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Background
Asthma is a chronic inflammatory airway disease characterized by variable airflow limitation, airway hyperresponsiveness, mucus hypersecretion, and structural changes to the airways that include proliferation of smooth muscle. Interleukin (IL)-9, a multifunctional cytokine produced by type 2 T helper cells (Th2), lymphocytes, and mast cells, is proposed to be a central mediator in the pathogenesis of asthma. Interest in IL-9 was first triggered by genetic linkage studies and supported by the finding that expression of IL-9 and its associated receptor is higher in the airways of subjects with asthma compared with healthy controls. Further evidence has come from in vitro studies showing that IL-9 enhances the growth and/or activity of a variety of cell types and pro-inflammatory and pro-fibrotic mediators that are implicated in the pathogenesis of asthma. IL-9 induced the release of Th2-associated chemokines in cultured human airway smooth muscle cells and enhanced the stem cell factor-dependent growth of human mast cell progenitors, particularly those from children with asthma. Another study reported that IL-9 upregulated mucin expression in human lung cells, suggesting that it is involved in the control of mucus secretion.
Preclinical studies in animal models of asthma support a contributing role for an IL-9 mast cell axis in the immunopathology of asthma. In one study, anti-IL-9 antibody treatment had a protective effect against airway remodeling in mouse models of airway inflammation, together with a concomitant reduction in the number and activation of mature mast cells. Furthermore, impaired lung function related to airway remodeling was reversed by IL-9 neutralization. Taken together, evidence from these and other experimental studies indicated that targeting IL-9 may offer a novel approach to the treatment of asthma.
MEDI-528 is a humanized immunoglobulin G1 monoclonal antibody that binds to IL-9, and hence reduces the activity of a variety of cell types implicated in asthma pathogenesis. Preliminary clinical studies in healthy adults and subjects with mild or mild-to-moderate asthma have demonstrated that MEDI-528 administered subcutaneously has linear pharmacokinetics and an acceptable safety profile with no reports of serious adverse events (SAEs). One study in subjects with mild asthma showed that MEDI-528 had no effect on pulmonary function or the use of rescue medication, although there were positive trends for improvement in asthma symptom scores and for a reduction in the number of asthma exacerbations. Another study in a small number of subjects with mild-to-moderate asthma suggested that MEDI-528 may decrease sensitivity to exercise-induced bronchoconstriction that is dependent on mast cell degranulation. We now report the results from a larger study (ClinicalTrials.gov, NCT00968669) that was designed to further investigate the potential clinical benefits of MEDI-528 in treating subjects with asthma. The primary objective of this study was to evaluate the effect of multiple dose subcutaneous administration of MEDI-528 on symptom control in adults with uncontrolled, moderate-to-severe, persistent asthma.
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