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

描述（由申请方提供）：该2期SBIR提案的总体目标是开发和商业化一种用于过敏原特异性免疫治疗的新型生物制剂，作为猫过敏/哮喘的有效治疗方法。猫过敏是常见的，17%的美国人口，年龄6-59岁，是皮肤试验阳性的猫和60%的人有症状时，暴露于猫皮屑猫过敏原，Fel d1，是特别普遍的，因为空气中的猫皮屑颗粒的小尺寸，是一个关键的空气过敏原牵连在目前流行的过敏性哮喘。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年的时间内反复访问过敏症医生的办公室，并且通常会引起过敏反应。分子，包括我们的新方法是一种基因工程猫过敏原-人Fc？1融合蛋白，其被设计用于更大的安全性特征，使得其可以作为注射免疫疗法给予（i）具有更大的安全性，（ii）在更快的时间范围内，和（iii）没有当前过敏原免疫疗法的促过敏作用。在该SBIR的第1阶段，我们创建并表达了最佳的猫-人嵌合融合蛋白，并获得了当前良好生产工艺（cGMP）质量的CHO细胞系，该细胞系可用于生产药物非临床研究质量管理规范（GLP）毒理学材料。该2期提案包括预计将在完成后为全面I期/IIa期临床试验提供强有力的研究性新药（IND）申请的研究。为了实现这一目标，我们将实现六个关键目标。目标1：开发生物化学和基于细胞的试验，以表征用于制剂开发、GLP毒理学研究和支持cGMP生产的材料;这些试验将根据GLP SOP进行，并进行独立的质量保证监测。目的2：进行处方前和稳定性实验，准备转移至cGMP生产商。目标3：完成细胞系开发、主细胞库生产、cGMP生产和纯化、配制和融合蛋白制剂的最终无菌灌装。目的4：开发一种改进的纯化工艺，生产和配制拟定GLP毒理学研究所需的材料。目的5：按照IND备案的要求，在2个种属（大鼠和非人灵长类动物）中进行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临床试验的启动奠定基础，以测试FDG在美国试验中的安全性和有效性。我们设想这种用于猫过敏的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，而且也是开发这种用于治疗严重IgE介导的食物过敏的方法的标志。

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.