Abstract
Introduction: Janus kinase (JAK) enzymes mediate signaling of many cytokines associated with asthma. TD-8236 is a pan-JAK inhibitor designed to maximize lung selectivity.
Aims: The aim of this study was to establish methods for detection of target engagement biomarkers from bronchoalveolar lavage fluid (BALF), including cytokine-induced pSTAT in cells and inflammatory mediators in supernatant.
Methods: BALF samples were obtained from asthmatic patients. Cells isolated from BALF were stimulated with cytokine cocktail (IL-6, IL-13, IFNγ, GM-CSF) ± TD-8236 and pSTAT expression quantified by flow cytometry. Additionally, detection of inflammatory mediators (periostin, MUC5AC, ECP) by chemiluminescence assay in BALF supernatant was explored. TD-8236 was administered to mice by oral aspiration 1 or 6 hours prior to BALF collection to establish durability of drug effect on pSTAT inhibition and assess the impact of compound loss due to BALF cell washing.
Results: Co-incubation of TD-8236 inhibited cytokine-induced pSTAT in human asthmatic BALF cells in a dose-dependent manner (IC50 30-100 nM). The detection of a number of relevant inflammatory mediators was also confirmed in asthmatic BALF supernatant. TD-8236 resulted in durable inhibition of cytokine-induced pSTAT when administered to mice 1 or 6 hours prior to BALF collection.
Conclusions: These data support methods to evaluate target engagement and anti-inflammatory activity in the BALF of asthmatic patients dosed with TD-8236.
Footnotes
Cite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 2891.
This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2020