Targeting of eosinophils in asthma

Abstract

Severe asthma continues to be an important source of morbidity despite the availability of bronchodilators and corticosteroids. Although new treatments are needed, better identification of asthma phenotypes may improve treatment effectiveness. One phenotype that has emerged is eosinophilic asthma. Eosinophils in asthma have been studied for many years, and the evidence suggests they play a major role in some forms of asthma. Eosinophilic asthma can be diagnosed using peripheral blood, sputum eosinophil count or exhaled nitric oxide. Depletion of eosinophils can be achieved by corticosteroids, specific anti-interleukin 5 (IL-5) or anti-IL-5-receptor-alpha therapies, or anti-immunoglobulin E approaches. This editorial refers to the approaches that are being taken in eosinophilic asthma with emphasis on the new investigational anti-IL-5-receptor-alpha antibody, benralizumab.

Keywords::

• asthma
• benralizumab
• eosinophils
• interleukin 5
• interleukin 5 receptor
• mepolizumab

The eosinophil was discovered by TW Jones in 1846, and its staining with aniline was described by Paul Ehrlich in 1879 [1]. The function of the eosinophil has been disputed, with characterizations ranging from deleterious to protective against fungi and parasites in particular [2]. Evidence exists in the literature, however, that eosinophilia is associated with a severe form of asthma and atopic conditions [3]. Eosinophil counts can be reduced by corticosteroids [4], by the anti-immunoglobulin E monoclonal antibody omalizumab [5-7] and by more specific therapies that neutralize or diminish the expression of IL-5, or bind to one of the IL-5 receptor chains [8]. Reductions in the number of eosinophils in sputum by the therapies mentioned above have been associated with a reduction in exacerbation rates and reduced use of oral corticosteroids in subjects with asthma [9-11]. Uncertainty still exists about the extent of the eosinophil depletion needed in the asthmatic airway wall for a therapy to achieve clinical efficacy. Two clinical studies, one negative [12] and one positive [9], achieved similar reductions of eosinophil counts in airway biopsy in subjects with asthma (around 50 – 60% from baseline) after multiple intravenous (i.v.) doses of mepolizumab, which neutralizes IL-5. An apparent difference between the studies was the subject inclusion criteria, with a higher degree of sputum eosinophilia being present in subjects treated in the latter study [9]. Interestingly, in the Haldar study, history of sputum eosinophilia – but not necessarily its presence at baseline – also qualified an individual to enter the study. This suggests that having sputum eosinophilia at any time may qualify an individual as a potential responder to specific anti-IL-5 therapies. Yet sputum is impractical, and its induction and assessment, which are difficult in the clinical setting, require considerable expertise and standardization. It also seems that sputum may not be the best predictor of treatment efficacy, as seen in the study by Castro et al. [11], which showed marginal efficacy (i.e., improvement of at least 0.5 in Asthma Control Questionnaire score) even though the median percentage reduction of sputum eosinophilia was 95.4 in the reslizumab group versus 38.7 in the placebo group. Other markers of eosinophilic asthma – including the simple peripheral blood eosinophil count and exhaled nitric oxide – are being explored, but their positive predictive value is low. Thus, better markers or a panel of markers to identify subjects with eosinophilic asthma phenotype are desirable.

In addition to IL-5, other cytokines, such as interleukin 3 and granulocyte-macrophage colony-stimulating factor, influence the growth and maturation of eosinophils, as well as the homing of eosinophils at inflammatory sites [8]. Notably, the homing of eosinophils in peripheral tissues also seems to be under the influence of interleukin 13 (IL-13). Indeed, blocking IL-13 not only leads to improvements of forced expiratory volume in 1 s in subjects with asthma, but also leads to mild peripheral blood eosinophilia, apparently due to mobilization of eosinophils from the periphery to the blood [13]. Blocking one of the signals responsible for the differentiation, growth, maturation and homing of eosinophils may not be sufficient for treating asthma, whereas blocking several signals may not be feasible presently.

By inducing apoptosis of the culprit cell, the eosinophil [14], benralizumab provokes sustained eosinopenia in peripheral blood and tissues in nonhuman primates. Apoptosis, which is programmed natural cell death, is considered to be a beneficial process, whereas necrosis, which is premature cell death by external factors such as infections, ischemic injury or trauma, is deleterious [15]. Upon development of apoptosis, there is no apparent release of eosinophilic-derived proteins, although interleukin 6 and C-reactive protein levels increase in the first few hours of an i.v. infusion of benralizumab, returning to baseline levels within 24 h [16].

There is a hypothesis that activated eosinophils may lose the expression of the IL-5 receptor [17]. This may potentially influence the activity of benralizumab. It is unclear, however, if this is generalizable to all asthma patients, as all subjects exposed to benralizumab have exhibited eosinophil depletion [16].

In the January 2012 issue of Expert Opinion on Biological Therapy, Ghazi et al. [18] describe some of the early trials conducted with benralizumab. The two main questions that still remain to be answered are what is the level of eosinophil depletion that is achieved in the airways of subjects with asthma following single and multiple dosing; and how may that translate into clinical benefits, if any? We are starting to get answers to these questions.

In a recent study, we assessed the effects of i.v. and subcutaneous (s.c.) doses of benralizumab on airway eosinophils in adults with asthma (unpublished data). Twenty-seven subjects with asthma with sputum eosinophilia ≥ 2.5% were randomized to placebo or varying doses of benralizumab. All subjects were receiving inhaled but not oral corticosteroids. Subjects received an i.v. infusion of placebo or benralizumab (1 mg/kg in cohort 1) or 3 monthly s.c. doses of placebo or benralizumab (100 or 200 mg in cohort 2). Mucosal airway biopsies were obtained via bronchoscopy at baseline and on day 28 after the last dose. The median percent decreases from baseline in mucosal airway eosinophils were 61.9 and 88 – 98% in the i.v. and s.c. regimens, respectively. Although the sample size was small, these reductions in airway eosinophils were greater than those achieved after 1 year of treatment with inhaled steroids [19] or 12 monthly doses of mepolizumab [9], albeit in different patient populations. The safety profile of such tissue depletion in subjects with asthma is currently being tested in a relatively large Phase II trial.

While we await the safety profile and efficacy results of benralizumab-induced eosinopenia, the results summarized by Ghazi et al. in Expert Opinion on Biological Therapy and the results of our recent airway biopsy study support the view that benralizumab may offer clinical benefits in asthma.

Expert opinion

As more insight into the pathogenesis of eosinophilic asthma is obtained, better identification of patients with this form of asthma has led to positive findings. However, the main challenge in this area of research remains finding easier ways than sputum to identify this asthma phenotype. The ultimate goal is to achieve asthma control and reduce exacerbations and health care utilization in easily identifiable eosinophilic asthma patients. The easier identification of the phenotype and its association with more severe asthma, longitudinally, will continue to be challenges in this area. The many clinical trials in subjects with eosinophilic asthma will provide answers to the questions at hand.

Declaration of interest

NA Molfino is a full-time employee of MedImmune, LLC, which is developing benralizumab.

Acknowledgements

The author would like to thank C Lancos and M Gitler of MedImmune, LLC, for their help in editing the article.