Browsing by Author "Kim, Baksun"

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    Covalent Heterobivalent Inhibitor Design for Inhibition of IgE-Dependent Penicillin Allergy in a Murine Model
    (Science Publications, 2019-05-17) Deak, Peter E.; Kim, Baksun; Koh, Byunghee; Qayum, Amina Abdul; Kiziltepe, Tanyel; Kaplan, Mark H.; Bilgicer, Basar; Pediatrics, School of Medicine
    Drug allergies occur when hapten-like drug metabolites conjugated to serum proteins, through their interactions with specific immunoglobulin E (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 antibody 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 (RBL) 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 seperate 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 antibody and inhibited degranulation in cellular degranulation assays using RBL 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.
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    Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen
    (National Academy of Sciences, 2019-04-30) 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; Pediatrics, School of Medicine
    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.