Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

Nature. 2021 May;593(7859):424-428. doi: 10.1038/s41586-021-03461-y. Epub 2021 Mar 25.

Abstract

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

Publication types

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

MeSH terms

  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Bispecific / immunology*
  • Antibodies, Bispecific / therapeutic use
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / therapeutic use
  • Body Weight
  • COVID-19 / drug therapy
  • COVID-19 / immunology*
  • COVID-19 / prevention & control
  • COVID-19 / virology*
  • Dependovirus / genetics
  • Disease Models, Animal
  • Epitopes, B-Lymphocyte / chemistry
  • Epitopes, B-Lymphocyte / immunology
  • Female
  • Humans
  • Immune Evasion / genetics
  • Immunoglobulin G / immunology*
  • Mice
  • Mice, Inbred C57BL
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / immunology

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Epitopes, B-Lymphocyte
  • Immunoglobulin G
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants