia; De Francesco, Raffaele; Wilson, Ian A.; Rappuoli, Rino; Ward, Andrew B.

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). 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 has low nanomolar affinity against 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 Summary Potent neutralizing monoclonal antibody J08 binds SARS-CoV-2 spike independent of known escape mutations.