Modifications to an Fcgamma-Fcvarepsilon fusion protein alter its effectiveness in the inhibition of FcvarepsilonRI-mediated functions

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Christopher Kepley, Associate Professor (Creator)
The University of North Carolina at Greensboro (UNCG )
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Abstract: Background: GE2, a human bifunctional Fcg-Fce fusion protein cross-links FcgRIIb and FceRI on human mast cells and basophils and results in inhibition of FceRI-mediated functions. Objective: Three modified Fcg-Fce (GE) proteins were compared with GE2 for their effect on inhibition of FceRI-mediated cellular responses. Methods: GE2 was modified to potentially improve its therapeutic efficacy by increasing binding to FcgRIIb (GE S mutant) and decreasing binding to FcgRIII (GE H mutant) or reversing the Fcg and Fce domains and removing nonhuman linker sequences (E2G). These proteins were tested for their ability to bind a basophil-like cell line, block FceRI-mediated degranulation in human basophils, and inhibit passive cutaneous anaphylaxis in human FceRIa-transgenic mice. Results: All 4 GE proteins bound cells that express FceRI and FcgRIIb, although the original GE2 retained the strongest ability to bind to these cells. E2G was as effective as GE2 in its ability to inhibit anti-Fel d 1 IgE-mediated histamine release from human basophils and block passive cutaneous anaphylaxis reactions. The GE S and GE H mutants were less effective. Conclusion: Optimization of GE2 as an inhibitor of FceRI-mediated functions showed that effectiveness was maintained when potentially immunogenic linker sequences were removed and Ig domain positions were reversed, but specific residue changes within the IgG CH2 domain aimed at enhancing GE2's inhibitory function by increasing FcgRII binding or additionally decreasing FcgRIII binding were not beneficial.Clinical implications: GE2 and E2G molecules are effective inhibitors of FceRI-mediated degranulation and are of interest as potential therapeutics for IgE-mediated allergic reactions.

Additional Information

Journal of Allergy and Clinical Immunology 2007; 120(2):462-8.
Language: English
Date: 2007
GE2, IgE, IgG, FceRI, FcgRIIb, allergy

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