Inhibition of weak-affinity epitope-IgE interactions prevents mast cell degranulation

Michael W. Handlogten, Tanyel Kiziltepe, Ana P. Serezani, Mark H. Kaplan, Basar Bilgicer

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Development of specific inhibitors of allergy has had limited success, in part, owing to a lack of experimental models that reflect the complexity of allergen-IgE interactions. We designed a heterotetravalent allergen (HtTA) system, which reflects epitope heterogeneity, polyclonal response and number of immunodominant epitopes observed in natural allergens, thereby providing a physiologically relevant experimental model to study mast cell degranulation. The HtTA design revealed the importance of weak-affinity epitopes in allergy, particularly when presented with high-affinity epitopes. The effect of selective inhibition of weak-affinity epitope-IgE interactions was investigated with heterobivalent inhibitors (HBIs) designed to simultaneously target the antigen- and nucleotide-binding sites on the IgE Fab. HBI demonstrated enhanced avidity for the target IgE and was a potent inhibitor of degranulation in vitro and in vivo. These results demonstrate that partial inhibition of allergen-IgE interactions was sufficient to prevent mast cell degranulation, thus establishing the therapeutic potential of the HBI design.

Original languageEnglish (US)
Pages (from-to)789-795
Number of pages7
JournalNature chemical biology
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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