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Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies¹

Margaret A. Lindorfer^2,*, Alessandra Nardin^2,3,*, Patricia L. Foley, Michael D. Solga^*, Alexander J. Bankovich^*, Edward N. Martin^*, Andrea L. Henderson^*, Carol W. Price, Edit Gyimesi^*, Colin P. Wozencraft^*, Joanna B. Goldberg, William M. Sutherland and Ronald P. Taylor^4,*

^* Department of Biochemistry and Molecular Genetics, Center for Comparative Medicine, and Departments of Microbiology and Cell Biology, University of Virginia Health Sciences Center, Charlottesville, VA 22908

We examined the ability of a bispecific mAb reagent, consisting of a mAb specific for the primate erythrocyte complement receptor cross-linked with an anti-bacterial mAb, to target bacteria in the bloodstream in an acute infusion model in monkeys. In vitro studies demonstrated a variable level of complement-mediated binding (immune adherence) of Pseudomonas aeruginosa (strain PAO1) to primate E in serum. In vivo experiments in animals depleted of complement revealed that binding of bacteria to E was <1% before administration of the bispecific reagent, but within 5 min of its infusion, >99% of the bacteria bound to E. In complement-replete monkeys, a variable fraction of infused bacteria bound to E. This finding may have significant implications in the interpretation of animal models and in the understanding of bacteremias in humans. Treatment of these complement-replete monkeys with the bispecific reagent led to >99% binding of bacteria to E. Twenty-four-hour survival studies were conducted; several clinical parameters, including the degree of lung damage, cytokine levels, and liver enzymes in the circulation, indicate that the bispecific mAb reagent provides a degree of protection against the bacterial challenge.

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