title: Targeting of Pseudomonas aeruginosa in the bloodstream with bispecific monoclonal antibodies.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Center for Comparative Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: A
authors.initials: A
authors.lastname: Nardin
authors.forename: P L
authors.initials: PL
authors.lastname: Foley
authors.forename: M D
authors.initials: MD
authors.lastname: Solga
authors.forename: A J
authors.initials: AJ
authors.lastname: Bankovich
authors.forename: E N
authors.initials: EN
authors.lastname: Martin
authors.forename: A L
authors.initials: AL
authors.lastname: Henderson
authors.forename: C W
authors.initials: CW
authors.lastname: Price
authors.forename: E
authors.initials: E
authors.lastname: Gyimesi
authors.forename: C P
authors.initials: CP
authors.lastname: Wozencraft
authors.forename: J B
authors.initials: JB
authors.lastname: Goldberg
authors.forename: W M
authors.initials: WM
authors.lastname: Sutherland
authors.forename: R P
authors.initials: RP
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D018033:Antibodies, Bispecific / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000097:blood*; D003165:Complement System Proteins / Q000172:deficiency / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D049452:Green Fluorescent Proteins; D007104:Immune Adherence Reaction; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D007262:Infusions, Intravenous; D008164:Luminescent Proteins / Q000008:administration & dosage / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011552:Pseudomonas Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000097:blood / Q000276:immunology; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000382:microbiology
chemical_list: D000907:Antibodies, Bacterial; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D016207:Cytokines; D008164:Luminescent Proteins; D011108:Polymers; D017463:Receptors, Complement 3b; D049452:Green Fluorescent Proteins; D003165:Complement System Proteins