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.

Objective: The type III secretion system is an important Pseu- domonas 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, pharmaco- kinetics, and ability to prevent Pseudomonas aeruginosa ventila- tor-associated pneumonia of KB001, a recombinant, PEGylated, engineered, human Fabfragment that specifically binds to a Pseudomonas aeruginosa PcrV epitope and blocks its function. Design: Multicenter, randomized, placebo-controlled, double- blind, phase-2a trial. Setting: Ten intensive care units across France. Patients: Thirty-nine Pseudomonas aeruginosa-colonized, but not infected, mechanically ventilated patients. Interventions: Patients were randomized 1:1:1 to receive a sin- gle intravenous infusion of KB001, 3 mg/kg (n = 13) or 10 mg/kg (n = 14), or placebo (n = 12). Measurements and Main 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 Pseu- domonas aeruginosa pneumonia rate within 28 days of its infu- sion. 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 elimina- tion half-lives of 8.1 and 9.3 days. KB001 was detected in endo- tracheal 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 recipi- ents (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. (Critical Care Medicine 2012;00:0-0)