A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy. [Display omitted] •Characterization of potent human monoclonal SARS-CoV-2-neutralizing antibodies•Some SARS-CoV-2 antibodies reacted with mammalian self-antigens in different organs•Crystal structures of two antibodies in complex with SARS-CoV-2 RBD at 2.55/2.70 Å•Post-exposure antibody treatment protected from lung damage in infected hamsters Kreye et al. report isolation and characterization of monoclonal antibodies from COVID-19 patients, some of which were found to display autoreactivity with mammalian self-antigens in different organs. Crystal structures of two antibodies in complex with the SARS-CoV-2 spike RBD reveal antibody engagement with the ACE2 binding site from different approach angles. One antibody was evaluated further for in vivo efficacy and found to be both protective and efficacious post-challenge in a hamster infection model.