title: Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  The type III secretion system is an important Pseudomonas aeruginosa-virulence determinant in animal models of infection and in humans. Antibody-mediated inhibition of the PcrV protein, an essential component of this system, might abrogate the Pseudomonas aeruginosa ability to damage epithelial cells, neutrophils, and macrophages, thereby limiting its pathogenicity. The objective of the trial was to determine the safety, pharmacokinetics, and ability to prevent Pseudomonas aeruginosa ventilator-associated pneumonia of KB001, a recombinant, PEGylated, engineered, human Fab' fragment that specifically binds to a Pseudomonas aeruginosa PcrV epitope and blocks its function.
  
  
  METHODS
  Multicenter, randomized, placebo-controlled, double-blind, phase-2a trial.
  
  
  METHODS
  Ten intensive care units across France.
  
  
  METHODS
  Thirty-nine Pseudomonas aeruginosa-colonized, but not infected, mechanically ventilated patients.
  
  
  METHODS
  Patients were randomized 1:1:1 to receive a single intravenous infusion of KB001, 3 mg/kg (n=13) or 10 mg/kg (n=14), or placebo (n=12).
  
  
  RESULTS
  The primary end points were KB001 safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Secondary end points included serum and lung KB001 pharmacokinetics, and Pseudomonas aeruginosa pneumonia rate within 28 days of its infusion. KB001 was well tolerated and not immunogenic. The 3- and 10-mg/kg groups had respective maximum serum concentrations of 52,811-88,660 and 121,857-285,454 ng/mL, with mean elimination half-lives of 8.1 and 9.3 days. KB001 was detected in endotracheal aspirates from all patients receiving it, as early as day 1 and up to 28 days. Respective mean endotracheal aspirate/serum concentration ratios were 0.092 and 0.085 for the 3- and 10-mg/kg groups, who developed Pseudomonas aeruginosa pneumonia less frequently (33% and 31%, respectively) than placebo recipients (60%).
  
  
  CONCLUSIONS
  KB001 was safe and well tolerated in this study, with a favorable pharmacokinetic profile and promising potential for reducing Pseudomonas aeruginosa pneumonia incidence in intensive care unit mechanically ventilated patients colonized with this bacterium.
authors.affiliation: Réanimation Polyvalente), CIC 0801 Inserm, CHU Dupuytren, Limoges, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: François
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.forename: Anthony
authors.initials: A
authors.lastname: Dugard
authors.forename: Michel
authors.initials: M
authors.lastname: Wolff
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Diehl
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Forel
authors.forename: Denis
authors.initials: D
authors.lastname: Garot
authors.forename: Eric
authors.initials: E
authors.lastname: Kipnis
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.forename: Benoit
authors.initials: B
authors.lastname: Misset
authors.forename: Antoine
authors.initials: A
authors.lastname: Andremont
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Ploy
authors.forename: Alan
authors.initials: A
authors.lastname: Jacobs
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yarranton
authors.forename: Tillman
authors.initials: T
authors.lastname: Pearce
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Fagon
authors.forename: Jean
authors.initials: J
authors.lastname: Chastre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000517:prevention & control*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; C000595441:KB001 antibody