Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

Science. 2020 Nov 20;370(6519):950-957. doi: 10.1126/science.abe3354. Epub 2020 Sep 24.

Abstract

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / immunology
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / isolation & purification
  • Antibodies, Viral / administration & dosage
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / isolation & purification
  • Betacoronavirus / immunology*
  • CHO Cells
  • COVID-19
  • Coronavirus Infections / prevention & control*
  • Coronavirus Infections / therapy
  • Cricetinae
  • Cricetulus
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / immunology
  • Microscopy, Electron
  • Pandemics / prevention & control*
  • Peptidyl-Dipeptidase A / immunology*
  • Pneumonia, Viral / prevention & control*
  • Pneumonia, Viral / therapy
  • Protein Domains / immunology
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / immunology

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunodominant Epitopes
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2