A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma

描述(由申请人提供)：这一第二阶段SBIR提案的总体目标是在完成关键的临床前开发研究活动的情况下，将我们的新型生物GE2定位于人类过敏疾病的临床试验。GE2是一种经过基因工程的人类融合蛋白，由部分人类Gamma1 Fc连接到人类epsilon Fc链的一部分组成，具有独特的机械性能，应该会转化为严重过敏性哮喘和食物过敏患者的下一代治疗选择。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。GE2已被证明可以直接抑制Fc？RI效应器功能，这是一种治疗人类过敏性疾病的有效机制，并已在几种非人类灵长类过敏性疾病模型中证明了有效性。在这项SBIR的第一阶段，我们通过创建GE2的恒河猴同源基因并将其长期应用于恒河猴来解决潜在免疫原性的关键问题。与将人类GE2重复注射到食蟹猴体内时观察到的免疫原性不同，注射同源蛋白的耐受性很好，没有产生任何不良反应，也没有抗GE2抗体。最值得注意的是，恒河猴GE2阻止了对屋尘螨主动致敏的动物中过敏原特异性IgE的上升，我们根据人类B细胞的体外研究结果预测可能会发生这一发现。因此，GE2似乎具有显著的“双重”治疗效果：抑制急性Fc？RI依赖的嗜碱性细胞/肥大细胞的激活，同时下调传入相IgE抗体的产生。这一第二阶段的建议包括免费的作用机制实验、疗效研究和关键的临床前活动，预计完成后将为全面的I期/IIa期临床试验提供强有力的研究性新药(IND)申请。为了实现这一目标，我们将实现五个主要目标。目的1：在GLP协议下，生成IND应用所需的分析、过程和试剂--包括恒河猴和小鼠GE2。目的：明确GE_2‘S双作用机制在单剂量和多剂量方案下对恒河猴的治疗效果，探讨其抑制免疫球蛋白E和一过性嗜碱性粒细胞减少的作用后果。目标3：开发“下一代”GE2作为潜在的改进候选者。目的4：评价当前候选和“下一代”GE2在过敏性非人类灵长类哮喘模型中的疗效。目标5：准备和归档IND。第二阶段SBIR的成功完成，与GMP制造和GLP毒理学相结合，将为启动临床试验奠定基础，以测试GE2在美国TRIA的安全性和有效性。

DESCRIPTION (provided by applicant): The overall goal of this phase 2 SBIR proposal is to position our novel biologic GE2 for human clinical trials in allergic disease though the completion of critical preclinical development research activities. GE2, a genetically engineered human fusion protein consisting of portions of the human gamma1 Fc linked to portions of the human epsilon Fc chain, has unique mechanistic properties that should translate to a next-generation therapeutic option for patients with severe allergic asthma and food allergy. 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. GE2 had been shown to directly inhibit Fc¿RI effector function, a validated mechanism for treatment of human allergic disease, and efficacy has been demonstrated in several non-human primate models of allergic disease. In phase 1 of this SBIR, we addressed the key issue of potential immunogenicity by creating the rhesus homolog of GE2 and administering it chronically to rhesus macaques. In contrast to the immunogenicity observed when human GE2 was injected repeatedly to cynomologus macaques, administration of the homologous protein was well-tolerated, producing no adverse events and no anti-GE2 antibodies. Most notably, rhesus GE2 blocked the rise in allergen-specific IgE in the animals actively sensitized to house dust mite, a finding we predicted might occur based on in vitro findings with human B cells. Thus, GE2 appears to have a remarkable "dual" therapeutic effect: inhibition of acute Fc¿RI-dependent basophil/mast cell activation plus down-regulation of afferent phase IgE antibody production. This phase 2 proposals comprises complimentary mechanism-of action experiments, efficacy studies and critical preclinical activities 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 five key Aims. Aim 1: under GLP protocols, generate the assays, processes and reagents - including rhesus human and murine GE2 - necessary for the IND application. Aim 2: define the therapeutic benefit of GE2's dual mechanism of action in rhesus macaques in single and multiple-dose protocols, exploring the functional consequence of IgE inhibition and transient basophil decrease. Aim 3: develop a "next generation" GE2 as a potential improved candidate. Aim 4: evaluate the efficacy of the current candidate and "next-generation" GE2 in an allergic non-human primate asthma model. Aim 5: prepare and file the IND. Successful completion of this phase 2 SBIR would, in conjunction with GMP manufacturing and GLP toxicology, set the stage for the initiation of clinical trials to test the safety and efficacy of GE2 in US-based trias.