Tailored therapy for severe asthma: eosinophils and IL-5


The maturation, recruitment and survival of eosinophils in the respiratory tract are determined by IL-3, GM-CSF, but especially by IL-5, which has a key role in mediating airways eosinophilic inflammation in asthmatic patients.
IL-5 induces the final differentiation of activated B cells into antibody-forming cells and enhances the proliferation and differentiation of eosinophil precursors into mature eosinophils.
In murine models it seems also involved in the airways remodeling, so that the administration of antibodies antagonizing IL-5 largely prevents the sub-epithelial and peribronchial fibrosis induced by the inhalation of allergens.

Different conditions are associated with eosinophilia, such as asthma, atopic diseases, helminth infestation, drug hypersensitivity and malignancies; for these reasons several monoclonal antibodies such as anti-IL5 Mepolizumab ( Bosatria ), Reslizumab and Benralizumab have been studied.

Mepolizumab is a humanized antibody that binds IgG1κ-type IL-5 preventing its linking to the specific receptor. A first study was conducted on the treatment of idiopathic hypereosinophilic syndrome and Churg-Strauss syndrome, in which a significant reduction was demonstrated in the administration of systemic corticosteroids with a good disease control.

The available data show a reduced number of exacerbations in steroid-dependent asthma patients with a concomitant reduction of sputum eosinophils; on the contrary, lung function and bronchial hyperresponsiveness did not improve.

A more recent work suggested that Mepolizumab administered at a dose of 75, 250 and 750 mg significantly reduces the need for systemic steroids and the number of exacerbations in severe eosinophilic asthma patients.
The efficacy of this drug in terms of improved asthma control and discontinuation of systemic steroids was evident only in trials focused on persistently hypereosinophilic patients, confirming the need for defining asthma phenotypes.
In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma requiring daily oral glucocorticoid therapy to maintain control, Mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms.
Another recent, randomized, double-blind, double-dummy study, involved 576 patients assigned to receive Mepolizumab administered as either a 75-mg intravenously dose or a 100-mg subcutaneously dose, or placebo every 4 weeks for 32 weeks. The rate of exacerbations was reduced by 47% among patients receiving intravenous Mepolizumab and by 53% among those receiving subcutaneous Mepolizumab, as compared to those receiving placebo.

A clinical trial tested Reslizumab in poorly controlled asthma and airways eosinophilia. A significant reduction of sputum eosinophils was found with a parallel significant improvement in quality of life, FEV1, and disease control, in particular reference to a reduction of exacerbations.

Benralizumab is another drug tested in clinical trial. It is a monoclonal antibody directed against the alpha chain of IL-5 receptor, administered intravenously.
In clinical trials Benralizumab reduced the levels of peripheral eosinophils in moderate asthma patients, its effects persisting up to 8–12 weeks.
Other authors have demonstrated that Benralizumab induces antibody dependent cell-mediated cytotoxicity on eosinophils and basophils, resulting in a significant reduction of blood eosinophils and their bone marrow precursors. ( Xagena )

Menzella F, Lusuardi M, Galeone C, and Zucchi L, Multidiscip Respir Med 2015; 10(1): 1

XagenaMedicine_2015



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