Nebulizing Eculizumab for intrapulmonary C5 inhibition

描述（由申请人提供）：补体成分C5是所有三种补体激活途径所共有的。其在哮喘发病机制中的参与是有争议的。我们最近发现，肺内激活的C5是至关重要的哮喘动物模型（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，特别是在那些患有严重气道炎症或正在进行的哮喘发作的个体中，对特异性或非特异性刺激的反应。此外，多项研究支持C5的肺内激活可能是感染或暴露于过敏原的结果。在活化后，可能在肺内免疫复合物形成后，C5组分C5 a和C5 b-9介导各种有效的促炎事件，包括炎性细胞向支气管气道腔的趋化性和随后多种有害炎性介质的释放。此外，C5 a与其受体（广泛表达于气道平滑肌细胞和上皮细胞上）的直接接合可增强气道阻塞。该资助提案的目的是开发一种雾化形式的人源化抗C5 mAb，艾库组单抗（目前处于多种自身免疫性疾病适应症的晚期临床试验中），用于肺内给药，浓度足以有效抑制促炎介质C5 a和C5 b-9。研究活动将包括开发用于充分吸入递送依库珠单抗的适当制剂和装置，将通过旨在支持哮喘患者中依库珠单抗人体雾化试验的肺毒理学研究进行评估。这项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申请和在哮喘患者中进行雾化依库珠单抗的I期临床试验。因此，我们将提交NIAID第二阶段拨款申请，主要集中在这种药物的临床开发上。在第二阶段拨款中提出的活动将包括I和II期材料的药物制造，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