Novel IgE Inhibitors for the Treatment of Food Allergies
Technical Report,30 Sep 2014,29 Sep 2015
LeLandStanford University School of Medicine Stanford United States
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Omalizumab is currently the only FDA approved monoclonal anti-IgE therapy. We solved the IgEomalizumab crystal structure to 2.54 . This structure elucidates the mechanism of omalizumab inhibition of IgEFcRI and IgECD23 interactions, and explains omalizumabs selectivity for free circulating IgE. Surprisingly, the complex structure shares significant similarity with the disruptive IgE inhibitor E279, and provides mechanistic insight into the efficiency with which disruptive inhibitors are able to bind to, and accelerate FcRI dissociation from preformed IgEFcRI complexes. Structural information from the IgEomalizumab complex was used to generate a point mutation in the IgE-Fc, yielding an omalizumab-resistant IgE. Omalizumab-resistant IgE, in combination with omalizumab, promotes the exchange of the IgE repertoire on human basophils. This combination treatment demonstrates the possibility of substituting rather than depleting the IgE repertoire, thereby exchanging harmful, allergen-specific IgE while maintaining endogenous IgE-dependent regulatory mechanisms that may further suppress the allergic response.