Therapeutic peanut allergen Fc gamma chimeric proteins to treat peanut allergy

描述(由申请人提供)：这一第二阶段STTR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，作为治疗严重食物过敏的一种方法。目前，预防严重食物反应的治疗是一项尚未得到满足的主要需求。没有有效的治疗方法，唯一的治疗方法是严格避免，并在发生接触时采取紧急措施。组成这个平台的分子是基因工程食物过敏原-人类Fc？1嵌合融合蛋白。在实现了第一个花生-人类嵌合体(AraH2)2-Fc？1的生产之后，我们现在计划确定特定花生免疫治疗所需的最佳嵌合蛋白类型或混合蛋白。这项第二阶段的提案将有助于完成这一严重食物过敏治疗方法商业化所需的主要里程碑。在第一阶段，构建了先导分子(AraH2)2-Fc？1(AraH2-G)，并作为其他花生过敏原的模型进行了测试。在第二阶段，我们将通过实现以下特定目标来定义和生成用于启用IND的研究和临床开发的最佳产品。在目标1中，我们将建立研究水平的表达系统，并鉴定几种关键的花生过敏原-Fc？1蛋白。这些将包括：(A)生产超越(AraH2)2-G的“经典”二聚体；(B)单体Arah-G蛋白，其中单个Arah蛋白与Fc？1二聚体连接；(C)聚合(AraH2+AraH1)2-G；以及(D)双二聚体，其中一个Arah二聚体与两个Fc？1二聚体连接。这些变种可能会改善最终产品的可制造性，并将在目标3中测试改进的安全配置的关键特性。在目标2中，我们将测试假设 这种交叉脱敏可以对Arah-G蛋白产生。如果是这样的话，这一策略可能会改变游戏规则，因为它将简化整体食物过敏免疫治疗，加快产品商业化，并降低治疗成本。目的3将通过一系列体外和体内实验确定最佳的临床候选(S)花生-人FCG嵌合蛋白(S)，确定其安全性和有效性；安全性是它们不能作为过敏性反应，而有效性是它们能在先前致敏的动物中诱导对花生的耐受性。如果我们在目标2中观察到交叉脱敏，精确的实验和可能的先导化合物(S)将受到很大的影响。最后，在目标4中，我们将建立稳定、高表达GMP的高质量细胞系，产生通过实现特定目标1-3而确定的最终临床候选人(S)。第二阶段的成功将为为正式的IND使能研究生产材料和为首次人体试验生产GMP材料奠定基础，该试验旨在证明临床候选人缺乏过敏性。如果在花生方面取得成功，将这种方法推广到其他关键的食物抗原将是相对简单的。 公共卫生相关性：治疗性花生过敏原-Fc-γ嵌合蛋白治疗食物过敏的有效治疗方法对于严重过敏性食物过敏是一个主要未获满足的问题 医疗需要。与吸入性过敏相反，标准的过敏原免疫疗法已被证明对食物过敏过于危险，不能进行。严重的食物过敏影响了2.5%的美国人口，估计有800万人，其中包括300万儿童，导致美国每年有20多万急诊科就诊。此外，对意外暴露的恐惧给患者及其家人带来了巨大的情感负担，并在学校和其他公共论坛产生了广泛的社会影响。花生是最普遍和最严重的食物过敏，因此我们选择花生作为关键的食物过敏原和其他重要的食物过敏原的模型。本研究的目的是开发和商业化一种安全高效的花生变应原疫苗平台，利用花生-变应原人Fc？1融合蛋白诱导对食物变应原的过敏耐受。

DESCRIPTION (provided by applicant): The overall goal of this Phase 2 STTR is to develop and commercialize a novel approach for allergen specific immunotherapy as a treatment for severe food allergy. Currently treatment to prevent severe food reactions is a major unmet need. There is no effective therapy, the only treatment being strict avoidance and emergency measures should an exposure occur. The molecules that comprise this platform are genetically engineered food allergen-human Fc?1 chimeric fusion proteins. Having achieved the production of the first peanut-human chimeric (AraH2)2-Fc?1, we now plan to define the optimal type of chimeric protein or mixture of proteins necessary for specific peanut immunotherapy. This Phase 2 proposal will serve to accomplish the major milestones necessary for commercialization of this therapeutic approach for severe food allergy. In Phase 1, the lead molecule (AraH2)2-Fc?1 (AraH2-G) was constructed and tested as a model for other peanut allergens. In Phase 2, we will define and generate the optimal product for IND-enabling studies and clinical development by accomplishing the following Specific Aims. In Aim 1 we will establish research-level expression systems and characterize several types of the key peanut allergen-Fc?1 proteins. These will include (a) production of "classic" dimers, beyond (AraH2)2-G; (b) monomeric AraH-G proteins in which a single AraH protein is joined to the Fc?1 dimer; (c) polymeric (AraH2+AraH1)2-G; and (d) double-dimers, in which an AraH dimer is joined to two Fc?1 dimers. These variants may improve manufacturability of the final product and will be tested for key feature of an improved safety profile in Aim 3. In Aim 2 we will test the hypothesis that cross-desensitization can be generated for AraH-G proteins. If it does, this strategy could be game changing as it would simplify overall food allergy immunotherapy, speed product commercialization and decrease the cost of the therapy. Aim 3 will define the optimal clinical candidate(s) chimeric peanut-human FcG protein(s) through a series of in vitro and in vivo experiments defining both their safety and efficacy; safety being their inability to act as allerge while efficacy being their ability to induce tolerance to peanut in previously sensitized animals. The exact experiments and the likely lead compound(s) will be greatly impacted if we observe cross-desensitization in Aim 2. Finally, in Aim 4 we will establish stable high-expressing GMP-quality cell lines producing the final clinical candidate(s) identified by accomplishing Specific Aims 1-3. Success in Phase 2 will set the stage for production of material for formal IND-enabling studies and GMP material for a first-in human trial designed to demonstrate the lack of allergenicity of the clinical candidate. If successful with peanut, extending this approach to othe key food antigens will be relatively straightforward. PUBLIC HEALTH RELEVANCE: Therapeutic peanut allergen-Fc-gamma chimeric proteins to treat food allergy Effective treatments to for severe allergic food allergy represent a major unmet medical need. As opposed to inhalant allergy, standard allergen immunotherapy has proven too dangerous to undertake for food allergy. Severe food allergy affects 2.5% of the US population, an estimated 8 million persons, including 3 million children, resulting in more than 200,000 annual US emergency department visits. Additionally, fear of unsuspected exposures places a large emotional burden on the patient and their family and has had a wide societal impact in schools and other public forums. Peanut is the most prevalent and profound food allergy and thus we have chosen to address peanut both as key food allergen and as a model for other important food allergens. The goal of this proposal is to develop and commercialize a safe and efficient peanut allergen vaccine platform employing of peanut-allergen human Fc?1 fusion proteins capable of being used to induce allergic tolerance to the food allergen.