Broadly neutralizing(BN) pan-IgE supersite vaccine for allergic asthma

ABSTRACT SUMMARY Immunoglobulin EIgEin the lung plays a key role in allergic asthmatic inflammationAsthmatic patients also exhibit elevated serum IgE levelswhich may re equilibrate with the lung IgE pool or enhance IgE mediated allergic asthmaA seminal finding of IgE downregulation by active IgE immunization was first reported in our labThis led to the product concept of the mAb omalizumaband a subsequent collaboration with the pharmaceutical industry led to FDA approval of the XolairIn the proposed projectthe native conformation of receptor binding IgE loopse gthe Xolairbinding FG loop epitopeare conformationally constrained in a selected thermostable b strand pairdubbed super b strandsand then fused to an immunogenic and thermostable protein scaffold as a bifunctional vaccineThe use of ImiquimodIMQMIncthrough a safe transcutaneous route of administrationfollowed by vaccine IN challenge in salineensures that mucosal IgA and IgG subclass anti IgE antibodies target asthmogenic lung IgE as well as the removal of serum IgE by systemic anti IgE antibodiesThis specific targeting improves safetyand is unlikely to cause typehypersensitivity or chronic urticariaIn the absence of a vaccine reboostemerging anti IgE producing B cells are naturally tolerized by the endogenous self IgE recovered during the rest period as another safety featureAjust in timevaccine reboost is required to break self IgE tolerance to protect against allergen re exposureThe lack of persistent IgE suppression preserves IgE competence for parasitic defensesOur three aims areAimStudy immunogenicity of human FG supersite vaccine in rodentslocationdurationand efficaciesAimEvaluate therapeutic vaccination in alleviating IgE mediated asthmatic inflammation and AHR in rodent modelsAimEvaluate therapeutic vaccination in alleviating IgE mediated asthmatic inflammation and AHR in rhesus macaques Project Narrative Allergic asthma afflictsmillion people in the USincludingmillion childrenof adult asthma cases are not related to allergyImmunoglobulin EIgEin the lung plays a key role in allergic asthmatic inflammationStudies of Xolairhave shown that IgE is a central mediator of asthmatic inflammation in human allergic asthmaAdministration of Xolairis known to improve severe asthmatic syndromes of inner city asthmatics by ameliorating IgE mediated responses and reducing IgE amplified innate immunity to pathogenic house dust mitesHDMcockroachesand pet allergensNEJMA seminal finding of downregulating IgE by active immunization was first reported in our labThis led to the product concept of the mAb anti IgE omalizumaband a subsequent collaboration with the pharmaceutical industry led to the FDA approval of the productXolairIgE binding loops to FceRI on mast cellse gthe Xolairbinding FG loop epitopethat are appropriately conformationally constrained can serve as a therapeutic pan IgE supersite active vaccine for eliciting broadly neutralizingBNanti IgE antibodies to neutralize as well as to remove IgE from cells and inflammatory tissuesThereforethis phaseProject aims to develop a BN pan IgE supersite vaccineThe high cost of Xolair$to $per patientlimits its availability to onlysevere asthmaticswhile the low vaccine cost renders it affordable tomillion patients with mildmoderatemoderate to severeand severe allergic asthma in the USThereforedeveloping this innovative pan IgE vaccine product will meet the market need