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

过敏原???Fc-gamma1蛋白治疗食物过敏

• 批准号: 7807490
• 负责人: ANDREW SAXON
• 金额: $ 17.24万
• 依托单位: TUNITAS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807490
• 关键词: Accident and Emergency department; Affect; Allergen Immunotherapy; Allergens; Allergic; Allergic Reaction; Allergy to peanuts; Animal Model; Antigens; Basophils; Binding; Biological Markers; Biological Models; California; Cells; Cessation of life; Characteristics; Child; Chimeric Proteins; Chinese Hamster Ovary Cell; Data; Development; Emergency Situation; Engineering; FUS-1 Protein; Fc Immunoglobulins; Felis catus; Food; Food Hypersensitivity; Future; Gene Expression; Genes; Goals; Human; Hypersensitivity; Hypersensitivity skin testing; IgE; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Lead; Leg; Licensing; Measures; Mediation; Mediator of activation protein; Medical; Modeling; Mus; Peanuts - dietary; Phase; Population; Principal Investigator; Production; Proteins; Reaction; Sales; Science; Small Business Technology Transfer Research; Staging; System; Testing; Therapeutic; Therapeutic Index; Universities; Visit; allergic airway disease; base; commercialization; cost; desensitization; effective therapy; efficacy testing; expectation; falls; food allergen; in vivo; mast cell; novel; novel strategies; prevent; programs; prototype; public health relevance; receptor; respiratory protein; success; therapeutic vaccine; therapy design

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.

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过敏原特异性免疫疗法的新方法，用于治疗严重食物过敏。食物过敏影响约3.5%的美国人口和6%至8%的幼儿。这显然是在上升。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30，000次急诊和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，并且太危险而不能用作严重食物（例如花生过敏）的治疗。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 β 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 β 1特异性免疫抑制蛋白的整个平台的原型模型。预计Ara h2-Fc β 1蛋白具有显著增强的治疗指数，因为过敏原部分将充当免疫原以诱导标准过敏原免疫疗法的益处，而Fc β 1片段起到阻断任何过敏反应的作用。因此，Ara h2-Fc β 1蛋白将作为免疫原而不是过敏原，从而提供安全有效形式的特异性免疫疗法。该方法的基础是大量的科学研究，其显示人Fc（RIIb）抑制性受体急性抑制过敏效应机制的能力。这些关于食物过敏的研究将建立在我们成功开发用于呼吸道过敏的嵌合人Fc（1-猫过敏原蛋白的基础上。Tunitas Therapeutics，Inc.已经与加州大学谈判了开发用于治疗食物过敏的嵌合过敏原-Fc β 1蛋白的独家许可。目前的提案将提供使用Ara h2（主要的花生过敏原）作为模型系统的这种治疗方法商业化的初步步骤。具体而言，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 β 1融合蛋白，并纯化所得嵌合蛋白。然后，我们将表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不能在体外或体内诱导过敏反应。花生特异性嵌合疫苗治疗药物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的机会。目前一个疗程的免疫治疗费用为1500 -2500美元，费用分摊在3-5年内。由于Ara h-Fc（1蛋白免疫疗法保守目标的治疗过程的成本落在类似范围内，并且预期只有最严重的花生过敏个体最初可能选择接受免疫疗法，预计几年内美国的年销售额将达到100 -300 MM。PHS 398/2590（2004年9月修订，2006年4月重新印发） 公共卫生相关性：预防严重食物反应的治疗是一个主要的未满足的医疗需求。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30，000次急诊和200多人死亡。该提案的目标是开发和商业化一种用于过敏原特异性免疫疗法的新方法，作为严重食物过敏的治疗。