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

描述(由申请人提供)：这一第二阶段SBIR提案的总体目标是开发一种新的生物过敏原特异性免疫疗法并将其商业化，作为猫过敏/哮喘的有效治疗方法。猫过敏很常见，在6-59岁的美国人口中，有17%的人皮肤测试对猫呈阳性，其中60%的人在接触猫皮屑猫变应原FEL D1时出现症状，由于空气中猫皮屑颗粒较小，因此尤其普遍，是目前过敏性哮喘流行所涉及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经过基因工程的猫过敏原-人类Fc？1融合蛋白，它的设计具有更高的安全性，因此它可以作为可注射免疫疗法使用，(I)更安全，(Ii)在更快的时间范围内，(Iii)不会出现目前过敏原免疫疗法的亲过敏效应。在这项SBIR的第一阶段，我们创造并表达了最佳的猫-人嵌合融合蛋白，并获得了目前良好的制造工艺(CGMP)质量的CHO细胞系，该细胞系准备好生产良好实验室规范(GLP)毒理学材料。这项第二阶段的建议包括的研究预计将在完成后为全面的第一阶段/第二阶段临床试验提供强有力的研究性新药(IND)应用。为了实现这一目标，我们将实现六个主要目标。目标1：开发生化和基于细胞的分析方法，对用于配方开发、GLP毒理学研究和支持cGMP生产的材料进行表征；这些分析将在GLP SOP下运行，并有独立的质量保证监测。目的2：进行处方前试验和稳定性试验，为转移到cGMP生产厂家做准备。目的3：完成细胞系的培养，掌握细胞库的生产，cGMP的制备和纯化，融合蛋白药物产品的配制和最终的无菌填充。目的4：开发改进的纯化工艺，生产和配制拟议的GLP毒理学研究所需的材料。目的5：按照IND备案的要求，对2种动物(大鼠和非人灵长类)进行GLP毒理学检测。目标6：准备并向FDA提交IND申请，并与该机构合作批准这一申请。第二阶段的成功完成将为启动临床试验奠定基础，以在美国的试验中测试FDG的安全性和有效性。我们认为，这一猫过敏融合蛋白平台的成功开发，不仅是治疗猫过敏/哮喘的重要新疗法，也是开发这一方法治疗严重IgE介导的食物过敏的标志。 公共卫生相关性：严重吸入性过敏的有效治疗是一个主要的未得到满足的医疗需求，猫过敏是涉及的关键过敏原之一。在美国，有症状的猫过敏影响着3000万人，也是30%(300万)哮喘病例的主要诱因。猫过敏原，由于其所在颗粒物的物理特性，基本上在学校、公共建筑和家庭中无处不在。免疫疗法(过敏针)有效，但其治疗指数相对较低，依从性较差，因为需要在较长时间内多次注射，并伴随相关的局部甚至全身反应。这项提议的目标是开发一种新的猫过敏疫苗并将其商业化，该疫苗将比目前的治疗方法更安全、更快、更有效。

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. PUBLIC HEALTH RELEVANCE: Effective treatments to for severe inhalant allergy represent a major unmet medical need with cat allergy being one of the key allergens involved. Symptomatic cat allergy affects 30 million people in the United States and is primary trigger for 30% (3 million) asthma cases as well. Cat allergen, because of the physical characteristics of the particles it is on is essentially ubiquitous in schools, public buildings and homes. Immunotherapy (allergy shots) works but it has a relatively low therapeutic index and poor compliance due to the need for multiple injections over a prolonged period of time with associated local and even systemic reactions. The goal of this proposal is to develop and commercialize a novel cat allergy vaccine that will be safer, faster and more effective than the current treatments.