Recent advances in the use of genetically engineered negative signaling molecules to treat allergic diseases

This review summarizes current knowledge regarding the control of human mast cell and basophil signaling and recent developments using a new therapeutic platform consisting of a human bifunctional gamma and epsilon heavy chain (Fcgamma-Fcepsilon) protein to inhibit allergic reactivity.

Crosslinking of FcgammaRIIb to FcepsilonRI on human mast cells and basophils by a genetically engineered Fcgamma-Fcepsilon protein (GE2) leads to the inhibition of mediator release upon FcepsilonRI challenge. GE2 protein was shown to inhibit cord blood-derived mast cell and peripheral blood basophil mediator release in vitro in a dose dependent fashion including inhibition of human IgE reactivity to cat. In addition, IgE-mediated release from lung tissue was inhibited through GE2. The mechanism of inhibition in mast cells included alterations in IgE-mediated Ca2+ mobilization, Syk phosphorylation and the formation of Dok-Grb2-SHIP complex. Proallergic effects of Langerhans-like dendritic cells and B cell IgE switching were also inhibited by GE2. In vivo, GE2 was shown to block passive cutaneous anaphylaxis (PCA) driven by human IgE in mice expressing the human FcepsilonRI and inhibit skin test reactivity to dust mite antigen in a dose dependent manner in rhesus monkeys. The balance between positive and negative signaling controls mast cell and basophil reactivity that is critical in the expression of human allergic diseases. This approach using a human Fcgamma-Fcepsilon fusion protein to co-aggregate FcepsilonRI with the FcgammaRII holds promise as a new therapeutic platform for the immunomodulation of allergic diseases and potentially other mast cell/basophil-dependent disease states.