A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo

Michael W. Handlogten, Ana P. Serezani, Anthony L. Sinn, Karen Pollok, Mark Kaplan, Basar Bilgicer

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Current treatments for allergies include epinephrine and antihistamines, which treat the symptoms after an allergic response has taken place; steroids, which result in local and systemic immune suppression; and IgE-depleting therapies, which can be used only for a narrow range of clinical IgE titers. The limitations of current treatments motivated the design of a heterobivalent inhibitor (HBI) of IgE-mediated allergic responses that selectively inhibits allergen-IgE interactions, thereby preventing IgE clustering and mast cell degranulation. The HBI was designed to simultaneously target the allergen binding site and the adjacent conserved nucleotide binding site (NBS) found on the Fab of IgE Abs. The bivalent targeting was accomplished by linking a hapten to an NBS ligand with an ethylene glycol linker. The hapten moiety of HBI enables selective targeting of a specific IgE, whereas the NBS ligand enhances avidity for the IgE. Simultaneous bivalent binding to both sites provided HBI with 120-fold enhancement in avidity for the target IgE compared with the monovalent hapten. The increased avidity for IgE made HBI a potent inhibitor of mast cell degranulation in the rat basophilic leukemia mast cell model, in the passive cutaneous anaphylaxis mouse model of allergy, and in mice sensitized to the model allergen. In addition, HBI did not have any observable systemic toxic effects even at elevated doses. Taken together, these results establish the HBI design as a broadly applicable platform with therapeutic potential for the targeted and selective inhibition of IgE-mediated allergic responses, including food, environmental, and drug allergies.

Original languageEnglish
Pages (from-to)2035-2041
Number of pages7
JournalJournal of Immunology
Volume192
Issue number5
DOIs
StatePublished - Mar 1 2014

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Cell Degranulation
Mast Cells
Allergens
Immunoglobulin E
Ligands
Haptens
Binding Sites
Nucleotides
Mast-Cell Leukemia
Hypersensitivity
Drug Hypersensitivity
Passive Cutaneous Anaphylaxis
Food Hypersensitivity
Ethylene Glycol
Poisons
Histamine Antagonists
Epinephrine
Cluster Analysis
Steroids

ASJC Scopus subject areas

  • Immunology

Cite this

A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo. / Handlogten, Michael W.; Serezani, Ana P.; Sinn, Anthony L.; Pollok, Karen; Kaplan, Mark; Bilgicer, Basar.

In: Journal of Immunology, Vol. 192, No. 5, 01.03.2014, p. 2035-2041.

Research output: Contribution to journalArticle

Handlogten, Michael W. ; Serezani, Ana P. ; Sinn, Anthony L. ; Pollok, Karen ; Kaplan, Mark ; Bilgicer, Basar. / A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo. In: Journal of Immunology. 2014 ; Vol. 192, No. 5. pp. 2035-2041.
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