The Intriguing Role of Interleukin 13 in the Pathophysiology of Asthma.

Giancarlo Marone,Stefania Loffredo,Enrico Heffler,Valentina Pucino,Antonio Pecoraro,Francescopaolo Granata,Gilda Varricchi,Guy W Scadding

doi:10.3389/fphar.2019.01387

Abstract

Approximately 5–10% of asthmatic patients worldwide suffer from severe asthma. Experimental and clinical studies have demonstrated that IL-13 is an important cytokine in chronic airways inflammation. IL-13 is involved in Th2 inflammation and has been identified as a possible therapeutic target in the treatment of asthma. Two different human monoclonal antibodies (mAbs) anti-IL-13 (tralokinumab and lebrikizumab) block binding and signaling of IL-13 to its receptors, IL-13Rα1 and IL-13Rα2. Several randomized, double-blind, placebo-controlled multicenter studies have evaluated the safety and efficacy of tralokinumab and lebrikizumab in the treatment of adult patients with severe asthma, but all have failed to meet their primary endpoints. No serious adverse events related to the treatment with these anti-IL-13 mAbs have been reported in these studies. These negative clinical results contrast with positive findings from blocking IL-13 signaling in experimental models of asthma, raising doubts about the transferrable value of some models. Interestingly, dupilumab, a mAb which blocks both IL-4 and IL-13 signaling reduces exacerbation rates and improves lung function in severe asthmatics. These results suggest that IL-4 and IL-13 share some, but not all functional activities in airway inflammation. Tralokinumab might show efficacy in a highly selected cohort of asthmatics characterized by overexpression of IL-13.

Highlights

Bronchial asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction, bronchial hyperreactivity (BHR), mucus overproduction, angiogenesis, and airway remodeling (Detoraki et al, 2010; Holgate et al, 2015)
Patients treated with dupilumab, a monoclonal antibody (mAb) against IL-4Rα, the common receptor for both IL-4 and IL-13 had a significant reduction in polyp size and improvement in symptoms and nasal and olfactory function (Bachert et al, 2016)
Three phase 2 clinical trials (Piper et al, 2013; Brightling et al, 2015; Russell et al, 2018) and three phase 3 clinical trials (Panettieri et al, 2018; Busse et al, 2019) have shown that tralokinumab did not lower the annual exacerbation rate and did not improve asthma control questionnaire (ACQ)-6 scores compared to placebo in severe uncontrolled asthmatic patients

Summary

Introduction

Bronchial asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction, bronchial hyperreactivity (BHR), mucus overproduction, angiogenesis, and airway remodeling (Detoraki et al, 2010; Holgate et al, 2015). Despite promising findings in several experimental models of allergic inflammation, the results of multicenter studies evaluating the efficacy of anti-IL-13 mAbs in patients with asthma were surprisingly negative.

Results

Conclusion