1017 Preclinical and Clinical Findings: Role Of Periostin, IL-13, Lebrikzumab and Corticosteroid Resistance

Friday, 13 December 2013
Michigan Ballroom (Westin - Michigan Avenue)

Robert Townley, MD , Creighton, Creighton University, Omaha, NE

Pradeep Gendapodi, DVD , Creighton, Creighton University, Omaha, NE

Swati Agrawal, MBBS , Creighton, Creighton University, Omaha, NE

Yang Wang, MS , Creighton, Creighton University, Omaha, NE

Tony Romero, MS , Creighton, Creighton University, Omaha, NE

Peter Abel, PhD , Creighton, Creighton University, Omaha, NE

Background: Patients with severe asthma which are not controlled despite taking effective therapy are most in need of new treatment approaches. IL-13 was demonstrated as “central mediator of allergic asthma”. IL-13 has been implicated in the pathogenesis of asthma, idiopathic pulmonary fibrosis, and COPD. IL-13 levels in the sputum and bronchial biopsy samples remain elevated in severe asthma despite the use of inhaled and systemic corticosteroids. The preclinical purpose of this study was to determine the effect of fluticasone on contractility and relaxation of airway smooth muscle (ASM) treated with IL-13. 

Methods: Balb/c mice were treated with fluticasone, 33µg /ml nebulized for 10 min, for two consecutive days in vivo. Mice were sacrificed and the tracheas incubated with 10µg/ml IL-13 in vitro for 24 hours at 4 °C. Tracheal rings were suspended in a muscle bath. Contraction to KCL, concentration response contraction curves to acetylcholine (ACh) and concentration response relaxation curves to isoproterenol (Iso) and salmeterol were then generated in vitro.

Patients were randomly assigned to receive lebrikizumab or placebo in a 1:1 ratio. Lebrikizumab was given subcutaneously at a dose of 250mg or placebo once a month for total of 24 weeks.

Results: ACh contraction after fluticasone alone was not different from that after fluticasone +IL-13. In untreated ASM, Iso caused approximately 50% of maximal relaxation. However, after treatment with IL-13 the relaxation to Iso and salmeterol was significantly diminished. Relaxation to Iso and salmeterol after fluticasone alone was not significantly different from untreated controls. Iso and salmeterol relaxation after fluticasone +Il-13 was reduced to the same extent as after IL-13 alone.

IL-13 significantly inhibits the relaxation response in vitro and the diminished response to Iso and salmetrol was not restored by fluticasone.

 Lebrikizumab is a monoclonal antibody against IL-13. Lebrikizumab improved lung function in asthmatics who were symptomatic despite treatment with long acting beta agonist and inhaled corticosteroids and provided benefit in the treatment of severe uncontrolled asthma. IL-13 induces bronchial epithelial cells to secrete periostin. Periostin and exhaled nitric oxide may be biomarkers for Th2 induced airway inflammation.

Conclusions: Thus IL-13 is a mediator involved in corticosteroid resistance in both preclinical and clinical studies. In high periostin patients mean reduction in serum periostin was significantly reduced P< 0.001.There was a significant reduction in exhaled nitric oxide in the high periostin subgroup than in the low periostin subgroup.