Better understanding of the role of cytokines in inflammation has led to novel therapies using cytokine antagonists as potential therapy for the airway inflammation in asthma. These include monoclonal antibodies against interleukin (IL) 5, tumor necrosis factor-alpha (TNF-alpha) and IL-4/IL-13.
IL-5 is involved in the maturation and survival of eosinophils. Asthma patients have increased levels of IL-5 in serum and BAL fluid that correlates with airway inflammation after allergen exposure. Mepolizumab is a monoclonal anti-IL-5 antibody. It was studied in mild asthmatics where it was shown to decrease eosinophils, but had no improvement in asthma scores. Two subsequent studies looked at patients with severe asthma. Blood and sputum eosinophil counts were significantly reduced and quality of life measures improved. These data suggest that targeting eosinophils using anti-IL-5 is more beneficial for severe asthma with significant eosinophilia. Other anti-IL-5 antibodies are currently in clinical trials.
TNF-alpha is a pro-inflammatory cytokine in asthma. It up-regulates adhesion molecules, increases mucin secretion, and promotes airway remodeling. Early studies with TNF-alpha antagonists were encouraging. However, the most recent and definitive study using golimumab, an anti-TNF-alpha antibody, showed no measurable changes in pulmonary function, symptoms, or exacerbation rates. A large number of serious adverse events prompted discontinuation of the study. Because of the poor safety profile and limited efficacy in this last study, further trials of anti-TNF alpha are not likely.
IL-4 and IL-13 share similar activities (isotype switching from IgM to IgE, upregulation of VCAM-1 expression, and increased mucus secretion) and structure. A recombinant human IL-4 variant, pitrakinra, binds to the IL-4R alpha complex and prevents the binding of both IL-4 and IL-13. In two small studies, pitrakinra showed promising results by reducing asthma-related adverse events.
Another approach to inhibiting IL-4 and IL-13 is using a humanized monoclonal antibody that blocks the shared IL-4R alpha chain (AMG 317). A 12-week dose ranging study did not show improvement with asthma symptoms overall, but there were improvements in other parameters in a subgroup of patients with more severe asthma.
Other new cytokine targets being investigated are IL-9, IL-13, thymic stromal lymphopoietin (TSLP), and IL-17.
There has been some promising data in the past decade of clinical trials with anti-cytokine agents in asthma. But there have also been varying results of efficacy between milder patients compared to more severe steroid-resistant asthma patients. This reinforces the knowledge that these new treatments may be limited by asthma phenotypes. There still is hope that one or more of the cytokine antagonists will prove to be effective for treating the most difficult to control asthmatics.