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

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 al...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (18), p.8966-8974
Main Authors: Deak, Peter E., Kim, Baksun, Qayum, Amina Abdul, Shin, Jaeho, Vitalpur, Girish, Kloepfer, Kirsten M., Turner, Matthew J., Smith, Neal, Shreffler, Wayne G., Kiziltepe, Tanyel, Kaplan, Mark H., Bilgicer, Basar
Format: Article
Language:English
Subjects:
Allergens
Allergens - immunology
Allergies
Arachis - immunology
Basophils - immunology
Biological Sciences
Cell Degranulation
Covalence
Covalent bonds
Crosslinking
Design
Epitopes
Epitopes - chemistry
Epitopes - immunology
Food allergies
Galectin 3 - pharmacology
Humans
Hypersensitivity
Immunoglobulin E
Immunoglobulin E - immunology
Inhibitors
Leukocytes (basophilic)
Mast cells
Mast Cells - immunology
Nanoparticles - therapeutic use
Nuts
Peanut Hypersensitivity - immunology
Peanuts
PNAS Plus
Reagents
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1820417116