METHODS: Allergy is an immune system disorder which is elicited by the allergen-mediated-clustering of the IgE/FceRI complexes on surface of mast cells and basophils. Our ultimate goal in this project is to engineer hetero-bivalent inhibitors (HBIs) that selectively inhibit allergen from binding to IgE on mast cells and basophils, thereby inhibiting clustering of the IgE/FceRI complexes before the allergic response occurs. This is accomplished via designing HBIs that simultaneously target two nearby sites located on the Fab domain of an IgE, the antigen binding site and the less renowned “unconventional nucleotide binding site”. Simultaneous bivalent binding to both these sites provide HBI with enhanced avidity and selectivity for the target IgE, and enabled competitive inhibition of allergen binding to the IgEs.
RESULTS: First, we used the nanoallergen system (developed in our labs) to identified the immunodominant epitopes of peanut allergens to aid in the design of HBIs. We demonstrated that the engineered HBIs inhibit degranulation in RBL cells primed with IgE from patient sera when peanut allergen proteins are introduced. Importantly, we also established the safety of HBIs through toxicology studies in mice.
CONCLUSIONS: Our results indicate that inhibition of the allergen protein-IgE interaction with HBIs can in turn inhibit the allergic reaction.