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种途径中都是共同的。它在哮喘发病机制中的作用是有争议的。我们最近发现C5的肺内激活在哮喘动物模型中是至关重要的（手稿，提交）。我们的数据表明，C5抑制在哮喘发病的所有关键点上都有深远的影响，特别是在那些对特异性或非特异性刺激有严重气道炎症或持续哮喘发作的个体中。此外，多项研究支持肺内C5激活可能是感染或暴露于过敏原的结果的观点。C5成分C5a和C5b-9在激活后，可能是在肺内免疫复合物形成后，介导各种有效的促炎事件，包括炎症细胞趋化进入支气管气道管腔以及随后释放多种有害炎症介质。此外，C5a与其广泛表达于气道平滑肌细胞和上皮上的受体直接接触，可能会加重气道阻塞。该资助提案的目的是开发一种雾化形式的人源抗c5单抗eculizumab（目前处于多种自身免疫性疾病适应症的后期临床试验中），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一种适当的制剂和设备，以充分吸入eculizumab，这将通过肺毒理学研究进行评估，旨在支持eculizumab在哮喘患者中的人体雾化试验。提出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申请和雾化eculizumab用于哮喘患者的I期临床试验。因此，我们将提交NIAID II期拨款申请，主要关注该药物的临床开发。II期拨款中提议的活动将包括I期和II期材料的药物生产，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