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

ABSTRACT

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 stimulation 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.

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.

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.

A 30-minute aerosol exposure to a 10 mM BIO-11006 solution was maximally effective in inhibiting MChinduced airway obstruction and mucus hypersecretion. There was a long-lasting effect on inhibition of airway obstruction after a single treatment with BIO-11006 (t1/2~4 hrs). The duration of effect on inhibition of mucin secretion was shorter (t1/2~2 hrs).

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.