Accentuate the negative, eliminate the positive: Engineering allergy therapeutics to block allergic reactivity through negative signaling

By targeting the dominant-negative signaling receptor Fc gamma RIIb expressed on proallergic cells, we have developed 2 novel platforms for the treatment of IgE-mediated allergic disease. First is a genetically engineered bifunctional human fusion protein GE2, which is comprised of the Fc portions of human IgE and IgG1 with an interposed flexible linker designed as a long-term parenteral allergen-nonspecific therapy. GE2 blocks the effector phase of the IgE response in vitro in mice and human subjects and in vivo in the skin and airway and systemically in mice and monkeys. Whether reactivity against human GE2 in human subjects will limit its applicability remains to be determined. The second platform is designed to provide a safer form of allergen-specific immunotherapy and consists of genetically engineered chimeric human Fc gamma-allergen proteins, with Fc gamma-Fel d 1 as the prototype. The allergen portion binds to specific IgE on Fc epsilon Rs, whereas the Fc gamma portion coaggregates inhibitory Fc gamma RIIb and drives inhibition of allergic reactivity. Fc gamma-Fel d 1 blocked human mast cell Fel d 1-induced allergic reactivity in vitro and in vivo in murine models while functioning as an immunogen but not as an allergen.