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.