Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa

• DOI: 10.1097/ccm.0b013e31825334f6
• Publication Date: 2012-05-23T11:41:46Z
• Authors: Bruno François; Charles-Edouard Luyt; Anthony Dugard; Michel Wolff; Jean-Luc Diehl; Samir Jaber; Jean-Marie Forel; Denis Garot; Eric Kipnis; Alexandre Mebazaa; Benoit Misset; Antoine Andremont; Marie-Cécile Ploy; Alan Jacobs; Geoffrey Yarranton; Tillman Pearce; Jean-Yves Fagon; Jean Chastre
• Keywords: Pharmacodynamics; Tolerability

The type III secretion system is an important Pseudomonas aeruginosa-virulence determinant in animal models of infection and humans. Antibody-mediated inhibition the PcrV protein, essential component this system, might abrogate aeruginosa ability to damage epithelial cells, neutrophils, macrophages, thereby limiting its pathogenicity. objective trial was determine safety, pharmacokinetics, prevent ventilator-associated pneumonia KB001, a recombinant, PEGylated, engineered, human Fab' fragment that specifically binds epitope blocks function.Multicenter, randomized, placebo-controlled, double-blind, phase-2a trial.Ten intensive care units across France.Thirty-nine aeruginosa-colonized, but not infected, mechanically ventilated patients.Patients were randomized 1:1:1 receive single intravenous infusion 3 mg/kg (n=13) or 10 (n=14), placebo (n=12).The primary end points KB001 safety tolerability, assessed as treatment-related adverse-event frequency severity. Secondary included serum lung rate within 28 days infusion. well tolerated immunogenic. 3- 10-mg/kg groups had respective maximum concentrations 52,811-88,660 121,857-285,454 ng/mL, with mean elimination half-lives 8.1 9.3 days. detected endotracheal aspirates from all patients receiving it, early day 1 up Respective aspirate/serum concentration ratios 0.092 0.085 for groups, who developed less frequently (33% 31%, respectively) than recipients (60%).KB001 safe study, favorable pharmacokinetic profile promising potential reducing incidence unit colonized bacterium.