Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling
Introduction
Asthma is a chronic disease characterized by reversible airway obstruction, pulmonary inflammation and airway remodeling [1]. Although current standard therapies (including corticosteroids and β2 receptor agonists) effectively provide symptomatic control for the majority of asthma patients, patients with severe or difficult asthma do not respond well to these therapies [2]. Furthermore, no therapeutic agent is effective in preventing airway remodeling, which involves epithelial damage, mucus gland hyperplasia, airway smooth muscle hypertrophy, and subepithelial fibrosis [3]. These structural changes of the airway, caused by chronic airway inflammation and a repeated damage/repair process, are fundamental components for the development of irreversible airway hyperresponsiveness and directly contribute to the severity of asthma [4]. Therefore, developing therapeutic agents that can suppress airway tissue remodeling would fulfill a significant unmet medical need in the treatment of asthma.
IL-13 is an immunomodulating cytokine produced by activated T cells and many other cell types [5]. The involvement of IL-13 in asthma pathogenesis has been extensively studied [6]. In humans, IL-13 levels are upregulated in asthmatics both systemically and in the lungs during asthmatic attacks [7]. Certain IL-13 polymorphisms are associated with high serum IgE levels and high risk for asthma development [8]. Furthermore, IL-13 exhibits stimulatory activity to multiple cell types that are involved in asthma, including B cells, mast cells, eosinophils, pulmonary epithelial cells, fibroblasts and airway smooth muscle cells [5]. In animal studies, direct administration of recombinant IL-13 or overexpression of IL-13 in the lungs induced asthma-like airway inflammation and airway remodeling [9], [10]. Blockade of IL-13 using a receptor fusion protein inhibited the allergic asthma response in mice [11], [12]. Taken together, these results strongly suggest that IL-13 plays a crucial role in the pathogenesis of asthma. Therefore, a neutralizing monoclonal antibody (mAb) to IL-13 could provide therapeutic benefits to asthmatic patients.
A neutralizing rat anti-mouse IL-13 mAb was generated using standard hybridoma technology. To fully evaluate the impact of this anti-IL-13 mAb on different pathological aspects of asthma, especially on airway remodeling, a chronic asthma model was developed using repeated intranasal antigen (Ag) challenge to sensitized mice. After 5 weeks of weekly challenge, the mice developed multiple pathological features that represented those of human asthma, including airway hyperresponsiveness (AHR), severe pulmonary inflammation and airway remodeling. When administered at the same time as each Ag challenge, anti-IL-13 antibody effectively suppressed AHR, eosinophil infiltration, goblet cell hyperplasia, excessive mucus production, as well as subepithelial fibrosis. These results indicated that a neutralizing mAb to human IL-13 could potentially control asthma symptoms as well as preserve normal airway structure and function.
Section snippets
Neutralizing anti-IL-13 mAb inhibits AHR to methacholine stimulation
Increased airway responsiveness and sensitivity to nonspecific stimulation is a major pathological characteristic of human asthma. To evaluate the effect of anti-IL-13 mAb on airway constriction, whole body plethysmography was used to measure airway resistance to incremental concentrations of methacholine. Mice that were sensitized with OVA but challenged with PBS for 5 weeks revealed a low baseline airway resistance (represented as Penh) and the Penh values were slightly increased upon
Discussion
IL-13 is a pleiotropic cytokine that is involved in multiple physiological and pathological processes [5]. To date accumulating evidence indicates that IL-13 plays a key role in the pathogenesis of asthma [6], which makes it a very attractive target for the treatment of asthma. In this report, using a mouse model of chronic asthma, we found that the anti-IL-13 mAb significantly inhibited methacholine induced AHR, pulmonary inflammation, multiple cytokine/chemokine production, goblet cell
Mice
Naïve BALB/c mice were purchased from Charles Rivers Laboratories (Raleigh NC). All mice were maintained under specific pathogen free conditions, and all experimental protocols were approved by the Institutional Animal Care and Use Committee of Centocor.
Reagents
Ovalbumin (OVA) and methacholine were purchased from Sigma (St. Louis, MO).
Normal rat IgG and peroxidase-conjugated streptavidin were from Jackson ImmunoResearch (West Grove, PA). ELISA reagents for measuring serum immunoglobulin isotypes were
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