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 ? ?
