ANIMAL TESTING OF A BLOCKING ANTIBODY OF PCRV

DESCRIPTION (provided by applicant): This grant will determine the efficacy of a humanized monoclonal antibody in treating a lethal Pseudomonas-induced lung injury. We have shown that the airspace instillation of a strain of Pseudomonas aeruginosa that contains the type Il system predictably causes lung necrosis, sepsis and death (J Clin Invest 1999). We have also shown that the systemic administration of polyclonal antibody raised against recombinant PcrV, a type III bacterial protein involved in translocating the bacterial toxins into eukaryotic cells, prevented lung injury and death in mice pretreated with the antibody (Nature Med 1999). More recently, we have identified a mouse antiPcrV monoclonal antibody that when administered prior to the bacterial instillation, prevented mortality in mice airspace-infected with the virulent Pseudomonas. The proposed experiments will determine whether the systemic or lung administration of a humanized monoclonal antibody after the airspace instillation of the virulent Pseudomonas improves hemodynamics, gas exchange and/or improves the septicemia in airspace-infected, anesthetized rabbits. These results will be critical for deciding how to plan a clinical trial; the results will determine whether the antibody should be utilized as a therapy or as a prophylactic treatment. PROPOSED COMMERCIAL APPLICATIONS: Pseudomonas aeruginosa is a major cause of hospital infection, accounting for 20% of nosoconual pneumonias, 10-15% of nosocomial urinary tract infections, and 10% of sepsis. In addition, P. aeruginosa infection is the major cause of mortality in cystic fibrosis. Current treatment is associated with a high rate of antibiotic resistance and a 25-50% failure rate. The proposed treatment provides a novel approach to the prevention of P. aeruginosa infection in patients at high risk for this infection, including patients on ventilators, burn patients, patients with in-dwelling catheters, neutropenic patients, an patients with cystic fibrosis.