Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Cell. 2021 Apr 29;184(9):2316-2331.e15. doi: 10.1016/j.cell.2021.03.029. Epub 2021 Mar 16.


Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

Keywords: N-terminal domain; SARS-CoV-2; coronavirus; monoclonal antibodies; neutralizing antibodies; viral antibodies.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Neutralizing / pharmacology*
  • Binding, Competitive
  • COVID-19 / immunology
  • COVID-19 / virology
  • Chemokines / metabolism
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fab Fragments / metabolism
  • Immunoglobulin G / metabolism
  • Lung / metabolism
  • Mice, Inbred C57BL
  • Models, Molecular
  • Mutagenesis / genetics
  • Neutralization Tests
  • Protective Agents / pharmacology*
  • Protein Domains
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vero Cells


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Chemokines
  • Immunoglobulin Fab Fragments
  • Immunoglobulin G
  • Protective Agents
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2