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Nat Chem Biol. 2013 Dec;9(12):789-95. doi: 10.1038/nchembio.1358. Epub 2013 Oct 6.

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

Author information

1
Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana, USA.

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.

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PMID:
24096304
PMCID:
PMC3913000
DOI:
10.1038/nchembio.1358
[Indexed for MEDLINE]
Free PMC Article

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