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.