A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma

描述（由申请人提供）：本申请的总体目标是开发并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。具体来说，该提案将提供关键的免疫原性、机制和生物标志物数据，为过敏性疾病的人类临床试验定位新的生物制剂GE2。治疗性分子是一种基因工程的人类融合蛋白，由一部分人类γ - 1 Fc连接到一部分人类epsilon Fc链[(hinge-h2-3(1)-linker- (ch2-3-4()]，被指定为“GE2”。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。哮喘影响美国人口的5-10%，或估计有1400万至1500万人，其中包括500万儿童。据估计，1985年至1997年间，美国每年有180万人次急诊就诊，50万人次住院，5000人死亡，增幅超过100%，这些趋势最近趋于稳定。该提案旨在解决安全性和生物标志物实验，这对GE2的成功开发至关重要。广泛的临床前机制和治疗研究都确定了最佳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分子体内潜在的免疫原性。考虑到GE2靶向肥大细胞和嗜碱性细胞上的高亲和力IgE受体（FcRI），免疫原性不仅可能抑制GE2的功能，还可能导致严重的不良反应，这个问题就变得尤为重要。因此，第一阶段的拨款提案旨在使用恒河猴测试GE2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，并为使人类GE2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临床前实验步骤。为了实现这一目标，我们将生产恒河猴GE2 （rhGE2）用于免疫原性和机制研究，并获得稳定的高表达人GE2 (hGE2) CHO细胞系用于拟议资助的II期。将每隔四周给恒河猴皮下注射rhGE2（对照，1 mg/kg, 10 mg/kg），共3次剂量。GE2的免疫原性将在3个月的试验中通过动物试验来评估抗GE2抗体的发展。同时，我们将测试GE2(1)是否抑制非人类灵长类动物的IgE产生和(2)是否减少循环嗜碱性粒细胞，这两个重要的机制终点和未来1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，将定位这种新的生物制剂用于过敏性疾病的人类临床试验。

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.