Cytokine Antagonists for the Treatment of Asthma Progress to Date

Asthma is a disease of the airways in which several cytokines such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF alpha) play a major role in the development and progression of inflammation, airway hyperresponsiveness, mucus production, and airway remodeling. The conventional anti-inflammatory therapies, represented by inhaled corticosteroids and antileukotrienes, are not always able to provide optimal disease control and it is therefore hoped that cytokine antagonists could achieve this goal in such situations. Anticytokine therapies have been tested in preclinical studies and some have entered clinical trials. Anti-IL-4 therapies have been tested in animal models of allergy-related asthma, but because of unclear efficacy their development was discontinued. However, IL-4/IL-13 dual antagonists and IL-13-specific blocking agents are more promising, as they exhibit more sustained anti-inflammatory effects. IL-5 antagonists have been found to be of limited efficacy in clinical studies but might be useful in conditions characterized by severe hypereosinophilia, and in which asthma is one of the disease manifestations. Unlike other chronic inflammatory conditions, such as rheumatoid arthritis, the use of anti-TNF alpha therapies in asthma might be limited by the unfavorable risk/benefit ratio associated with long-term use. The identification of so-called asthma TNF alpha phenotypes and perhaps the use of a less aggressive treatment regimen might address this important aspect. Other cytokine antagonists (for example for IL-9 or IL-25) are currently being evaluated in the asthma setting, and could open new therapeutic perspectives based on their efficacy and safety.