Inhibition of allergen-specific IgE reactivity by a human Ig Fcγ-Fcε bifunctional fusion protein

Coaggregating FcεRI with FcγRII receptors holds great potential for treatment of IgE-mediated disease by inhibiting FcεRI signaling. We have previously shown that an Fcγ-Fcε fusion protein, human IgG-IgE Fc fusion protein (GE2), could inhibit FcεRI-mediated mediator releases in vitro and in vivo. We sought to test whether GE2 was capable of blocking mediator release from FcεRI cells sensitized with IgE in vivo or in vitro before exposure to GE2, a critical feature for GE2 to be clinically applicable. GE2 was tested for its ability to inhibit Fel d 1–induced mediator release from human blood basophils from subjects with cat allergy, human lung-derived mast cells, human FcεRIα transgenic mice sensitized with human cat allergic serum, and rhesus monkeys naturally allergic to the dust mite Dermatophagoides farinae. Basophils from subjects with cat allergy and lung mast cells degranulate when challenged with Fel d 1 and anti-IgE, respectively. GE2 itself did not induce mediator release but strongly blocked this Fel d 1– and anti-IgE–driven mediator release. GE2 was able to block Fel d 1–driven passive cutaneous anaphylaxis at skin sites sensitized with human serum from subjects with cat allergy in human FcεRIα transgenic mice, but by itself, GE2 did not induce a passive cutaneous anaphylaxis reaction. Finally, GE2 markedly inhibited skin test reactivity to D farinae in monkeys naturally allergic to this allergen, with complete inhibition being observed at 125 ng. GE2 is able to successfully compete for FcεRs and FcγRs on cells presensitized in vitro and in vivo and lead to inhibition of IgE-mediated reactivity through coaggregation of FcεRI with FcγRII.