A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma

描述（由申请人提供）：本提案的总体目标是开发和商业化一种用于治疗过敏性疾病，特别是过敏性哮喘的新型生物疗法。具体而言，该提案将提供关键的免疫原性、机制和生物标志物数据，这些数据将为过敏性疾病的人体临床试验定位一种新型生物制剂GE 2。该治疗分子是一种基因工程人融合蛋白，由人γ 1 Fc的一部分与人α 1 Fc链的一部分连接组成[（铰链-h2 -3（1）-接头-（ch 2 -3-4（）]，命名为“GE 2”。严重吸入性过敏/哮喘和食物过敏的有效治疗是主要未满足的需求。哮喘影响美国5-10%的人口，估计有1400 - 1500万人，其中包括500万儿童。据估计，1985年至1997年期间，美国每年有180万例急诊就诊、50万例住院和5000例死亡，增长率超过100%，最近这些趋势趋于稳定。该提案旨在解决对成功开发GE 2至关重要的安全性和生物标志物实验。广泛的临床前机制和治疗研究都定义了最佳的分子设计，并显示其治疗效果。我们现在准备将GE 2研究转移到人体临床试验。然而，剩下的关键问题是GE 2分子的潜在体内免疫原性。考虑到GE 2靶向肥大细胞和嗜碱性粒细胞上的高亲和力IgE受体（FcRI），因此免疫原性不仅可能抑制GE 2的功能，而且可能导致严重的不良反应，这个问题显得特别重要。因此，资助提案的第一阶段旨在使用恒河猴测试GE 2在同源动物中不具有免疫原性的假设，提供关键的机制信息和生物标志物，并为IND使能和第一阶段人类研究奠定基础。该提案的第二阶段旨在完成商业化道路上的关键实验性临床前步骤。为了实现这一目标，我们将生产恒河猴GE 2（rhGE 2）用于免疫原性和机制研究，并获得稳定的高表达人GE 2（hGE 2）CHO细胞系用于拟议补助金的第二阶段。将以四周间隔皮下给予恒河猴rhGE 2（对照，lmg/kg，10 mg/kg），总共3次剂量。在3个月方案中，将通过检测动物是否产生抗GE 2抗体来评估GE 2的免疫原性。同时，我们将测试GE 2是否（1）抑制IgE产生和（2）减少非人灵长类动物中的循环嗜碱性粒细胞，这两个重要的机制终点和未来I期临床试验的潜在生物标志物将被评估。一旦完成，该提案将提供关键的免疫原性，机制和生物标志物数据，这些数据将使这种新型生物制剂在过敏性疾病的人体临床试验中处于有利地位。 公共卫生相关性：严重过敏性哮喘和食物过敏的有效治疗是一个主要的未满足的医疗需求。哮喘影响美国人口的5-10%，估计有1400 - 1500万人，包括500万儿童，导致大约1亿天的工作和上学时间损失，每年有超过180万人到美国急诊室就诊。该提案的目标是开发和商业化一种能够抑制急性过敏反应的新型人类生物制剂，作为严重过敏疾病的治疗方法。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop and commercialize a novel biologic therapy for the treatment of allergic disease and particularly allergic asthma. Specifically, this proposal will provide the critical immunogenicity, mechanistic and biomarker data that will position a novel biologic, GE2, for human clinical trials in allergic disease. The therapeutic molecule is a genetically engineered human fusion protein consisting of a portion of the human gamma1 Fc linked to a portion of the human epsilon Fc chain [(hinge-h2-3(1)-linker- (ch2-3-4()] that is designated as "GE2". Effective treatments for severe inhalant allergy/asthma and food allergy represent major unmet needs. Asthma affects 5-10% of the US population or an estimated 14-15 million persons, including 5 million children. There were an estimated 1.8 million US emergency department visits, 500,000 hospitalizations and 5000 deaths annually and an increase of over 100% in the United States between 1985 and 1997 with these trends stabilizing more recently. This proposal is designed to address safety and biomarker experiments that are critical for the successful development GE2. Extensive preclinical mechanistic and therapeutic studies have both defined the optimal molecule design and shown its therapeutic efficacy. We are now poised to move GE2 studies to human clinical trials. However, the key remaining question is the potential in vivo immunogenicity of the GE2 molecule. This question assumes particular importance given the targeting of GE2 to the high affinity IgE receptor (FcRI) on mast cells and basophils whereby immunogenicity might not only inhibit GE2's function but could lead to serious adverse effects. Thus, Phase I of the grant proposal is designed to test the hypothesis that GE2 is not immunogenic in homologous animals using rhesus monkeys, provide key mechanistic information and biomarkers and lay the groundwork to make the human GE2 for IND-enabling and phase 1 human studies. Phase II of this proposal is designed to complete the key experimental pre-clinical steps on the path to commercialization. To achieve this goal, we will produce rhesus GE2 (rhGE2) for immunogenicity and mechanistic studies and derive a stable high-expressing human GE2 (hGE2) CHO cell line for Phase II of the proposed grant. Rhesus macaques will be given rhGE2 subcutaneously at four-week intervals (control, 1 mg/kg, 10 mg/kg) for a total of 3 doses. GE2's immunogenicity will be assessed by testing animals for the development of anti-GE2 antibodies over the 3- month protocol. Simultaneously, we will test whether GE2 (1) inhibits IgE production and (2) decreases circulating basophils in non-human primates, two important mechanistic endpoints and potential biomarkers for future phase 1 clinical trials will be assessed. Once completed, this proposal will provide the critical immunogenicity, mechanistic and biomarker data that will position this novel biologic for human clinical trials in allergic disease. PUBLIC HEALTH RELEVANCE: Effective treatments to for severe allergic asthma and food allergy represent a major unmet medical need. Asthma affects 5-10% of the US population, an estimated 14-15 million persons, including 5 million children resulting in lost work and school time of approximately 100 million days with more than 1.8 million annual US emergency department visits. The goal of this proposal is to develop and commercialize a novel human biologic capable of inhibiting acute allergic reactions as a treatment for severe allergy disease.