Handlogten, Michael WKiziltepe, TanyelSerezani, Ana PKaplan, Mark HBilgicer, Basar2016-03-072016-03-072013-12Handlogten, M. W., Kiziltepe, T., Serezani, A. P., Kaplan, M. H., & Bilgicer, B. (2013). Inhibition of weak-affinity epitope-IgE interactions prevents mast cell degranulation. Nature Chemical Biology, 9(12), 789–795. http://doi.org/10.1038/nchembio.13581552-4450https://hdl.handle.net/1805/8738Development 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.en-USPublisher PolicyCell DegranulationphysiologyEpitopesmetabolismImmunoglobulin EMast CellsArticle