Researchers from the University of Leicester have identified a new protein involved in airway inflammation in patients with severe asthma. The results from their study show that concentrations of a protein known as high-mobility group box 1 (HMGB1) are increased in the sputum of patients who have severe asthma. HMGB1 is secreted by cells in the airway in response to stimulation from various cytokines (proteins used for cell signaling), specifically cytokines involved in the immune system and inflammation. This causes the muscles in the airways to contract (bronchoconstriction) which narrows the airways of the lungs, resulting in asthmatic symptoms of shortness of breath, coughing, and wheezing.
Current asthma therapies:
- Respiratory inhalers
Current asthma therapies include respiratory inhalers, such as long and short acting beta2-agonist (LABA or SABA) and muscarinic antagonist (LAMA or SAMA) bronchodilators. These work by relaxing smooth muscles or preventing smooth muscle contraction respectively. Inhaled corticosteroids (ICS) are also used in asthma therapy to prevent airway inflammation. Unfortunately, these inhalers do not work for everyone and are dependent on the severity of the patients’ asthma as well as their endotype (subset of a condition defined by a particular mechanism).
- Monoclonal antibodies
In order to find treatments for patients who do not respond to current therapies, researchers have been focusing on more specific therapeutic targets involved in asthma. Asthma is often the result of an immune response to respiratory irritants such as pollen or dust (allergic asthma). In 2003, Xolair (omalizumab) was approved by the FDA for patients who have allergic asthma and do not respond to ICS therapy. Xolair is an injectable monoclonal antibody that prevents the protein immunoglobulin E (IgE) from binding to cells and activating allergic immune response that causes asthmatic symptoms in these patients. Clinical trials are underway for another injectable monoclonal antibody, benralizumab, designed for patients of a specific endotype with severe asthma. Benralizumab targets the interleukin-5 alpha subunit receptor which is expressed by immune cells called eosinophils. Activation of eosinophils via interleukin-5 (a cytokine) causes eosinophils to secrete additional cytokines that elicit an immune response that results in asthmatic symptoms. While benralizumab may be beneficial to asthma patients who have high eosinophil counts, what about the patients who have low eosinophil counts who do not fit that endotype?
A phase II trial for the monoclonal antibody risankizumab is being conducted for patients with severe asthma that may be effective for patients who do not have high eosinophil counts. While benralizumab and risankizumab both target cytokines, the specific target for risankizumab (interleukin-23) affects a different type of immune cell called neutrophils. Similar to eosinophils, activation of neutrophils via interleukin-23 causes neutrophils to secrete additional cytokines that results in an immune response and asthmatic symptoms.
Future asthma therapies
As the understanding of the diversity of asthma grows, so does the realization that diverse treatments are needed for patients different endotypes. The identification of HMGB1 and its role in bronchoconstriction makes it a potential therapeutic target for future asthma medications.