Novel IgE Inhibitors for the Treatment of Food Allergies
Abstract
Omalizumab is currently the only FDA approved monoclonal anti-IgE therapy. We solved the IgE:omalizumab crystal structure to 2.54 . This structure elucidates the mechanism of omalizumab inhibition of IgE:FcRI and IgE:CD23 interactions, and explains omalizumabs selectivity for free circulating IgE. Surprisingly, the complex structure shares significant similarity with the disruptive IgE inhibitor E2_79, and provides mechanistic insight into the efficiency with which disruptive inhibitors are able to bind to, and accelerate FcRI dissociation from preformed IgE:FcRI complexes. Structural information from the IgE:omalizumab 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1047226
Entities
People
- Theodore Jardetzky
Organizations
- Stanford University School of Medicine