Cat allergen-human Fc-gamma1 chimeric proteins to treat cat allergy

描述（由申请人提供）：本SBIR提案的总体目标是开发和商业化一种用于治疗猫过敏的过敏原特异性免疫疗法的新方法。该提案将为一种非常重要的吸入性过敏原提供一种新的治疗方法，并作为将这种方法应用于其他关键过敏原的模型。诱导吸入性变态反应（变应性鼻炎和变应性哮喘）的“变应性耐受”的有效治疗代表了主要的未满足需求，这是由IgE介导的变应性气道疾病的患病率和发病率增加驱动的。猫过敏原Fel d1是无处不在的，因为空气中猫皮屑的尺寸很小。17%的美国人口，年龄在6-59岁之间，对猫过敏原Fel d1的皮肤测试呈阳性，其中60%的人在暴露于猫皮屑时会出现症状。美国有近7800万只猫，40%的哮喘患者对Fel d1敏感，暴露于猫皮屑是全球哮喘高患病率的主要原因。虽然传统的免疫疗法在某些情况下有效地减少哮喘症状，但患有严重急性支气管痉挛或慢性哮喘的患者在3-5年的方案期间可能仍然严重受损，并且遭受依从性差和不良反应。我们建议开发和测试猫过敏原Fel d1-人Fc β 1嵌合融合蛋白作为新型过敏原-Fc β 1特异性免疫抑制蛋白的整个平台的原型模型，该蛋白设计用于治疗许多特定的过敏性疾病，包括最终的严重食物过敏。基于我们已经产生的大量数据以及其他人的数据，我们的假设是变应原-人Fc β 1嵌合蛋白将作为免疫原而不是变应原起作用，因此将提供一种机制上不同且更有效形式的变应原特异性免疫疗法。该提案将概述该方法商业化道路上的关键实验临床前步骤。我们已经确定了一种先导化合物- Fel d1-人Fc（1 -），并在体外和体内模型中证明了其治疗效果。基于这种最初的嵌合人31-猫过敏原蛋白用于呼吸道过敏的成功，我们希望继续其开发。在这个提议中，我们将创建并表达最佳的猫人嵌合融合蛋白，确认表达的嵌合蛋白保留了过敏原的关键特征，例如，完全IgE结合加上人Fc的关键功能特性（例如，Fc（RIIb）结合，证明嵌合蛋白不能诱导过敏反应性，并衍生出高水平表达的细胞系，准备生产用于GLP毒理学的材料。Tunitas Therapeutics，Inc.已经与加州大学谈判了开发用于治疗过敏的嵌合过敏原-Fc β 1蛋白的独家许可。该提案将为这种治疗药物的商业化提供关键的初始步骤。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Fel d1-Fc（1蛋白免疫治疗保守目标的疗程成本在类似范围内，并且预期只有最严重的猫过敏个体最初可能选择接受免疫治疗，预计几年内美国的年销售额将达到1.5亿美元。 公共卫生相关性：主要研究者/项目负责人（最后、第一、中间）：叙述：猫过敏原-人Fc-γ 1嵌合蛋白治疗猫过敏诱导吸入性过敏/哮喘过敏耐受的有效治疗是一项主要未满足的医疗需求。美国有近7800万只猫，40%的哮喘患者对猫过敏，接触猫过敏原是全球哮喘高患病率的主要原因。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，用于治疗严重的猫过敏。

DESCRIPTION (provided by applicant): The overall goal of this SBIR proposal is to develop and commercialize a new approach for allergen specific immunotherapy as treatment for cat allergy. This proposal will provide a novel therapeutic for a very important inhalant allergen and serve as a model for the application of this approach to other key allergens. Effective treatments to induce "allergic tolerance" for inhalant allergy (allergic rhinitis and allergic asthma) represent a major unmet need, driven by the increasing prevalence and incidence of IgE mediated allergic airway disease. The cat allergen Fel d1 is ubiquitous because of the small size of the airborne cat dander. 17% of US population, age 6-59, is skin test positive for cat allergen Fel d1 and 60% of those individuals have symptoms when exposed to cat dander. With nearly 78 million cats in the US and 40% of asthmatics sensitive to Fel d1, exposure to cat dander is a major contributor to the high prevalence of asthma throughout the world. While conventional immunotherapy is effective in reducing asthma symptoms in some cases, patients with severe acute bronchospasm or chronic asthma can remain seriously compromised during the 3-5 year regimen and suffer from the poor compliance and adverse reactions. We propose to develop and test a cat allergen Fel d1- 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 a number of specific allergic diseases, including ultimately severe food allergy. Our hypothesis, based on body of data we have generated as well as that of others is that an allergen-human Fc(1 chimeric protein will function as immunogen but not an allergen and thus will provide a mechanistically distinct and more effective form of allergen specific immunotherapy. This proposal will outline the key experimental pre-clinical steps on the path to commercialization for this approach. We have identified a lead compound - Fel d1-human Fc(1 - and have demonstrated its therapeutic efficacy in both in vitro and in vivo models. Building on the success with this initial chimeric human 31-cat allergen protein for respiratory allergy, we wish to continue its development. In this proposal, we will create and express an optimal cat human chimeric fusion protein, confirm that the expressed chimeric protein retains the key feature of the allergen, e.g., full IgE binding plus the key functional property of the human Fc(, e.g., Fc(RIIb binding, document that the chimeric protein fail to induce allergic reactivity, and derive a high level expressing cell line ready to produce material for GLP toxicology. Tunitas Therapeutics, Inc. has negotiated an exclusive license with the University of California to develop chimeric allergen-Fc(1 proteins for the treatment of allergy. This proposal will provide the critical initial steps on the path to commercialization of this therapeutic. 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 Fel d1-Fc(1 protein immunotherapy conservatively targeted to fall in a similar range and the expectation that only the most severe cat-allergic individuals may initially choose to receive immunotherapy, annual US sales of $150 MM would be expected within several years. PUBLIC HEALTH RELEVANCE: Principal Investigator/Program Director (Last, First, Middle): Narrative: Cat allergen-human Fc-gamma1 chimeric proteins to treat cat allergy Effective treatments to induce allergic tolerance for inhalant allergy/asthma represent a major unmet medical need. With nearly 78 million cats in the US and 40% of asthmatics allergic to cats, exposure to cat allergen is a major contributor to the high prevalence of asthma throughout the world. The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe cat allergy.