Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

Science. 2020 Sep 18;369(6510):1505-1509. doi: 10.1126/science.abc5881. Epub 2020 Jul 23.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we report a humanized monoclonal antibody, H014, that efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar concentrations by engaging the spike (S) receptor binding domain (RBD). H014 administration reduced SARS-CoV-2 titers in infected lungs and prevented pulmonary pathology in a human angiotensin-converting enzyme 2 mouse model. Cryo-electron microscopy characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a previously uncharacterized conformational epitope, which was only accessible when the RBD was in an open conformation. Biochemical, cellular, virological, and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncovered broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antibodies, Monoclonal, Humanized / chemistry*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / therapeutic use
  • Betacoronavirus / immunology*
  • COVID-19
  • Chlorocebus aethiops
  • Coronavirus Infections / therapy
  • Epitope Mapping
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Lung / immunology
  • Mice
  • Pandemics
  • Peptidyl-Dipeptidase A / immunology*
  • Pneumonia, Viral / therapy
  • Protein Domains
  • Protein Multimerization
  • Receptors, Virus / immunology*
  • SARS Virus / immunology*
  • SARS-CoV-2
  • Vero Cells

Substances

  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Immunoglobulin Fab Fragments
  • Receptors, Virus
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2