These findings, together with human clinical data showing complement activation in asthmatic patients, strongly suggest that complement activation is likely to be very important in the development of inflammation in allergic asthma. Since this is a new area of exploration in asthma, anti-C5 therapy may have the advantage of providing a novel class of therapeutics for the treatment of this severe disease
The results of a new study revealed that treatment with an anti-C5 complement blocking antibody may help position eculizumab, its lead antibody drug currently in late stage clinical trials, as a clinical candidate for treatment in severe asthma.
Eculizumab, works by blocking activity of the C5 protein of the complement cascade. Complement is a complex series of blood proteins that work in concert with antibodies; the complement cascade refers to the precise series of events, which activate each component of the complement system. As an anti-C5 complement antibody, eculizumab blocks C5 breakdown into its inflammatory components, C5a and C5b-9.
The study demonstrated that both C5a and C5b-9 contribute to the initiation of airway inflammation and in immediate and sustained airway hyperreactivity. Importantly, the researchers found that animals given an anti-C5 blocking antibody, either systemically or when inhaled through a nebuliser (a common asthma inhalation device), showed substantial reductions in airway reactivity even in the face of 'airway challenges' with methacholine, a drug administered to confirm an asthma diagnosis.
The findings also demonstrate that C5 blockade provides more comprehensive and significant reductions in both airway hyperreactivity and pulmonary inflammation than does blockade of a related target, C5a alone. The anti-C5 blocking antibody, unlike other existing asthma therapies, high-dose inhaled and oral corticosteroids, blocked a wide range of inflammatory mediators known to contribute to the severity and persistence of asthma, including white blood cells and inflammatory mediators from eosinophils and neutrophils. This data suggests a direct role for complement-mediated inflammation in the pathogenesis of severe asthma.
"I believe that these researchers have identified an extremely exciting and highly relevant new target for the treatment of asthma," stated Dr Stephen Holgate, professor, respiratory, cell and molecular biology, University of Southampton School of Medicine.
"Importantly, this comprehensive body of research further demonstrated the potential utility of a nebulised form of the anti-C5 mAb for the treatment of the more chronic, indolent forms of asthma where oedema and the ongoing release of inflammatory mediators from neutrophils and eosinophils are occurring. This form of asthma has historically been highly resistant to effective treatment with currently available therapies," he added.
The study, conducted in animal models by researchers at Alexion Pharmaceuticals, the Yale University School of Medicine and the Brigham and Women's Hospital, is published in the June 2005 issue of the Journal of Clinical Investigation.