Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

Science. 2021 Feb 19;371(6531):823-829. doi: 10.1126/science.abf4830. Epub 2021 Jan 25.

Abstract

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Viral / genetics
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / metabolism
  • Antibody Affinity
  • Betacoronavirus / immunology*
  • Binding Sites
  • Binding Sites, Antibody
  • Broadly Neutralizing Antibodies / genetics
  • Broadly Neutralizing Antibodies / immunology*
  • Broadly Neutralizing Antibodies / metabolism
  • COVID-19 / prevention & control
  • COVID-19 / therapy
  • Cell Surface Display Techniques
  • Directed Molecular Evolution
  • Epitopes / immunology
  • Humans
  • Immunization, Passive
  • Immunoglobulin Fc Fragments / immunology
  • Mice, Inbred BALB C
  • Protein Domains
  • Protein Engineering
  • Receptors, Coronavirus / metabolism
  • SARS Virus / immunology
  • SARS-CoV-2 / immunology*
  • Severe Acute Respiratory Syndrome / immunology
  • Severe Acute Respiratory Syndrome / prevention & control
  • Severe Acute Respiratory Syndrome / therapy
  • Spike Glycoprotein, Coronavirus / immunology*
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Epitopes
  • Immunoglobulin Fc Fragments
  • Receptors, Coronavirus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • COVID-19 serotherapy