Neutralizing antibodies represent a valuable therapeutic approach to countermeasure the current COVID-19 pandemic. Emergence of SARS-CoV-2 variants emphasizes the notion that antibody treatments need to rely on highly neutralizing monoclonal antibodies (mAbs), targeting several distinct epitopes for circumventing therapy escape-mutants. Previously, we reported efficient human therapeutic mAbs recognizing epitopes on the spike receptor binding domain (RBD) of SARS-CoV-2. Here we report the isolation, characterization and recombinant production of 12 neutralizing human mAbs, targeting three distinct epitopes on the spike N-terminal domain (NTD) of the virus. Neutralization mechanism of these antibodies involves receptors other than the canonical hACE2 on target cells, relying both on amino-acid and
-glycan epitope-recognition, suggesting alternative viral cellular-portals. Two selected mAbs demonstrated full protection of K18-hACE2 transgenic mice when administered at low doses and late post-exposure, demonstrating the high potential of the mAbs for therapy of SARS-CoV-2 infection.