The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen–antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections. Here, the authors identify and characterize two mouse-derived monoclonal antibodies against SARS-CoV-2 spike protein that target different epitopes in RBD and block the interaction S/ACE2 and show that a formulated humanized version cocktail exhibits prophylaxis and therapeutic antiviral effects in an hACE2-adenovector expressed mouse model.
【저자키워드】 Microbiology, structural biology, 【초록키워드】 COVID-19, coronavirus disease, neutralizing antibody, SARS-CoV-2, Coronavirus disease 2019, coronavirus, pandemic, Drug development, Neutralizing antibodies, antibody, SARS-COV-2 infection, monoclonal antibody, drug, in vitro, severe acute respiratory syndrome Coronavirus, monoclonal antibodies, IC50, Spike protein, Antiviral effect, Prophylaxis, Protein, Epitopes, Receptor-binding domain, antibody cocktail, mice, RBD, SARS-CoV-2 spike protein, therapeutic, respiratory, information, mouse model, epitope, SARS-CoV-2 infections, mAbs, cryo-EM structures, neutralizing monoclonal antibody, binding, SARS-CoV-2 spike, Fab, Interaction, characterization, Post-infection, acute respiratory syndrome, two groups, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, complex, option, treat, inhibitory concentration, treating COVID-19, trimeric S protein, Administered, humanized, cryo-EM structure, neutralize, S trimer, identify, caused, determine, expressed, the receptor-binding domain, conformational, representing, complexes, two group, groups, exhibit, the SARS-CoV-2, 【제목키워드】 development, treating SARS-CoV-2 infection,