The interleukin-13 paradox in asthma: effective biology, ineffective biologicals

Interleukin-13 (IL-13) is a pleiotropic cytokine produced by type-2 helper T-cells (Th2), mast cells and basophils, and is thought to be involved in many of the features of asthma. IL-13 induces many biological responses relevant to asthma, such as B-cell immunoglobulin E production, generation of eosinophil chemoattractants, maturation of mucus-secreting goblet cells, production of extracellular matrix proteins and myofibroblast differentiation, and enhanced contractility of airway smooth muscle cells in response to cholinergic agonists. These cytokines activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling cascades, which may contribute to allergic responses. IL-13 is involved in almost all aspects of asthma pathobiology, yet, anti-IL-13 mAb clinical trials, including the prednisone-sparing TROPOS study published in this issue of the ERJ, have been ineffective http://ow.ly/ZMnd30n27VN

[1]  W. Busse,et al.  Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma , 2019, European Respiratory Journal.

[2]  A. Scrimgeour,et al.  Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942 , 2018, EBioMedicine.

[3]  C. Brightling,et al.  Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. , 2018, The Lancet. Respiratory medicine.

[4]  V. Backer,et al.  Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. , 2018, The Lancet. Respiratory medicine.

[5]  K. Rabe,et al.  Efficacy and Safety of Dupilumab in Glucocorticoid‐Dependent Severe Asthma , 2018, The New England journal of medicine.

[6]  I. Pavord,et al.  Dupilumab Efficacy and Safety in Moderate‐to‐Severe Uncontrolled Asthma , 2018, The New England journal of medicine.

[7]  E. Hoffman,et al.  Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction , 2018, The Journal of clinical investigation.

[8]  Yutaka Nakamura,et al.  Docking analysis and the possibility of prediction efficacy for an anti-IL-13 biopharmaceutical treatment with tralokinumab and lebrikizumab for bronchial asthma , 2017, PloS one.

[9]  K. Rabe,et al.  Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma , 2017, The New England journal of medicine.

[10]  E. Bateman,et al.  Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. , 2016, The Lancet. Respiratory medicine.

[11]  A. Heatherington,et al.  A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies , 2016, mAbs.

[12]  P. O'Byrne,et al.  Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. , 2015, The Lancet. Respiratory medicine.

[13]  I. Pavord,et al.  Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. , 2014, The New England journal of medicine.

[14]  N. Jarjour,et al.  The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge , 2013, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[15]  C. Brightling,et al.  A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma , 2012, European Respiratory Journal.

[16]  Nicola A Hanania,et al.  Lebrikizumab treatment in adults with asthma. , 2011, The New England journal of medicine.

[17]  L. Boulet,et al.  Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. , 2011, American journal of respiratory and critical care medicine.

[18]  Parameswaran Nair,et al.  Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. , 2009, The New England journal of medicine.

[19]  S. Wenzel,et al.  IL‐13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[20]  I. Pavord,et al.  Increased sputum and bronchial biopsy IL-13 expression in severe asthma. , 2008, The Journal of allergy and clinical immunology.

[21]  S. Toda,et al.  Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. , 2006, The Journal of allergy and clinical immunology.

[22]  M. Wills-Karp,et al.  Interleukin‐13 in asthma pathogenesis , 2004, Immunological reviews.

[23]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .