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Proc Natl Acad Sci U S A. 2019 Apr 8. pii: 201820417. doi: 10.1073/pnas.1820417116. [Epub ahead of print]

Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen.

Author information

1
Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556.
2
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202.
3
Department of Pediatrics, Section of Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202.
4
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202.
5
Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202.
6
Food Allergy Center, Massachusetts General Hospital, Boston, MA.
7
Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556; BBilgicer@nd.edu.
8
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
9
Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, IN 46556.

Abstract

Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.

KEYWORDS:

IgE; allergy; epitope; peanut; selective inhibition

PMID:
30962381
DOI:
10.1073/pnas.1820417116

Conflict of interest statement

The authors declare no conflict of interest.

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