Interleukin 13 - a potential therapeutic target in the management of allergic asthma. Author Affiliations:

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1 40 Interleukin 13 - a potential therapeutic target in the management of allergic asthma Authors: Matthew Boroditsky¹, BHSc, Michelle Yee¹, BSc, John-Paul Oliveria¹, BSc, PhD(c) Author Affiliations: 1. Department of Medicine, Division of Respirology, McMaster University, Hamilton, Ontario Author for Correspondence: John Paul Oliveria, BSc, PhD(c) olivejp@mcmaster.ca ABSTRACT: Asthma is a common chronic non-communicable disease, affecting nearly 334 million people globally, and 3 million Canadians across all age ranges. The allergic asthma phenotype is one of the more dominant forms of asthma in early life. Allergic asthma has been defined as a chronic inflammatory disorder mediated by IgE, and is associated with variable airflow obstruction, bronchial hyperresponsiveness and type 2 inflammation. The pathogenesis of allergic asthma has been associated with an increase in type 2 cytokines including IL-4, IL-5, and IL-13, which play pivotal roles in the development of IgE-mediated responses. Specifically, IL-13 plays a diverse and fundamental role in allergic asthma pathogenesis. IL-13 promotes airway inflammation through the activation of macrophages, dendritic cells, and eosinophils. It further induces airway remodeling by enhancing the proliferation of fibroblasts. IL-13 also plays a predominant role in mucus production through the stimulation of airway epithelial cells and induction of goblet cell hyperplasia. Finally, IL-13 has been shown to be one of the key drivers of airway hyperresponsiveness (AHR) through the activation of airway smooth muscle cells. This suggests that IL-13 may drive the disease progression and contribute to corticosteroid resistance in some patients. Thus, already existing anti-il-13 monoclonal antibodies has shown great promise as an ideal therapeutic agent in the management of asthma, and the effect of anti-il-13 therapeutics in managing allergic asthma need to be further elucidated. BACKGROUND Asthma is a common chronic non-communicable disease, affecting nearly 334 million people globally across all age ranges.1 Specifically, the Global Burden of Asthma estimates that roughly 14% of the world s pediatric population experience asthmatic symptoms.1 Looking at Canadian demographics, approximately 3 million people are affected by asthma, which is about 10% of the population2. Due to their profound prevalence, respiratory diseases (namely lung cancer, asthma, and COPD) are placing a large burden on the Canadian economy, with roughly $12 billion dollars required for both direct health care costs (hospitals, therapies, and physicians) and indirect costs (premature death and long term disability) in ,4 Out of all respiratory illnesses, asthma is contributing significantly to these costs.3 It is projected by the Conference Board of Canada that without concerted action, the cost of asthma management alone by the Canadian Health Care system will rise to $4.2 billion by It is apparent that the burden of asthma is rising, both in incidence and economic demand, standing as a significant obstacle to the health care system. Thus, the understanding behind the pathogenesis of asthma and the many factors that contribute to its progression are essential to moving forward as a nation. Pathogenesis of Allergic Asthma Asthma is understood as a heterogeneous disease with differences in severity, natural history, comorbidities, and responses to treatment.6 Asthma has been defined as a chronic inflammatory disorder associated with variable airflow obstruction and bronchial hyperresponsiveness.6 Furthermore, the asthmatic response has been elucidated as an integrated and multifaceted response in the conducting airways of the lungs.6 The allergic asthma phenotype is one of the more dominant forms of asthma in early life.6 The pathogenesis of allergic asthma has been associated with an increase in helper T lymphocytes (CD4+ T cells), and the release of type 2 cytokines including IL- 4, -5, and -13, which play pivotal roles in the development of

2 Interleukin 13 - a potential therapeutic target in the management of allergic asthma 41 this IgE-mediated response. 7,8 Furthermore, these cytokines are associated with complex pathways leading to IgE production and the proliferation of inflammatory cells, specifically eosinophils and mast cells, contributing to the bronchial hyperresponsiveness seen in patients with asthma.7 Allergen bronchoprovocation tests have been key in providing further information surrounding allergic respiratory diseases.9 The general paradigm for atopic disease development revolves around the ability of the first allergen exposure to lead to IgEmediated sensitization, consequently shifting the immune response towards atopic development.6 The presentation of the allergen by antigen-presenting cells (APCs) to CD4+ Th2 cells has been elucidated as a primary mechanism in the development of atopy.8 The airways of allergic asthmatics have been characterized structurally by the presence of lymphocytes, eosinophils, and mast cells, in addition to epithelial desquamation, goblet cell hyperplasia, and the thickening of the submucosal layer.8 Antigen cross-linking of IgE antibodies bound on airway mucosal mast cells and basophils initiates an inflammatory response.9 Specifically, mediators such as histamine and leukotrienes are released from these cells, in addition to the type 2 cytokines, IL-4, -5, and In allergic asthma, bronchial inflammation is hallmarked primarily by eosinophilia, and changes in the levels of eosinophils can be used to determine severity and treatment of disease.9 It is apparent that the pathogenesis of allergic asthma has a very broad range of interacting contributing factors, making it a very elusive disease for which it is difficult to provide a direct treatment suitable for everyone. Current Guidelines in the Treatment of Allergic Asthma Currently, the Global Initiative for Asthma (GINA) has outlined a step-wise approach for the management of allergic asthma. 10 GINA outlines a specific control based management cycle for asthma involving the constant review, assessment, and adjustment of treatment regimens for patients (Refer to GINA guidelines). 10 The first process involves reviewing the asthmatic patient s response, including their symptoms, exacerbations, medication side-effects, and their overall satisfaction with the treatment. 10 Secondly, the guidelines highlight the assessment of the patient, which involves making a diagnosis, providing a method for symptom control, consideration of risk factors (including lung function), evaluating inhaler technique and adherence, and taking the patient s preference into consideration throughout. 10 Finally, the guidelines discuss adjusting the patient s treatment, which involves looking into a variety of asthmatic medications, discussing non-pharmacological strategies, and treating modifiable risk factors. 10 Overall, these three steps work in a continuous cycle throughout the patient s life with asthma. According to GINA guidelines, the first preferred choice in controlling asthmatic symptoms is purely using a short acting beta agonist (SABA) as needed. 10 This treatment would then progress to using low dose inhaled corticosteroids (ICS), with the possibility of substituting a leukotriene receptor antagonist (LTRA) if the ICS were not effective. 10 Further progression in the treatment will involve increasing the doses of both ICS and LTRA. Furthermore, the addition of high dose ICS or tiotropium (>12 years old) should also be taken into consideration. 10 Finally, the last step for patients who are not showing benefits from conventional treatments, would be the progression to more specialized treatments like omalizumab (anti-ige) or mepolizumab (anti-il-5), in conjunction with low dose oral corticosteroids (OCS). 10 The classic interventions in managing asthma are meeting resistance due to the heterogeneity behind the pathogenesis of asthma and the inefficacy of GOLD standard treatments in managing all asthmatic patient. Furthermore, the use of ineffective treatments in managing asthma is putting a large financial burden on the health care system due to increased exacerbations and hospitalizations.3 Thus, there is a large push towards the individualization of treatment regimens for patients who may not be as compliant with conventional therapies, and patients known to have severe refractory asthma (SRA). 10 SRA has been characterized by persistent airway obstruction with frequent and often severe asthma exacerbations.1 These exacerbations have shown to continue despite the patients being on high doses of ICS given with or without long acting beta agonist (LABA) or OCS. 11,12 Patients with SRA represent roughly 5-10% of the overall asthmatic population, contributing disproportionately to health care expenditures, and thus creating a significant need for new therapies for asthma control. 13,14 Overall, although concrete guidelines for treating the asthmatic population do exist, a small subset of that population continues to create a large burden for the health care system, pushing the need for new treatment options and therapy regimens in line with personalized medicine. IL-13 and its Role in Allergic Asthma The diverse role of type 2 cytokines in allergic asthma has been extensively researched and continues to be an area of interest. Specifically, IL-13 plays a diverse and fundamental role in allergic asthma pathogenesis. Human IL-13 is a 17-kDa glycoprotein cloned from activated T cells8. The IL-13 gene is located on chromosome 5q, at the loci 5q31-q33.7 It has been shown to have effects on both inflammatory and structural cells in the progression of the disease. 8,15 Specifically, IL-13 promotes airway inflammation through the activation of macrophages, dendritic cells, and eosinophils. 8,15 It further induces airway remodeling by enhancing the proliferation of fibroblasts. 8,15,16 IL-13 plays a predominant role in mucus production through the stimulation of airway epithelial cells and induction of goblet cell hyperplasia. 8,15,16 Finally, IL-13 has shown to be one of the key drivers of airway hyperresponsiveness (AHR) through the activation of airway smooth muscle cells. 8,15,16 It is clear that IL- 13 has a multifaceted role in allergic asthma pathogenesis and has been elucidated as a cause behind the resistance to many interventions (Figure 1). Specifically, persistence of asthma symptoms, despite increasing doses of ICS, has been linked to increased levels of IL-13 in the airways. 17,18,19,20 This suggests that IL-13 may drive the disease progression and contribute to corticosteroid resistance in some patients. IL-13 is produced by both hematopoietic and nonhematopoietic cells, 21,22 but most noticeably from activated T lymphocytes (especially Th2), mast cells, basophils, and ILC2s (Innate Lymphoid Cell 2).9 The effector functions of this cytokine have been investigated in primary literature using transgene-positive mice16. Researchers used a Clara cell 10-kDa promoter to up-regulate IL-13 selectively in the lung,

3 42 McMASTER UNIVERSITY MEDICAL JOURNAL Figure 1: IL-13 and IL-4 Effector Functions. Schematic diagram of potential cellular effects of IL-4/IL-13 on inflammatory and structural cells in asthma. Both cytokines can be produced by Th2 cells and mast cells, promoting airway inflammation through the activation of eosinophils, macrophages and dendritic cells. They also induce airway remodeling by enhancing proliferation and activation of fibroblasts. They further induce IgE class switching by B-cells. They induce increased mucus production through stimulating airway epithelial and goblet cells. Finally, they induce airway hyperresponsiveness by activating airway smooth muscle. which in contrast to transgene-negative littermates, demonstrated significant inflammatory responses around small and large airways and in the surrounding parenchyma. 16 Specifically, these transgene-positive mice demonstrated an increase in airway eosinophilic inflammation, mucus production, collagen deposition, eotaxin production, and airway hyperresponsiveness (AHR). 16 Further confirming IL-13 s role in asthma pathogenesis, Blanchard et al. demonstrated, in a mouse model, a dose-dependent relationship between human IL-13 and AHR/eosinophilia responses. 23 This relationship was strengthened when mice were administered an anti-human IL-13 monoclonal antibody, which resulted in significantly decreased levels of airway eosinophils and AHR. 23 IL-4 and IL-13 Comparison The effector and signaling functions of IL-13 have significant overlap with IL-4 and both have been thought to play a very similar role.9 The gene encoding IL-13 is only 25kb upstream of the IL-4 gene with the same orientation, raising questions into whether a gene duplication event existed during evolution.8 Furthermore, IL-13 has been shown to have approximately 25% homology with IL-4 and shares many structural characteristics and functional properties.8 It is speculated that the similarities in functional properties are due to the sharing of the receptor chain in their individual multimeric receptor complexes8. Specifically, both IL-4 and IL-13 share a signaling pathway through JAK/STAT6.8 Nevertheless, in the analysis of their effector functions, IL-4 and IL-13 both demonstrated distinct effector functions. For example, mucus production was unaffected by allergen exposure in STAT6 deficient mice, while IL-4 deficient mice still demonstrated increased mucus production, highlighting a pathway distinct from IL- 4, possibly mediated by IL-13.9 Furthermore, when IL-13 knockout mice were exposed to allergen, they did not develop goblet cell hyperplasia. 24 Thus, the individual roles of IL-4 and IL-13 both have similarities and distinct differences, and thus should not be primarily associated with redundant responses. IL-13 Signaling Functions in Type 2 Response IL-13 displays unique receptor signaling characteristics in the pathogenesis behind type 2 inflammatory response, as shown in studies evaluating STAT6 in genetically modified mice. 25 IL-13 interacts primarily with two receptors, a heterodimeric receptor composed of an IL-4Rα chain linked to an IL-13Rα1 chain, and a monomeric receptor composed of an IL-13Rα2 chain (Figure 2). 26,27 IL-13 has been shown to predominantly signal through the heterodimeric receptor with the IL-13Rα1 chain. 27 Nevertheless, the IL-13Rα1 chain has been shown to bind directly with both soluble IL-4 and IL-13 proteins and is able to send a downstream signaling cascade through the activation of JAK/ STAT6. 25 This heterodimeric receptor, along with the IL-4α1/Υc chain binding strictly to IL-4, is primarily associated with the initiation of the type 2 response. The role of the monomeric IL-13 receptor, IL- 13Rα2, has been unclear for a while; however, it has been speculated to act as a decoy receptor providing a regulatory mechanism for IL- 13 activity. 27 The independent signaling role of the IL-13Rα2 receptor has provided insight into the role of IL-13 signaling outside a type 2 inflammatory context, specifically in areas such as cancer development and lung fibrosis, diseases not covered within the scope of this review. 28 Current Anti-IL-13 Therapies The persistence of physiologic improvements associated with anti-il-13 therapies and the subsequent decrease in type 2 serum markers creates a unique area for clinical trials to investigate. 29 Specifically, studies are analyzing whether these interventions can normalize the activity of innate immune cells that modify or present allergen to T cells and thus reduce their ability in exacerbating and maintaining a type 2 response. 29 There have been several studies utilizing IL-13 blockades as a treatment option for asthmatics. For example, Gauvreau et al. looked into the ability of humanized IgG1 antibodies (IMA-638 and IMA-026) to neutralize IL- 13 bioactivity (n=56), which was hypothesized to inhibit the allergeninduced late-phase asthmatic responses, AHR, and inflammation in patients with asthma. 30 Furthermore, studies have been investigating

4 Interleukin 13 - a potential therapeutic target in the management of allergic asthma 43 Figure 2 45 : IL-4 and IL-13 receptor signaling pathways. IL-13 interacts primarily with two receptors, the heterodimeric receptor composed of IL-4Rα chain linked to an IL-13Rα1 chain, and a monomeric receptor composed of IL-13Rα2 chain, binding strictly to IL-13. Additionally, IL-4 also interacts with two receptors, the heterodimeric receptor composed of IL-4α chain linked to IL-13Rα1 chain, and another heterodimeric receptor composed of an IL-4α1 chain and Υc chain. When bound onto their respective receptors, signals are directed through STAT6, a transcription factor, which further activates downstream signaling via transcription of genes associated with IgE production via class switch recombination. the use of monoclonal antibodies targeting the IL-4Rα receptor subunit (Dupilumab), which mediates both IL-4 and IL-13 signaling, in the treatment of asthma and atopic dermatitis. Currently there is an ongoing randomized, double blind, placebo-controlled, parallel group study underway evaluating the efficacy and safety of Dupilumab in patients with persistent asthma. 31 The primary endpoints of the study consist of analyzing the patient s rates of asthma exacerbation over 52 weeks and their absolute change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) over 12 weeks. 31 Recently, after conducting phase II clinical trials, Lebrikizumab, an anti-il-13 monoclonal antibody, was shown to reduce exacerbation rates and improve FEV1 measurements in patients with uncontrolled asthma, particularly those with high concentrations of type 2 biomarkers 32 (periostin and eosinophilia). 33 In 2016 there was an attempt to conduct two identical phase III multicenter placebo-controlled randomized controlled trials (LAVOLTA I and II) to assess the efficacy and safety of Lebrikizumab in asthmatics. 34 The study utilized more than patients across 28 countries with uncontrolled asthma, despite the use of ICS and at least one secondary control medication for their asthmatic symptoms. 34 The primary endpoint of both studies was the rate of asthma exacerbations over the 52 weeks of the study. In their results, one study met their primary endpoints, showing that Lebrikizumab significantly reduced exacerbations in people with severe asthma, while the second study did not replicate this reduction in exacerbations. 34 Clinical studies using Lebrikizumab in asthma, chronic-obstructive pulmonary disease (COPD), atopic dermatitis, and idiopathic pulmonary fibrosis are currently ongoing. 35,36,37,38 CONCLUSION Overall, our understanding of IL-13 s role has expanded substantially since its original discovery in the late 1980s in Th2 cells 39,40 to the first clinical trial using monoclonal antibodies to target this cytokine. 33 The scientific community has a good understanding of the role of IL-13 in the pathogenesis of allergic asthma. Nevertheless, there is still a need for more research surrounding the role of IL-13 in patients suffering from chronic lung diseases such as COPD and pulmonary arterial hypertension. 29 Furthermore, tests for gene polymorphisms show promise in becoming powerful pharmacogenetic biomarkers and predictors of ethnic variables contributing to asthma. 41,42 Most noticeably, there still remains opportunity to understand the role of IL-13 outside of a type 2 context and new possible points for intervention exist. Specifically, analyzing the role of IL-13 in specific forms of lymphoma and breast cancers remains an area of research. 29 Additionally, further research is needed to elucidate the mechanisms in which exogenous pollutants and the endogenous environment can upregulate IL-13 expression, leading to the development of many atopic diseases. 43,44 References 1. Global Asthma Network. The Global Asthma Report , (2014). 2. Asthma, by sex, provinces and territories (Number of persons). Statistics Canada (2016). at < cst01/health50a-eng.htm> 3. Public Health Agency of Canada. Economic burden of illness in Canada. Government of Canada, Ottawa, Canada (2014). at < gc.ca/publicat/ebic-femc98/pdf/ebic1998.pdf> 4. Public Health Agency of Canada. Chronic Respiratory Diseases Canadian Best Practices Portal - CBPP. (2010). at < chronic-diseases/chronic-respiratory-diseases/> 5. Lung Disease Imposes Major Costs on Canada s Economy. The Conference Board of Canada (2015). at < newsrelease/ /lung_disease_imposes_major_costs_on_canada_s_ economy.aspx> 6. Kushnir, N. et al. Allergic Asthma: Symptoms and Treatment. World Allergy Organization 127, (2015). 7. Wills-Karp, M. IMMUNOLOGIC BASIS OF ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS. Annu. Rev. Immunol. 17, (1999).

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