Anti-PcrV antibody in cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection

Abstract

Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality in cystic fibrosis (CF). The type III secretion system is one of the factors responsible for the increased virulence and pro-inflammatory effects of Pa. KB001 is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab' fragment that blocks the function of Pa TTSS. We studied the safety, pharmacokinetic (PK), and pharmacodynamic properties of KB001 in CF subjects with chronic Pa infection. Twenty-seven eligible CF subjects (≥12 years of age, FEV1 ≥40% of predicted, and sputum Pa density >10(5) CFU/g) received a single intravenous dose of KB001 (3 mg/kg or 10 mg/kg) or placebo. Safety, PK, Pa density, clinical outcomes, and inflammatory markers were assessed. KB001 had an acceptable safety profile and a mean serum half-life of 11.9 days. All subjects had Pa TTSS expression in sputum. There were no significant differences between KB001 and placebo for changes in Pa density, symptoms, or spirometry after a single dose. However, compared to baseline, at Day 28 there was a trend towards a dose-dependent reduction in sputum myeloperoxidase, IL-1, and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001 10 mg/kg group versus placebo (-0.61 log(10) and -0.63 log(10) , respectively; P < 0.05). These results support targeting Pa TTSS with KB001 as a nonantibiotic strategy to reduce airway inflammation and damage in CF patients with chronic Pa infection. Repeat-dosing studies are necessary to evaluate the durability of the anti-inflammatory effects and how that may translate into clinical benefit. (NCT00638365).

Keywords: Pseudomonas aeruginosa; cystic fibrosis; elastase; inflammation; type III secretion system.

Figure 1. Schematic of study design

On Day 0 subjects were randomized to receive KB001 or placebo. Filled circles, clinical study visits. Open circle, telephone interview. Filled squares, times of sample collection for safety and efficacy analyses.

Figure 2. Subject disposition

A total of 27 subjects were randomized to one of three study treatments in successive cohorts. Two subjects receiving KB001 withdrew from the study due to infusion-related AEs and no subjects were lost to follow-up. Three subjects who completed the study were excluded from efficacy analyses due to administration of prohibited medications during the study period and one subject was unable to expectorate enough sputum for all analyses on Day 28.

Figure 3. Baseline sputum inflammatory marker concentrations and effects of study drug infusion at Day 28

Baseline mean values (log transformed with 95% confidence intervals) are shown on the left and changes from baseline observed at Day 28 are shown on the right for evaluable subjects (Figure 2). Left and right panel ordinates are not of equivalent scales.