XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Front Immunol. 2021 Nov 15:12:761250. doi: 10.3389/fimmu.2021.761250. eCollection 2021.

Abstract

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

Keywords: COVID-19; SARS-CoV-2; neutralization; polyclonal antibody (PAb); variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Heterophile / immunology*
  • Antibodies, Heterophile / therapeutic use
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / therapeutic use
  • Antigenic Variation
  • Broadly Neutralizing Antibodies / immunology*
  • Broadly Neutralizing Antibodies / therapeutic use
  • COVID-19 / therapy
  • COVID-19 / virology
  • COVID-19 Serotherapy
  • Disease Models, Animal
  • Epitopes
  • Humans
  • Immunization, Passive
  • Lung / drug effects
  • Lung / virology
  • Mice
  • Protein Interaction Domains and Motifs
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology*
  • Swine
  • Viral Load / drug effects

Substances

  • Antibodies, Heterophile
  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Epitopes
  • Spike Glycoprotein, Coronavirus
  • XAV-19
  • spike protein, SARS-CoV-2

Supplementary concepts

  • SARS-CoV-2 variants