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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues, with devasting consequences for human lives and the global economy 1,2 . The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this coronavirus. Here we report the isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml −1 . Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, 'all RBD-down' conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.The novel coronavirus SARS-CoV-2 1,2 has caused more than 14 million confirmed infections globally, and has caused more than 600,000 deaths. This pandemic has also put much of the world on pause, with unprecedented disruption of lives and unparalleled damage to the economy. A return to some semblance of normality will depend on the ability of science to deliver an effective solution, and the scientific community has responded admirably. Drug development is well underway, and vaccine candidates have entered clinical trials. Another promising approach is the isolation of SARS-CoV-2-neutralizing monoclonal antibodies (mAbs) that could be used as therapeutic or prophylactic agents. The primary target for such antibodies is the viral spike, a trimeric protein 3,4 that is responsible for binding of the virus to the ACE2 receptor on the host cell 1,3,5,6 . The spike protein is comprised of two subunits. The S1 subunit has two major structural elements, RBD and NTD; the S2 subunit mediates virus-cell membrane fusion after the RBD has engaged ACE2. Reports of the discovery of neutralizing mAbs that target the RBD have been published recently [7][8][9][10][11] . We now describe our efforts in isolating and characterizing a collection of mAbs that not only target multiple epitopes on the viral spike but also show very high potency in neutralizing SARS-CoV-2. Patient selectionForty patients with PCR-confirmed SARS-CoV-2 infection were enrolled in a cohort study on virus-neutralizing antibodies. Plas...

Highlights d Structures of seven NTD-directed neutralizing antibody complexes with spike or NTD d Structures define distinct recognition classes, one observed in multiple donors d Supersite is glycan free, electropositive, with mobile b-hairpin and flexible loops d Most potent NTD-directed neutralizing antibodies may target this supersite