CTL for supertype natural IgE cytotoxic peptide (nECP) to guard against allergic asthma

DESCRIPTIONprovided by applicantAllergic asthma is a multi faceted inflammatory disease in the lungIgE and Thmediated inflammation play a critical role in extrinsic allergic asthmaOur labs have identified naturally processed IgE cytotoxic peptidesnECPon IgE producing cellswhich serve as CTL vaccineThe feasibility of using nECP with helper peptide PADRE as a universal IgE vaccineor vaccineto treat severe IgE mediated allergic asthma is due to the following observationspreliminary resultsibroad coverage of nECP supertype based product concept for pan IgE vaccine can be designed and applied to broad coverage of ethnically unbiased populationSecondprogress was made for vaccine delivery platformse gtranscutaneous immunization with nECP PADRE in an FDA approved imiquimod for topical usefollowed by nECP PADRE in saline intranasallyINThe mucosal immunization stimulating dendritic cellsDCsand CDT cells enriched the lung to protect against IgE production in the rodent modeliiisafety of the vaccine in its unique IgE isotype suppressionwhile sparing other antibody isotypesand IgE recovery after the treatment windowivtesting human supertype nECP in the HLA AB tg rodentsand in particular testing IgE suppression by in vitro nECP CTL immunization of human PBMCswhich suppress human IgE productionThe goal is to develop a commercial product of supertype based universal IgE peptide vaccine with broad HLA AB supertype coverage to treat IgE mediated severe asthmaThe vaccine will suppress human IgE producing B cells plasma cellsincluding long lived plasma cells in human lung in a safe IgE isotype specific therapeutic windowpermitting IgE recovery and parasite defenseThe top priority is to compete studies in the rodent model and supertype composition of human nECP vaccineThe next Development Phase will require venture capitalthe pharmas capital or licensing revenuewhich is dependent on the completion of Research Phase of the three Aims proposed through this SBIR grant application for CMC or cGMP of vaccine manufactureOur three aims are as followAimEvaluate efficacy and safety of a universal nECP asthma vaccine in the rodent model AimEvaluate the routes and mechanisms of therapeutic vaccination AimEvaluate a universal human nECP supertype asthma vaccine forpopulation coverage Milestones AimAimAimYearProtection and recovery cycleevaluating different helper peptides for sustaining protective CDT cell responsestolerant unresponsive CDT cells and restore responsiveness breaking toleranceThe role of cDCs in the skin via TCI vaccination by FACS and analysis of migratory cDCs by T cell stimulationthe role cDCs via NALT and nasal tract in the Bmodelfunction of cDCs excluding blood monocytesEvaluate high affinity human nECPs in Aand more BAsupertypes in inhibiting canonical peptide binding to purified HLA ABYearAnalysis of changes in Bcells and IgE plasma cells following CTL attackIgE clearancechanges in submucosal mast cellsIgEmast cell axis after TCI IN vaccinationAHR and Airway Remodeling analysisAnalysis of langerinDTR knockout of migratory CDcDCsAnalysis of TCMTEM and TRM In lymphoid and nonlymphoid organs after TCI or IN or TCI INlongevity of each subset with without PADREin vivo conversion of TEM vsTRMthe role of TCMTg studies for Asupertypes in A Kb tg miceand more Band Asupertypes in BAtg micehigh resolution mapping in human PBMCalso cryopreserved for a large aliquotsfor combined supertype epitopes for vitro CTL for IgE suppression in vitroYearConfirm protection in airway inflammation and AHR in the Aspergillus fumigatus and cockroach models using TCI IN vaccinationAnalysis of trafficking in langerinCDcDCs depletion alone vscombined CDcDCs and CDTRM in CDknockout miceInvestigating the strength magnitude by IFNspots and lytic potential and quality of CTL of multiple supertype induced culturesand expand into three additional supertypesAAand Bfor high percentage human coverage