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

Authors

  • Carlos E. Milla MD,

    Corresponding author
    1. Center For Excellence in Pulmonary Biology, Stanford University, Palo Alto, California
    • Correspondence to: Carlos Milla, MD, Center for Excellence in Pulmonary Biology, Stanford University 770 Welch Road, Suite 350, Palo Alto, CA 94304. E-mail: cmilla@stanford.edu

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  • James F. Chmiel MD,

    1. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Frank J. Accurso MD,

    1. The Children's Hospital of Denver, University of Colorado, Denver, Colorado
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  • Donald R. VanDevanter PhD,

    1. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Michael W. Konstan MD,

    1. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Geoffrey Yarranton PhD,

    1. KaloBios Pharmaceuticals, Inc., South San Francisco, California
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  • David E. Geller MD,

    1. Florida State University College of Medicine, Orlando, Florida
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  • for the KB001 Study Group

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    • †Carlos Milla, MD, Center for Excellence in Pulmonary Biology, Stanford University, Palo Alto, CA; James F. Chmiel, MD, Rainbow Babies and Children's Hospital, Cleveland, OH; Frank J. Accurso, MD, Children's Hospital Colorado, Aurora, CO; Karen S. McCoy, MD, Nationwide Children's Hospital, Columbus, OH; Joanne L. Billings, MD, University of Minnesota, Minneapolis, MN; Jeffrey J. Atkinson, MD, Washington University School of Medicine, St. Louis, MO; Theodore G. Liou, MD, University of Utah Health Sciences Center, Salt Lake City, UT; John P. Clancy, MD, University of Alabama, Birmingham, AL; Joseph M. Pilewski, MD, Children's Hospital of Pittsburgh, Pittsburgh, PA; James D. Acton, MD, Cincinnati Children's Hospital, Cincinnati, OH; Jane L. Burns, MD, Seattle Children's Hospital, Seattle, WA.

  • Conflict of interest: None.

Summary

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 >105 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 log10 and −0.63 log10, 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) Pediatr Pulmonol. 2014; 49:650–658. © 2013 Wiley Periodicals, Inc.

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