Current therapies for asthma are aimed at controlling disease symptoms. For the majority of asthmatics glucocorticoid-based inhaled anti-inflammatory therapy is effective. However, a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Biopharmaceutical approaches may identify small molecules that target key cells and mediators that drive the inflammatory responses underlying the pathogenesis of asthma. Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IgE, IL-4 and IL-5.
by Dr Garry M. Walsh
Background
Asthma is now one of the most common chronic diseases in developed countries and is characterised by reversible airway obstruction, airway hyper reactivity (AHR) to normally benign inhaled substances and airway inflammation. The key pathological features of airway inflammation in asthma include infiltration of the airways by activated lymphocytes and eosinophils; damage to, and loss of, the bronchial epithelium; mast cell degranulation; mucous gland hyperplasia; and collagen deposition in the epithelial sub-basement membrane area. Asthma pathology is associated with the release of myriad pro-inflammatory substances including lipid mediators, inflammatory peptides, chemokines, cytokines and growth factors. In addition to infiltrating leukocytes, structural cells in the airways, including smooth muscle cells, endothelial cells, fibroblasts and airway epithelial cells, are all important sources of asthma-causing or -enhancing mediators [1]. This complex scenario means that potential targets for therapeutic intervention are many and varied and the task of developing successful therapy a challenging one.
Current therapy
Anti-inflammatory therapy in asthma is largely reliant on glucocorticoids (GC) - particularly in their inhaled form - with or without the addition of short- or long-acting bronchodilators. Although the symptoms of most asthmatics are satisfactorily controlled by regular use of inhaled GC, these are symptomatic medications requiring lifetime therapy for the patient and their use often raises concerns with respect to compliance, particularly in children and adolescents. There is increasing evidence that long-term use of inhaled GC, especially in high doses, can cause systemic adverse effects, including adrenal suppression, reduced growth and reduced bone-mineral density, as well as local side effects such as dysphonia. Moreover, a significant sub-group of asthmatic patients responds poorly or not at all to high-dose inhaled or systemic GC treatment. As there are few alternative treatments, these patients can be difficult to treat and may require frequent hospitalisation [1]. Thus the identification of potential targets for therapeutic intervention is an important goal in asthma research. Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs.
Interleukin-5
Much of the inflammation in asthma is due to the inappropriate accumulation of eosinophils in the asthmatic lung. Eosinophil numbers in the lungs correlate with disease severity and their pro-inflammatory products are major contributors to airway inflammation in asthma, including epithelial damage and loss, AHR, mucus hypersecretion and airway remodelling [Figure 1]. Interleukin (IL)-5 is crucial to the development and release of eosinophils from the bone marrow, their enhanced adhesion to endothelial cells lining the post-capillary venules and their persistence, activation and secretion in the tissues. Several animal models of asthma including the use of primates have provided good evidence that inhibiting the effects of IL-5 using specific mAb inhibited eosinophilic inflammation and AHR. Given its central role in regulating eosinophil development and function IL-5 was therefore chosen as a potentially attractive target to prevent or blunt eosinophil-mediated inflammation in patients with asthma. Several clinical trials with mepolizumab, a humanised anti-IL-5 mAb, reported that treatment of patients with mild to severe asthma resulted in a significant reduction in the numbers of blood and sputum eosinophils but no significant effects on clinical outcomes [2]. The most likely cause was that subjects were recruited to the studies on the basis of clinical and physiological characteristics rather than the presence of eosinophilic airway inflammation. Eosinophilic inflammation of the airway is associated with the risk of disease exacerbations in asthma which are one of the most common causes of hospitalisation of these patients. Importantly therefore, two randomised, double-blind, placebo-controlled, parallel-group studies demonstrated that mepolizumab treatment of asthmatics not only reduced eosinophil numbers in the blood and sputum but also resulted in a significant reduction in asthma exacerbations [3,4]. The main study outcomes are summarised in Table 1. Mepolizumab attenuates aspects of eosinophil-induced airway inflammation refractive to GC therapy in highly selected asthma patient populations and may therefore potentially interfere with eosinophil-induced airway remodelling in addition to reducing asthma exacerbations. The actual proportion of asthmatic patients who might benefit from treatment with mepolizumab or other anti-IL-5 mAb such as reslizumab can only be established by more comprehensive, well-designed and controlled clinical trials.
Chemokines are a family of small, secreted proteins that control migration of monocytes, lymphocytes, neutrophils, eosinophils and basophils. Eotaxin is an inducible, secreted chemokine that promotes selective recruitment of eosinophils from the blood into inflammatory tissues via CCR3, a seven-transmembrane-spanning G protein-coupled receptor. Several clinical studies have suggested a pivotal role for CCR3 ligands/CCR3 in the eosinophilic inflammation characteristic of atopic dermatitis, asthma and allergic rhinitis, thus blockade of this receptor may have pronounced beneficial effects in asthma. Furthermore, there is evidence from animal models that IL-5 and eotaxin may work in a synergistic fashion to promote the release of mature eosinophils from the bone marrow. Thus it might be that combination therapies of CCR3 antagonist and humanised anti-IL-5 mAb could prove an effective approach to limit or prevent eosinophil toxicity in the asthmatic lung [1].
Interleukin-4 & 13
IL-4 and its close relative IL-13 are important in IgE synthesis by B lymphocytes. Both cytokines are important in eosinophil accumulation and activation signalling through a shared surface receptor, IL-4Ra which then activates the transcription factor STAT-6. Studies with soluble IL-4Ra given in a nebulised form demonstrated that the fall in lung function induced by withdrawal of inhaled corticosteroids was prevented in patients with moderately severe asthma. However, despite these promising findings subsequent trials were not as successful and consequently this treatment is no longer being developed. Other approaches for blocking the IL-4 receptor include administration of antibodies against the receptor and mutant IL-4 proteins. For example, a peptide-based vaccine for blocking IL-4 was recently developed by antigenic prediction and structure analysis of the IL-4/receptor complex. Vaccine construction involved a truncated hepatitis B core antigen as carrier with the peptide inserted using gene engineering methods. Compared with control animals, immunised allergen-challenged OVA-sensitised mice had significant reductions in IgE, eosinophil accumulation in bronchoalveolar lavage, goblet cell hyperplasia, tissue inflammation and methacoline-induced respiratory responses [1].
In animal models, IL-13 mimics many of the pro-inflammatory changes associated with asthma and is therefore another potential therapeutic target for the resolution of airway inflammation. Two receptors for IL-13 have been described - IL-13Ra 1 and IL-13Ra2. The latter exists in soluble form and has a high affinity for IL-13 and can thus “mop up” secreted IL-13; in mice IL-13Ra2 blocked the actions of IL-13, including IgE production, pulmonary eosinophilia and AHR. A humanised IL-13Ra2 is now in clinical development as a novel therapy for asthma. As stated above IL-4Ra2 is the signaling component of the heterodimeric receptor complex shared by both IL-4 and IL-13. It therefore represents an attractive target to antagonise the effects of both cytokines as this approach may be more effective than targeting either IL-4 or IL-13 alone. Recently, a recombinant human IL-4 variant, pitrakinra (Aerovant), was developed that competitively inhibits the IL-4Ra receptor complex to interfere with the actions of both IL-4 and IL-13. In two independent small-scale parallel group phase 2a randomised, double-blind, placebo-controlled clinical trials, patients with atopic asthma were treated with pitrakinra or placebo given either as a single subcutaneous dose or via nebulisation twice daily. Compared with placebo, allergen challenge-induced decreases in lung function were significantly attenuated after four weeks of inhalation of pitrakinra. The frequency of spontaneous asthma attacks requiring rescue medication use was also diminished in the study in which pitrakinra was given subcutaneously. Further large scale clinical trials on patients with day to day asthma are required to fully establish whether pitrakinra is an effective and safe asthma treatment.
Tumour necrosis factor-a
TNF-a is expressed in asthmatic airways and is thought to contribute to AHR, airway remodelling and GC resistance in asthma, therefore representing a potential target for therapy. Humanised anti-TNF mAb (infliximab) and soluble TNF receptor blockers (etanercept) have been developed and preliminary clinical studies have shown significant improvements in lung function, airway hypereactivity and exacerbation rate, particularly in patients with severe asthma refractory to GC treatment. However, some clinical studies reported negative findings so there appears to be heterogeneity in response to TNF-a antagonism. There are also concerns over potential side-effects in some subjects treated with anti-TNF therapy including higher rates of solid organ malignancies or latent TB reactivation.
Immunoglobulin-E inhibitors
IgE plays a central role in the pathogenesis of diseases associated with immediate hypersensitivity reactions, including allergic asthma. IgE-dependent biological actions are a result of it binding to high-affinity (FceRI) receptors on mast cells and basophils and to low-affinity (FceRII) receptors on macrophages, dendritic cells and B lymphocytes. Allergen molecules then crosslink adjacent Fab components of IgE on the cell surface thereby activating intracellular signal transduction that in mast cells, leads to the release of preformed mediators and the rapid synthesis and release of other mediators responsible for bronchoconstriction and airway inflammation. Omalizumab (rhuMab-E25) is a humanised monoclonal antibody directed to the FceRI binding domain of human IgE that has now progressed through clinical development. Consistent findings from several comprehensive randomised placebo-controlled trials demonstrate that omalizumab is an effective therapy for patients with symptomatic moderate-severe allergic asthma. It reduced the frequency of exacerbations and improved symptom control while allowing a reduction in the use of GC and a2-agonists. It appears to be well tolerated and also improved patient quality of life and produced a significant improvement in lung function. Although more long-term studies are needed to fully elucidate the benefit and safety of anti-IgE therapy in asthma, its niche may be in the treatment of patients with severe asthma who are dependent on oral GC.
Conclusion
A large body of evidence from in vitro studies and asthma animal models has informed development of promising novel compounds targeted at diverse aspects of the inflammatory cascade underlying asthma pathogenesis. To date antagonism of IL-5 or IgE appears to offer the most promise although both treatments are expensive and require careful patient selection. However, more carefully conducted trials with anti-IL-5 mAb are required to determine the actual proportion of asthmatic patients who might benefit from treatment. Furthermore, it may transpire that the use of novel anti-inflammatory therapies in tandem rather than as monotherapy may be the way forward. The ultimate goal would be to develop asthma treatments that are truly disease modifying rather than the symptomatic treatments currently available.
References
1. Walsh GM. Emerging drugs for asthma. Expert Opin Emerg Drugs 2008; 13(4): 643-53.
2. Walsh GM. Mepolizumab and eosinophil-mediated disease. Curr Med Chem 2009; 16(36): 4774-8.
3. Haldar P et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: 973-84.
4. Nair P et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl J Med 2009; 360: 985-93
The author
Garry M. Walsh
School of Medicine & Dentistry
University of Aberdeen
Aberdeen, United Kingdom
e-mail: g.m.walsh@abdn.ac.uk
