title: 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).
authors.affiliation: Center for Excellence in Pulmonary Biology, Stanford University, 770 Welch Road, Suite 350, Palo Alto, CA 94304. cmilla@stanford.edu
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Milla
authors.forename: James F
authors.initials: JF
authors.lastname: Chmiel
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Accurso
authors.forename: Donald R
authors.initials: DR
authors.lastname: VanDevanter
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yarranton
authors.forename: David E
authors.initials: DE
authors.lastname: Geller
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000907:Antibodies, Bacterial / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000209:etiology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000209:etiology / Q000382:microbiology; D013183:Sputum / Q000378:metabolism / Q000382:microbiology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D007140:Immunoglobulin Fab Fragments; C000595441:KB001 antibody; D011994:Recombinant Proteins
keywords: Pseudomonas aeruginosa; cystic fibrosis; elastase; inflammation; type III secretion system
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