Mepolizumab
Mepolizumab is an IgG1-κ anti-IL-5 mAb approved as add-on treatment for severe eosinophilic asthma (SEA)138, 139. IL-5 is the most important growth, differentiation, and activation factor of human eosinophils140. This cytokine acts on eosinophils by binding to the specific IL-5 receptor (IL-5R), which consists of an IL-5 receptor α (IL-5Rα) subunit and the common receptor β subunit (βc)141. IL-5, together with IL-3 and GM-CSF, is crucial for the maturation of human eosinophils in the bone marrow 141, 142. IL-5 is mainly produced by type-2 ILC2s, Th2 cells, mast cells, invariant NKT cells, and eosinophils themselves 140. Human eosinophils can also be activated by IL-3396 and TSLP13.
The efficacy and safety of mepolizumab have been demonstrated in several RCTs 143-146. The DREAM study, conducted with mepolizumab at 3 different doses administered intravenously (i.v .), showed the clinical efficacy but there were no statistically significant changes in FEV1, although there was an improvement, compared to baseline, in FEV1 in the mepolizumab group versusplacebo 143. In the MENSA study, the FEV1 increase was rapid, starting from the first administration, and persisted over time146. Two additional studies showed a rapid and long-lasting improvement in pre-bronchodilator FEV1 in the mepolizumab group compared to placebo147, 148. There is some evidence that mepolizumab can also improve FEV1 in real-life settings149-151.
Interestingly, some patients first enrolled in the COSMOS study and subsequently in the long-term COSMEX study, with a suspension of more than 12 weeks of mepolizumab between the two, reported a transient worsening of their symptoms and FEV1, which rapidly improved upon reintroduction of mepolizumab145. A clinical trial (NCT03797404) is evaluating the effects on airway remodeling during mepolizumab treatment.
In a pioneering study, Flood-Page and collaborators examined the bronchial biopsies of mild atopic asthmatic patients obtained before and after treatment with three mepolizumab infusions57. They demonstrated that the thickness and density of tenascin in the RBM, the airway TGF-β1+ eosinophils and the BAL concentrations of TGF-β1 were increased in mild asthmatic patients compared to normal subjects. As expected, mepolizumab reduced bronchial eosinophil numbers but also TGF-β1+ eosinophils, thickness and tenascin immunoreactivity and the concentration of TGF-β1 in BAL fluid57.