Covalent Heterobivalent Inhibitor Design for Inhibition of IgE-Dependent Penicillin Allergy in a Murine Model.

Autor:	Deak PE; Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556., Kim B; Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556., Koh B; Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202., Qayum AA; Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202., Kiziltepe T; Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556., Kaplan MH; Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202., Bilgicer B; Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556; bbilgicer@nd.edu.; Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, IN 46556; and.; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Jul 01; Vol. 203 (1), pp. 21-30. Date of Electronic Publication: 2019 May 17.
DOI:	10.4049/jimmunol.1900225
Abstrakt:	Drug allergies occur when hapten-like drug metabolites conjugated to serum proteins, through their interactions with specific IgE, trigger allergic reactions that can be life threatening. A molecule termed covalent heterobivalent inhibitor (cHBI) was designed to specifically target drug hapten-specific IgE to prevent it from binding drug-haptenated serum proteins. cHBI binds the two independent sites on a drug hapten-specific Ab and covalently conjugates only to the specific IgE, permanently inhibiting it. The cHBI design was evaluated via ELISA to measure cHBI-IgE binding, degranulation assays of rat basophil leukemia cells for in vitro efficacy, and mouse models of ear swelling and systemic anaphylaxis responses for in vivo efficacy. The cHBI design was evaluated using two separate models: one specific to inhibit penicillin G-reactive IgE and another to inhibit IgE specific to a model compound, dansyl. We show that cHBI conjugated specifically to its target Ab and inhibited degranulation in cellular degranulation assays using rat basophil leukemia cells. Furthermore, cHBIs demonstrated in vivo inhibition of allergic responses in both murine models. We establish the cHBI design to be a versatile platform for inhibiting hapten/IgE interactions, which can potentially be applied to inhibit IgE-mediated allergic reactions to any drug/small-molecule allergy. (Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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