Nebulizing Eculizumab for intrapulmonary C5 inhibition

描述(由申请人提供)：补体成分C5在补体激活的所有三个途径中都是共同的。它在哮喘发病机制中的作用存在争议。我们最近已经证明C5的肺内激活在哮喘动物模型中是关键的(手稿，提交)。我们的数据表明，C5抑制在哮喘发病机制的所有关键点都有深远的影响，特别是在那些对特定或非特定刺激做出反应的严重呼吸道炎症或持续哮喘发作的个体中。此外，多项研究支持这样一种观点，即C5在肺内的激活可能是感染或接触变应原的结果。激活后，C5组分C5a和C5b-9可能在肺内免疫复合体形成后，介导各种强有力的促炎事件，包括炎症细胞向支气管腔的趋化作用，以及随后多种有害炎症介质的释放。此外，C5a与其受体的直接结合可能会增强气道阻塞。C5a受体广泛表达于气道平滑肌细胞和上皮细胞。这项赠款提案的目的是开发人源化抗C5单抗的雾化形式，eculizumab(目前处于多种自身免疫性疾病适应症的后期临床试验)，用于肺内给药，浓度足以有效抑制促炎介质C5a和C5b-9。研究活动将包括开发适当的制剂和设备，以充分吸入Eulizumab，将通过肺部毒理学研究进行评估，以支持Eulizumab在哮喘患者中的人体雾化试验。这项拟议的研究代表了一种治疗哮喘潜在炎症的新方法。如果成功完成，我们认为这项研究产生的数据将足以支持向FDA提交IND文件和哮喘患者雾化吸入Eulizumab的I期临床试验。因此，我们将提交NIAID第二阶段拨款申请，主要集中在该药物的临床开发上。在第二阶段赠款中提议的活动将包括第一阶段和第二阶段材料的药物制造、IND申请和临床试验的执行。

DESCRIPTION (provided by applicant): The complement component C5 is common to all three pathways of complement activation. Its involvement in the pathogenesis of asthma is controversial. We have recently shown that the intrapulmonary activation of C5 is critical in animal models of asthma (manuscript, submitted). Our data demonstrated that C5 inhibition has profound effects at all the critical points in the pathogenesis of asthma, in particular in those individuals with severe established airway inflammation or an on-going asthmatic attack in responding to either specific or non-specific stimuli. Furthermore, multiple studies support the notion that intrapulmonary activation of C5 is probably the results of infections or exposures to allergens. Upon activation, presumably after the formation of intrapulmonary immune complexes, the C5 components C5a and C5b-9 mediate various potent proinflammatory events including the chemotaxis of inflammatory cells into bronchial airway lumen and the subsequent release of multiple harmful inflammatory mediators. Furthermore, direct engagement of C5a with its receptors, which are widely expressed on airway smooth muscle cells and epithelium, may enhance airway obstruction. The aim of this grant proposal is to develop a nebulized form of the humanized anti-C5 mAb, eculizumab (currently in late stage clinical trials in multiple autoimmune disease indications) for intrapulmonary administration of the drug in concentrations sufficient to potently inhibit the pro-inflammatory mediators C5a and C5b-9. Research activities will include the development of an appropriate formulation and device for adequate inhalation delivery of eculizumab, which will be assessed by pulmonary toxicologic studies designed to support human nebulization trials of eculizumab in asthmatic patients. The proposed study represents a novel approach for treating the underlying inflammation of asthma. If successfully completed, we feel that the data generated from this study will be sufficient to support an IND filing with the FDA and a Phase I clinical trial of nebulized eculizumab in asthmatic patients. We would therefore file a NIAID phase II grant application focusing primarily on the clinical development of this drug. Activities proposed in the phase II grant would include drug manufacturing of Phase I &II materials, IND filings and the execution of the clinical trial