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

描述(由申请人提供)：这项SBIR提案的总体目标是开发一种新的过敏原特异性免疫疗法并将其商业化，作为猫过敏的治疗方法。这项提议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，并为将这种方法应用于其他关键过敏原提供一个模型。对吸入性过敏(过敏性鼻炎和过敏性哮喘)诱导“过敏性耐受”的有效治疗是一个尚未得到满足的主要需求，其驱动因素是IgE介导的过敏性呼吸道疾病的患病率和发病率不断增加。猫变应原FEL-D_1因猫毛皮屑体积较小而普遍存在。17%的美国人口，年龄在6-59岁之间，皮肤测试对猫过敏原FEL-D1呈阳性，其中60%的人在接触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，接触猫皮屑是全球哮喘高发的主要原因。虽然常规免疫疗法在某些情况下能有效缓解哮喘症状，但严重的急性支气管痉挛或慢性哮喘患者在3-5年的治疗方案中仍会严重受损，依从性差，并出现不良反应。我们建议开发和测试猫变应原FEL D1-人Fc(1)嵌合融合蛋白作为整个新型变应原-Fc(1特异性免疫治疗蛋白)平台的原型模型，设计用于治疗许多特定的过敏性疾病，包括最终严重的食物过敏。我们的假设是，基于我们产生的大量数据以及其他人的假设，过敏原-人类Fc(1)嵌合蛋白将作为免疫原发挥作用，但不是过敏原，因此将提供一种机械上独特的、更有效的过敏原特异性免疫治疗形式。该提案将概述该方法商业化道路上的关键实验前临床步骤。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。在首个用于呼吸道过敏的人31猫变应原嵌合蛋白成功的基础上，我们希望继续开发它。在这项建议中，我们将创造和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，例如完整的IgE结合以及人Fc(RIIb结合)的关键功能特性，证明嵌合蛋白未能诱导过敏反应，并获得高水平表达的细胞系，准备生产GLP毒理学材料。Tunitas Treateutics，Inc.已经与加州大学谈判达成了一项独家许可，开发嵌合过敏原Fc(1蛋白质)用于治疗过敏。这项提议将为这种治疗药物的商业化道路提供关键的初步步骤。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年期间。由于FEL D1-FC(1蛋白质免疫疗法)疗程的费用保守地落在类似的范围内，而且预计只有最严重的猫过敏患者最初可能会选择接受免疫疗法，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：首席调查员/项目主任(最后、第一、中间)：叙述：猫过敏原-人Fc-Gamma1嵌合蛋白治疗猫过敏有效治疗吸入性过敏/哮喘的过敏耐受是一个主要的未得到满足的医疗需求。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发的主要原因。这项提议的目标是开发一种新的过敏原特异性免疫疗法并将其商业化，作为治疗严重猫过敏的方法。

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.