A study reports the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies (mAbs) from five patients with severe COVID-19. Among these, 19 mAbs showed potent neutralization of SARS-CoV-2 in vitro, with some exhibiting 50% inhibitory concentrations (IC50) as low as 0.7 to 9 ng/ml. These mAbs targeted different regions of the viral spike protein, including the receptor-binding domain (RBD) and N-terminal domain (NTD), as well as quaternary epitopes. Cryo-electron microscopy (cryo-EM) revealed that these mAbs recognized the closed, 'all RBD-down' conformation of the spike. The study also identified that some mAbs, such as 2-43 and 2-51, targeted regions not previously mapped to the RBD or NTD. The mAb 2-15 showed strong in vivo protection against SARS-CoV-2 infection in hamsters, reducing viral load by 4 logs. The study highlights the diversity and potency of these mAbs, which could be valuable for developing therapeutic and prophylactic agents against SARS-CoV-2. The findings suggest that neutralizing antibodies targeting the RBD and NTD are important for virus neutralization, while those targeting other regions may offer additional therapeutic options. The study also emphasizes the importance of patient selection in generating diverse and potent mAbs. The results contribute to the understanding of SARS-CoV-2 immunology and provide potential targets for vaccine development.A study reports the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies (mAbs) from five patients with severe COVID-19. Among these, 19 mAbs showed potent neutralization of SARS-CoV-2 in vitro, with some exhibiting 50% inhibitory concentrations (IC50) as low as 0.7 to 9 ng/ml. These mAbs targeted different regions of the viral spike protein, including the receptor-binding domain (RBD) and N-terminal domain (NTD), as well as quaternary epitopes. Cryo-electron microscopy (cryo-EM) revealed that these mAbs recognized the closed, 'all RBD-down' conformation of the spike. The study also identified that some mAbs, such as 2-43 and 2-51, targeted regions not previously mapped to the RBD or NTD. The mAb 2-15 showed strong in vivo protection against SARS-CoV-2 infection in hamsters, reducing viral load by 4 logs. The study highlights the diversity and potency of these mAbs, which could be valuable for developing therapeutic and prophylactic agents against SARS-CoV-2. The findings suggest that neutralizing antibodies targeting the RBD and NTD are important for virus neutralization, while those targeting other regions may offer additional therapeutic options. The study also emphasizes the importance of patient selection in generating diverse and potent mAbs. The results contribute to the understanding of SARS-CoV-2 immunology and provide potential targets for vaccine development.