A therapeutic Fc gamma Fel d1 chimeric protein vaccine to treat cat allergy

描述（由申请人提供）：这个2期SBIR提案的总体目标是开发和商业化一种新的生物制剂，用于过敏原特异性免疫治疗，作为猫过敏/哮喘的有效治疗。猫过敏很常见，17%的美国6-59岁人口对猫的皮肤测试呈阳性，其中60%的人在接触猫皮屑时出现症状。猫过敏原Fel d1特别普遍，因为空气中猫皮屑颗粒很小，是目前过敏性哮喘流行的关键空气过敏原之一。目前，治疗猫过敏的免疫疗法是有问题的，因为它需要在3-5年的时间里反复去过敏专科医生的办公室，而且通常会引起过敏反应。构成我们新方法的分子是一种基因工程猫过敏原-人类Fc？1种融合蛋白，其设计具有更高的安全性，因此可以作为可注射的免疫疗法(1)具有更高的安全性，(2)在更短的时间内，(3)没有当前过敏原免疫疗法的促过敏作用。在该SBIR的第一阶段，我们创建并表达了一种最佳的猫-人嵌合融合蛋白，并衍生出当前良好生产工艺（cGMP）质量的CHO细胞系，该细胞系已准备好生产良好实验室操作（GLP）毒理学材料。该2期提案包括有望在完成后为全面I/ IIa期临床试验提供强有力的新药研究（IND）申请的研究。为此，我们将实现六个主要目标。目标1：开发生化和基于细胞的测定方法，以表征用于配方开发、GLP毒理学研究和支持cGMP生产的材料；这些检测将在GLP标准操作规程下进行，并有独立的质量保证监督。目标2：进行制剂前和稳定性实验，为转移到cGMP生产厂家做准备。目的3：融合蛋白药物产品的完整细胞系开发、主细胞库生产、cGMP生产和纯化、配方和最终无菌灌装。目标4：开发一种改进的纯化工艺，生产和配制提议的GLP毒理学研究所需的材料。目标5：根据IND申请要求，对2个物种（大鼠和非人类灵长类动物）进行GLP毒理学研究。目标6：准备并向FDA提交IND申请，并与该机构合作批准该申请。第二阶段的成功完成将为启动临床试验奠定基础，以便在美国试验中测试FDG的安全性和有效性。我们设想这种猫过敏融合蛋白平台的成功开发不仅是猫过敏/哮喘的重要新治疗方法，而且是开发这种方法治疗严重IgE介导的食物过敏的标志。

DESCRIPTION (provided by applicant): The overall goal of this phase 2 SBIR proposal is to develop and commercialize a novel biologic for allergen- specific immunotherapy as effective treatment for cat allergy/asthma. Cat allergy is common, with 17% of US population, age 6-59, being skin test positive for cat and 60% of those individuals have symptoms when exposed to cat dander Cat allergen, Fel d1, is particularly ubiquitous because of the small size of the airborne cat dander particles and is one of the key aeroallergens implicated in the current epidemic of allergic asthma. Presently, immunotherapy to treat cat allergy is problematic because it requires repeated visits to the allergists' office over a 3-5 year period and commonly elicits allergic reactions. The molecule that comprises our novel approach is a genetically engineered cat allergen-human Fc?1 fusion protein that is designed for a far greater safety profile so that it can be given as injectable immunotherapy (i) with greater safety, (ii) in a far more rapid time frame and (iii) without the pro-allergic effects of current allergen immunotherapy. In phase 1 of this SBIR, we created and expressed an optimal cat-human chimeric fusion protein and derived a current good manufacturing process (cGMP)-quality CHO cell line that is ready to produce material for good laboratory practice (GLP) toxicology. This phase 2 proposal comprises the studies that are expected to provide a strong Investigational New Drug (IND) application for full-scale Phase I/Phase IIa clinical trials upon completion. To achieve this, we will meet six key Aims. Aim 1: develop biochemical and cell-based assays for characterization of the material to be used for formulation development, GLP toxicology studies and in support of cGMP manufacture; these assays will be run under GLP SOPs with independent Quality Assurance monitoring. Aim 2: perform pre-formulation and stability experiments in preparation for transfer of the to a cGMP manufacturer. Aim 3: complete cell line development, master cell bank production, cGMP manufacture and purification, formulation and final sterile fill on the fusion protein drug product. Aim 4: develop an improved purification process, produce and formulate the material necessary for the proposed GLP toxicology studies. Aim 5: perform GLP toxicology in 2 species (rat and non-human primate) as required for IND filing. Aim 6: prepare and file an IND application with the FDA and work with that agency toward approval of this application. Successful completion of phase 2 would set the stage for the initiation of clinical trials to test the safety and efficacy of FDG in US-based trials. We envision the successful development of this fusion protein platform for cat allergy as not only an important new therapeutic for cat allergy/asthma but also as the sign post for development of this approach for the treatment of severe IgE mediated food allergy.