Peanut allergy has become a major health problem in the United States and the prevalence among young children appears to be increasing. Standard immunotherapy with unmodified peanut extracts was found to have an unacceptable risk:benefit ratio, due to the frequent provocation of adverse allergic reactions. We have developed """"""""engineered,"""""""" recombinant peanut proteins in which IgE-binding regions (epitopes) have been altered by the substitution of specific amino acids. These proteins bind minimal IgE but retain their ability to stimulate T cells. In a murine model of peanut anaphylaxis, heat-killed E. coli expressing and retaining (encapsulating) the modified forms of the three major peanut allergens, Ara h1, 2, and 3 (i.e. E. coli-containing engineered Modified Protein of Ara h?1?, ?2?, and ?3?, or """"""""EMP-123"""""""") administered rectally dramatically reduced the peanut allergic response without provoking allergic reactions during treatment. The overall goal of this project is to investigate the safety and efficacy of this novel immunotherapeutic agent, EMP-123, for the treatment of peanut allergy in humans. We will conduct an open-label Phase I clinical trial to assess the safety of EMP-123 when administered in suppository form to peanut-allergic subjects. In parallel, we will assess immunologic markers that may predict the response to immunotherapy and make a preliminary assessment of the efficacy of EMP-123 as determined by a double-blind, placebo-controlled peanut challenge (DBPCPC) following therapy. We will then conduct a multicenter Phase II clinical trial to assess the ability of EMP-123 to reduce the risk of peanut-allergic reactions by comparing the change in peanut tolerability thresholds in peanut-allergic subjects treated with EMP-123 compared to subjects treated with placebo. The tolerability threshold, defined as the quantity (dose) of peanut tolerated prior to the development of allergic symptoms, will be determined by dose-escalating DBPCPC before and after therapy. In addition, we will assess the effects of EMP-123 on a number of immunologic parameters, including prick skin test titration and peanut-specific basophil activation, investigate immunomodulatory mechanisms induced by EMP-123, and characterize the safety of EMP-123 in subjects with peanut allergy by determining the incidence of all adverse events throughout the duration of the study. If successful, this project could provide a safe and effective therapy for peanut allergy.
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