Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

Nat Commun. 2016 May 19:7:11610. doi: 10.1038/ncomms11610.

Abstract

Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.

Publication types

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

MeSH terms

  • Animals
  • Anti-Allergic Agents / chemistry
  • Anti-Allergic Agents / pharmacology*
  • Basophils / drug effects
  • Cell Line
  • Drug Synergism
  • Humans
  • Immunoglobulin E / chemistry
  • Immunoglobulin E / drug effects*
  • Immunoglobulin E / genetics
  • Mutation
  • Omalizumab / chemistry
  • Omalizumab / pharmacology*
  • Protein Conformation
  • Receptors, IgE / antagonists & inhibitors*

Substances

  • Anti-Allergic Agents
  • Receptors, IgE
  • Omalizumab
  • Immunoglobulin E