DESCRIPTION (provided by applicant): This translational proposal uses a rapid desensitization approach to develop a safe, effective and rapid way to suppress human IgE-mediated disease. We can already safely, rapidly desensitize mice to all antigens (Ags) by injecting them hourly with doubling doses of an anti-FcϵRIα monoclonal antibody (mAb), starting with a dose too small to elicit a clinical reaction. Using this protocol to treat mice with an anti-FcϵRIα mAb that only binds FcϵRI that is not occupied by IgE: (1) rapidly induces short-lived suppression of IgE/FϵRI signaling; and (2) slowly removes all mast cell membrane FcϵRI and IgE, even in mice that have high serum IgE levels. In mice, our approach is safer than rapid desensitization with Ag and can safely be maintained indefinitely by repeated injection of anti-FcϵRIα mAb. We will now adapt this approach to humans, make it more rapid, and make it even safer. Aim 1 uses an anti-human (hu) FcϵRIα mAb that has characteristics similar to our anti-mouse FcϵRIα mAb to desensitize: (1) huIgE-treated transgenic mice that express huFcϵRIα instead of mouse FcϵRIα; and (2) immunodeficient NOD/SCID mice that lack the cytokine receptor common ? chain, express transgenic huSCF, huIL-3, and huGM-CSF and have been reconstituted with human cord blood cells (these mice secrete human IgE and generate human mast cells and basophils). We also modify our desensitization protocol to make it more compatible with potential human use by injecting anti-huFcϵRIα mAb subcutaneously instead of intraperitoneally. Aim 2 accelerates desensitization with antihuFcϵRIα mAb by using a commercially available mAb that removes all mast cell huFcϵRI, regardless of its IgE occupancy. We also generate our own mAb that has this property so that we can modify its structure in Aim 3. Aim 3 increases the safety of rapid desensitization with anti-huFcϵRIα mAb. We further suppress any clinical reactions that might occur during rapid desensitization by: (1) inhibiting H1 and H2 receptors; (2) inhibiting the tyrosine kinase syk; and (3) engineering anti-FcϵRIα mAb to bind more avidly to the inhibitory receptor, FcγRIIb. Successful completion of these aims could provide a way to safely and rapidly protect against all FcϵRI-mediated disease.

PUBLIC HEALTH RELEVANCE: Mast cell/basophil activation mediated by IgE and FcϵRI is central to immediate hypersensitivity disorders. Omalizumab, a mAb that binds IgE that is not bound to FcϵRI, is useful for treating severe asthma and shows promise in the treatment of other allergic disorders, but is ineffective in individuals who have very high IgE levels and is relatively slow-acting. Our novel therapeutic approach should be more rapid and effective.