New approaches in the treatment of asthma

Asthma is a common and complex inflammatory disease of the airways that rem ains incurable. Current forms of therapy are long term and may exhibit asso ciated side-effect problems. Major participants in the development of an as thma phenotype include the triggering stimuli such as the allergens themsel ves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines Including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemo kines such as eotaxin. Significantly, the eosinophil, a specialized blood c ell type, is invariably associated with this disease. The eosinophil has lo ng been incriminated in the pathology of asthma due to its ability to relea se preformed and unique toxic substances as well as newly formed pro-inflam matory mediators. The regulation of eosinophil production and function Is c arried out by soluble peptides or factors. Of these IL-5, GM-CSF and IL-3 a re of paramount importance as they control eosinophil functional activity a nd are the only known eosinophilopoietic factors. In addition they regulate the eosinophil life span by inhibiting apoptosis. While one therapeutic ap proach in asthma is directed at inhibiting single eosinophil products such as leukotrienes or single eosinophil regulators such as IL-5, we believe th at the simultaneous inhibition of more than one component is preferable. Th is may be particularly important with eosinophil regulators in that not onl y IL-5, but also GM-CSF has been repeatedly implicated in clinical studies of asthma. The fact that GM-CSF is produced by many cells in the body and i n copious amounts by lung epithelial cells highlights this need further. Ou r approach takes advantage of the fact that the IL-5 and GM-CSF receptors ( as well as IL-3 receptors) utilize a shared subunit to bind with high affin ity, to these cytokines and the same common subunit mediates signal transdu ction culminating In all the biological activities mentioned. By generating the monoclonal antibody BION-1 to the cytokine binding region of the commo n subunit (beta (c)) we have shown that the approach of inhibiting IL-5, GM -CSF and IL-3 binding and the resulting stimulation of eosinophil productio n and function with a single agent is feasible. Furthermore wee have used B ION-1 as a tool to crystallize and define the structure of the cytokine bin ding domain of beta (c). This knowledge and this approach may lead to the g eneration of novel therapeutics for the treatment of asthma.