An Update on Biologic-based Therapy in Asthma

Garry M Walsh

Disclosures

Immunotherapy. 2013;5(11):1255-1264. 

In This Article

Abstract and Introduction

Abstract

Although it is recognized that airway inflammation is key to asthma pathogenesis, the marked heterogeneity in its clinical course and variations in response to treatment make it a challenging condition for the development of novel and effective biologic-based therapies. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibiting IL-4, IL-5 and IL-13. With the notable exception of the anti-IgE monoclonal antibody omalizumab, early clinical trials with cytokine-targeted biologics in patients with asthma were, for the most part, disappointing, despite being highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anticytokine-based therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review summarizes recent evidence demonstrating the effectiveness or otherwise of monoclonal antibody-based therapies in patients with asthma.

Introduction

Asthma represents a complex and heterogeneous chronic disease with diverse inflammatory events that lead to structural and functional changes in the lungs, including goblet cell hyperplasia, airway smooth muscle hypertrophy and subepithelial fibrosis in the airways that in turn give rise to airway hyperresponsiveness (AHR) and reversible airflow limitation.[1] The processes that underlie asthma are characterized by different patterns of cytokine-based inflammation involving diverse cell types such as T cells, B cells, mast cells, eosinophils, basophils, neutrophils and dendritic cells, as well as structural cell types including epithelial, smooth muscle and mesenchymal cells. Accumulating knowledge has driven the development of biological therapies that target the cytokines important in asthma pathobiology.[2] For the majority of asthmatic individuals, inhaled glucocorticoids (GCs) remain the gold-standard therapy because of their potent anti-inflammatory properties that primarily reduce AHR and exacerbations, while improving lung function and quality of life.[101] However, they have well-documented side effects that may contribute to problems of compliance in some patients and are symptomatic medications that require lifetime therapy, with asthma symptoms returning if GCs are withdrawn.[3] It is now generally accepted that asthma is a complex, heterogeneous mixture of syndromes that can be subdivided into several phenotypes on the basis of clinical, physiological and inflammatory markers.[4] Recently, our understanding of the various phenotypes of severe asthma and the identification of biomarkers for each of these phenotypes has improved. Furthermore, the concept of the endotype has been gaining acceptance with regard to the various subtypes of the disease, which are classified according to their unique functional or pathophysiological mechanisms.[2,5]

Approximately 5% of patients have severe refractory asthma that responds poorly or not at all to high-dose inhaled or systemic GC treatment, and these patients account for approximately half of health spending on asthma.[6] The mechanisms underlying this inadequate control of symptoms remain poorly understood. This review, based on English-language original articles in PubMed or Medline that reported significant clinical findings published in the last 5 years, will update the current status, therapeutic potential and potential problems of targeting cytokines in asthma therapy.

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