A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma

描述（由申请人提供）：该2期SBIR申请的总体目标是通过完成关键的临床前开发研究活动，将我们的新型生物制剂GE2定位于过敏性疾病的人类临床试验。GE2是一种基因工程人类融合蛋白，由部分人类γ - 1 Fc与部分人类ε - Fc链连接组成，具有独特的机制特性，应该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。GE2已被证明可以直接抑制Fc¿RI效应物功能，这是一种治疗人类过敏性疾病的有效机制，并且在几种非人类过敏性疾病的灵长类动物模型中也证明了其功效。在该SBIR的一期研究中，我们通过创建GE2的恒河同源物并长期给药恒河猴，解决了潜在免疫原性的关键问题。与人类GE2反复注射到食蟹猴体内观察到的免疫原性相反，同源蛋白的耐受性良好，没有产生不良事件，也没有抗GE2抗体。最值得注意的是，恒河猴GE2阻断了对屋尘螨积极敏感的动物中过敏原特异性IgE的上升，我们预测这一发现可能会基于人类B细胞的体外研究结果。因此，GE2似乎具有显著的“双重”治疗效果：抑制急性Fc¿ri依赖性嗜碱性粒细胞/肥大细胞活化，下调传入期IgE抗体产生。该2期提案包括互补的作用机制实验，功效研究和关键的临床前活动，预计将在完成后为全面的I/ IIa期临床试验提供强有力的新药研究（IND）申请。为此，我们将实现五个主要目标。目标1：在GLP协议下，生成IND申请所需的检测、工艺和试剂（包括恒河猴和小鼠GE2）。目的2：确定GE2在恒河猴单剂量和多剂量方案中的双重作用机制的治疗益处，探索IgE抑制和短暂性嗜碱性粒细胞减少的功能后果。目标3：开发“下一代”GE2作为潜在的改进候选人。目的4：评估当前候选药物和“下一代”GE2在过敏性非人类灵长类动物哮喘模型中的疗效。目标5：准备并提交IND。SBIR二期的成功完成将与GMP生产和GLP毒理学相结合，为启动临床试验奠定基础，以测试GE2在美国临床试验中的安全性和有效性。

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.