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

Nature Chemical Biology volume 9, pages 789–795 (2013)Cite this article

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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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Figure 1: Design of the HtTA and the HBI for the selective inhibition of mast cell degranulation.
Figure 2: Chemical structures of the haptens and tetravalent synthetic allergens.
Figure 3: Characterization of hapten/IgE binding interactions.
Figure 4: Mast cell degranulation in response to tetravalent synthetic allergens.
Figure 5: Inhibition of mast cell degranulation via the HBI design.
Figure 6: Inhibition of PCA via the HBI in an in vivo mouse allergy model.

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Acknowledgements

We thank B. Wilson (University of New Mexico) for generously providing us with IgEDNP and the RBL cells, and P. Bryce (Northwestern University) for providing protocols and advice on the PCA model. We thank B. Boggess at the Mass Spectrometry and Proteomics Facility in the University of Notre Dame for the use of MS instrumentation. This work was supported by the National Institutes of Health–National Institute of Allergy and Infectious Diseases (grant number R03 AI085485 (to B.B.) and R01 AI095282 (to M.H.K.)).

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Authors and Affiliations

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

    Michael W Handlogten, Tanyel Kiziltepe & Basar Bilgicer

  2. Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, Indiana, USA

    Tanyel Kiziltepe & Basar Bilgicer

  3. Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Ana P Serezani & Mark H Kaplan

  4. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Basar Bilgicer

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  1. Michael W Handlogten
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Contributions

B.B. supervised and coordinated all of the research activities, designed the experiments and funded the study. M.W.H. designed the experiments, synthesized and characterized all of the molecules, performed the in vitro experiments and analyzed all of the data. T.K. designed and supervised the in vitro assays. M.H.K. designed and supervised the in vivo studies. A.P.S. performed the in vivo experiments. M.W.H., T.K. and B.B. wrote the manuscript.

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Correspondence to Basar Bilgicer.

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Handlogten, M., Kiziltepe, T., Serezani, A. et al. Inhibition of weak-affinity epitope-IgE interactions prevents mast cell degranulation. Nat Chem Biol 9, 789–795 (2013). https://doi.org/10.1038/nchembio.1358

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