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

University of California, Los Angeles, Los Ángeles, California, United States
Journal of Allergy and Clinical Immunology (Impact Factor: 11.48). 09/2004; 114(2):321-7. DOI: 10.1016/j.jaci.2004.03.058
Source: PubMed


Coaggregating FcepsilonRI with FcgammaRII receptors holds great potential for treatment of IgE-mediated disease by inhibiting FcepsilonRI signaling. We have previously shown that an Fcgamma-Fcepsilon fusion protein, human IgG-IgE Fc fusion protein (GE2), could inhibit FcepsilonRI-mediated mediator releases in vitro and in vivo.
We sought to test whether GE2 was capable of blocking mediator release from FcepsilonRI 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 FcepsilonRIalpha 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 FcepsilonRIalpha 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 FcepsilonRs and FcgammaRs on cells presensitized in vitro and in vivo and lead to inhibition of IgE-mediated reactivity through coaggregation of FcepsilonRI with FcgammaRII.

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    • "This concept was exploited in recent studies using two novel bio-engineered fusion proteins, one that consists of human Fc regions of IgG1 and IgE linked together and another a fusion protein made by linking an allergen to human IgG1 Fc region[73]. These proteins block pro-inflammatory mediator and cytokine release from allergic cells and prevent skin, lung and systemic allergic reactivity in a murine model[16], [73]–[77]. Our study demonstrates that FcγRIIb-dependent regulatory mechanism(s) control allergic airway inflammation, making this inhibitory receptor a physiologically relevant therapeutic target in allergic asthma. "
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    Full-text · Article · Feb 2010 · PLoS ONE
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    Full-text · Article · Jun 2006 · The Journal of Immunology
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