Allergen???Fc-gamma1 proteins to treat food allergy

描述（由申请人提供）：本提案的目标是开发和商业化一种用于治疗严重食物过敏的过敏原特异性免疫疗法的新方法。食物过敏影响约3.5%的美国人口和6%至8%的幼儿。这一数字显然在上升。花生过敏影响约1%的人口，是最严重的食物过敏之一，每年导致3万例急诊室就诊和200多人死亡。标准的基于过敏原蛋白的脱敏——用于过敏性气道疾病的免疫疗法——已被证明是不成功的，而且太危险，不能用于治疗严重的食物，如花生过敏。因此，预防严重食物反应的治疗是一个主要的未满足的需求。我们建议开发和测试花生过敏原(Ara h2)-人Fc(1)嵌合融合蛋白，作为设计用于治疗严重食物过敏的新型过敏原Fc(1)特异性免疫治疗蛋白的整个平台的原型模型。Ara h2-Fc(1)蛋白预计具有显著增强的治疗指数，因为过敏原部分将作为免疫原诱导标准过敏原免疫治疗的益处，而Fc(1)片段具有阻断任何过敏反应的功能。因此，Ara h2-Fc(1)蛋白将作为免疫原而不是过敏原，从而提供一种安全有效的特异性免疫治疗形式。这种方法的基础是广泛的科学研究，表明人类Fc（RIIb）抑制受体能够急性抑制过敏效应机制。这些关于食物过敏的研究将建立在我们成功开发出用于呼吸道过敏的嵌合人类Fc（1-cat）过敏原蛋白的基础上。Tunitas Therapeutics公司与加州大学就开发用于治疗食物过敏的嵌合过敏原fc(1)蛋白的独家许可进行了谈判。目前的提案将为这种治疗方法的商业化道路提供最初的步骤，使用Ara h2（主要的花生过敏原）作为模型系统。具体来说，我们将创建所需的基因，在优化的CHO细胞系统中表达Ara h2-Fc(1)融合蛋白，并纯化得到的嵌合蛋白。然后，我们将证明表达的嵌合蛋白保留了过敏原IgE和Fc（RIIb）结合的关键特征。最后，我们将证明嵌合蛋白在体外或体内都不能诱导过敏反应。花生特异性嵌合疫苗疗法的批准将为绝大多数花生过敏个体提供一个安全、有效的免疫治疗过程。目前一个疗程的免疫治疗费用为1500-2500美元，费用分摊为3-5年。Ara h-Fc(1)蛋白免疫疗法的一个疗程的成本保守地定位在类似的范围内，并且预计只有最严重的花生过敏个体才可能最初选择接受免疫疗法，预计几年内美国的年销售额将达到1 -3亿美元。小灵通398/2590 （Rev. 09/04，重新发布4/2006）页延续格式页

DESCRIPTION (provided by applicant): The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe food allergy. Food allergy affects about 3.5% of the US population and 6% to 8% of young children. It is clearly on the rise. Peanut allergy, which affects around 1% of the population, is among the most severe food allergies, resulting in 30,000 emergency room visits and over 200 deaths per year. Standard allergen protein-based desensitization - immunotherapy as is employed for allergic airways disease - has proven unsuccessful and far too dangerous to use as treatment of severe food, e.g. peanut allergy. Thus treatment to prevent severe food reactions is a major unmet need. We propose to develop and test a peanut allergen (Ara h2)-human Fc(1 chimeric fusion protein as the prototype model for an entire platform of novel allergen-Fc(1 specific immunotherapeutic proteins designed for the treatment of severe food allergy. The Ara h2-Fc(1 protein is predicted to have a marked enhanced therapeutic index as the allergen portion will act as an immunogen to induce the benefits of standard allergen immunotherapy while the Fc(1 piece functions to block any allergic reactions. Thus the Ara h2-Fc(1 protein will act as an immunogen but not an allergen and thereby provide a safe and effective form of specific immunotherapy. Underlying this approach is an extensive body of science showing the ability of human Fc(RIIb inhibitory receptors to acutely inhibit allergic effector mechanisms. These studies on food allergy will build on our success with development of a chimeric human Fc(1-cat allergen protein for respiratory allergy. Tunitas Therapeutics, Inc. has negotiated an exclusive license with the University of California to develop chimeric allergen-Fc(1 proteins for the treatment of food allergy. The current proposal will provide the initial steps on the path to commercialization of this therapeutic approach using Ara h2, the dominant peanut allergen, as a model system. Specifically we will create the required gene, express the Ara h2-Fc(1 fusion protein in an optimized CHO cell system, and purify the resulting chimeric protein. We will then show that the expressed chimeric protein retains the key features of allergen IgE and Fc(RIIb binding. Finally, we will document that the chimeric protein fails to induce allergic reactivity in vitro or in vivo. The approval of a peanut-specific chimeric vaccine therapeutic would be an opportunity to administer a safe, effective course of immunotherapy to the vast majority of peanut-allergic individuals. The current cost of a course of immunotherapy is $1500-2500, with costs spread over a 3-5 year period. With a cost for a treatment course of Ara h-Fc(1 protein immunotherapy conservatively targeted to fall in a similar range and the expectation that only the most severe peanut-allergic individuals may initially choose to receive immunotherapy, annual US sales of $100-300 MM would be expected within several years. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Treatment to prevent severe food reactions is a major unmet medical need. Peanut allergy, which affects around 1% of the population, is among the most severe food allergies, resulting in 30,000 emergency room visits and over 200 deaths per year. The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe food allergy.