Aerosolized BIO-11006, a Novel MARCKS- Related Peptide, Improves Airway Obstruction in a Mouse Model of Mucus Hypersecretion

Abstract

Rationale: Mucus hypersecretion has been shown to be an important cause of airway obstruction in COPD and asthma, and has been associated with fatal asthma. Previous in-vitro and in-vivo studies have provided direct evidence that the myristoylated alanine-rich C kinase substrate (MARCKS) is a central regulatory molecule linking secretagogue stimu- lation at the goblet cell surface to mucin granule release. BIO-11006 is a novel, highly soluble, aerosolized peptide that inhibits MARCKS function and results in reduced mucus secretion and improved airway obstruction. BIO-11006 is being tested in Phase 2 clinical studies of COPD. Objective: To determine access of BIO-11006 to the intracellular compartment of normal human bronchial epithelial (NHBE) cells, and assess the effectiveness of BIO-11006 inhalation solution in inhibiting airway obstruction caused by mucus hypersecretion as a function of dose and time. Methods: Biotin labeled BIO-11006 was incubated with NHBE cells and visualized with fluorescein-labeled streptavidin. Ovalbumin-sensitized and challenged mice with airway inflammation and hyperresponsiveness to methacholine (MCh) were treated with aerosolized BIO-11006 solution prior to MCh challenge, and effects on airway obstruction and mucus secretion were measured. Results: A 30-minute aerosol exposure to a 10 mM BIO-11006 solution was maximally effective in inhibiting MCh- induced airway obstruction and mucus hypersecretion. There was a long-lasting effect on inhibition of airway obstruction after a single treatment with BIO-11006 (t 1/2 ~4 hrs). The duration of effect on inhibition of mucin secretion was shorter (t 1/2 ~2 hrs). Conclusion: The pharmacodynamic properties of aerosolized BIO-11006 Inhalation Solution are suitable for therapeutic use. Inhaled BIO-11006 effectively inhibits mucin secretion and improves airway obstruction.