Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes

Cell. 2016 Jul 28;166(3):596-608. doi: 10.1016/j.cell.2016.05.073. Epub 2016 Jul 21.

Abstract

Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross-reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / isolation & purification
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / isolation & purification
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / isolation & purification
  • Antibody Specificity*
  • Binding Sites, Antibody
  • Crystallography, X-Ray
  • Epitopes / immunology
  • Ferrets
  • Humans
  • Influenza Vaccines
  • Influenzavirus A / immunology*
  • Mice
  • Orthomyxoviridae Infections / prevention & control
  • Protein Conformation

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Influenza Vaccines
  • MED18852