A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy

MAbs. Jan-Dec 2020;12(1):1804241. doi: 10.1080/19420862.2020.1804241.

Abstract

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance in vitro, inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.

Keywords: Biparatopic; COVID-19; SARS-CoV-2; antibody-ACE2 fusion; neutralizing antibody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Neutralizing / pharmacology*
  • Antibodies, Viral / pharmacology*
  • Betacoronavirus / drug effects*
  • Coronavirus Infections*
  • Drug Design
  • Drug Discovery
  • Humans
  • Pandemics*
  • Peptidyl-Dipeptidase A / drug effects*
  • Pneumonia, Viral*
  • Recombinant Proteins
  • Spike Glycoprotein, Coronavirus / drug effects

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Recombinant Proteins
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2