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一种新的生物疗法并将其商业化，用于治疗过敏性疾病，特别是过敏性哮喘。具体地说，这项提议将提供关键的免疫原性、机制和生物标记物数据，将为人类过敏性疾病的临床试验定位一种新的生物GE2。该治疗分子是一种基因工程的人类融合蛋白，由人Gamma1 Fc的一部分连接到人epsilon Fc链的一部分[(hinger-H2-3(1)-linker-(CH2-3-4())]，指定为“GE2”。严重吸入性过敏/哮喘和食物过敏的有效治疗是尚未得到满足的主要需求。哮喘影响着美国5%-10%的人口或估计1400万-1500万人，其中包括500万儿童。据估计，美国每年有180万急诊科就诊，500,000人住院，5000人死亡，1985年至1997年期间，美国的增长率超过100%，最近这些趋势趋于稳定。这项提议旨在解决对成功开发GE2至关重要的安全和生物标记物实验。广泛的临床前机制和治疗研究都定义了最优的分子设计，并显示了其治疗效果。我们现在准备将GE2研究转移到人体临床试验。然而，剩下的关键问题是GE2分子在体内的潜在免疫原性。鉴于GE2以肥大细胞和嗜碱性粒细胞上的高亲和力IgE受体(FcRI)为靶点，免疫原性不仅可能抑制GE2‘S功能，而且可能导致严重的不良反应，因此这个问题显得尤为重要。因此，拨款提案的第一阶段旨在检验GE2在使用恒河猴的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记物，并为使人类GE2能够用于IND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试验性临床前步骤。为了实现这一目标，我们将生产用于免疫原性和机制研究的恒河猴GE2(HGE2)，并为拟议拨款的第二阶段获得稳定高表达的人GE2(HGE2)CHO细胞系。猕猴皮下注射rhGE2，间隔4周(对照组，1 mg/kg，10 mg/kg)，共3次。S将在为期3个月的方案中通过测试动物的抗GE2抗体来评估GE2的免疫原性。同时，我们将测试GE2(1)是否抑制IgE的产生，以及(2)是否减少非人类灵长类动物循环中的嗜碱性粒细胞，两个重要的机制终点和未来第一阶段临床试验的潜在生物标志物将被评估。一旦完成，这项提案将提供关键的免疫原性、机制和生物标记物数据，将为人类过敏性疾病的临床试验定位这种新的生物学。 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尚未得到满足的主要医疗需求。哮喘影响着美国5%-10%的人口，估计有1400万-1500万人，其中包括500万儿童，导致失去工作和上学时间约1亿天，每年美国急诊科就诊超过180万人次。这项提案的目标是开发一种能够抑制急性过敏反应的新型人体生物制剂，并将其商业化，作为治疗严重过敏性疾病的方法。

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.