Pharmacodynamic and protective properties of a murine lipopolysaccharide-specific monoclonal antibody in experimental Pseudomonas aeruginosa pneumonia in mice.
We employed a Pseudomonas aeruginosa mouse pneumonia model to evaluate the ability of a murine monoclonal antibody (MAb) specific for the O-side chain of P. aeruginosa Fisher Immunotype-1 lipopolysaccharide (LPS) to achieve and sustain therapeutic levels in plasma and lung tissue, reduce bacterial populations in the lung, and prevent pneumonia-associated mortality. An IgG3 MAb (Y1-5A4) administered to mice i.v. over a dose range of 125-1,000 micrograms/mouse produced plasma and lung tissue levels at 2 hr of 61-507 micrograms/ml and 4.3-150 micrograms/g, respectively. The 1,000 micrograms MAb dose reduced bacterial counts in lung tissue (log10 cfu/g +/- S.D.) and blood (log10 cfu/ml +/- S.D.) 20 hr post-treatment (18 hr post-challenge) from 10.00 +/- 0.66 to 7.66 +/- 0.91 (P less than 0.01) and from 4.39 +/- 0.81 to less than 3.0, respectively. Administration of MAb to mice in doses of 125-500 micrograms 2 hr prior to a 3 x 50% lethal bacterial challenge produced significant protection against death, with a calculated 50% protective dose of 167 micrograms. Protection was noted following administration of 1,000 micrograms of MAb up to 6 hr after bacterial challenge (P less than 0.05, compared with untreated control). Histological examination of lung tissue from infected mice revealed less acute inflammation, necrosis, and hemorrhage in MAb-treated compared with untreated control animals and greater localization of Pseudomonas antigen within the phagocytic cells in alveolar space. These findings document the in vivo therapeutic efficacy of an LPS-specific IgG MAb in a murine model of acute P. aeruginosa pneumonia, based in part upon the achievability of effective MAb concentrations in plasma and lung tissue.
Oishi
K
K
Department of Internal Medicine, Nagasaki University, Japan.
Sonoda
F
F
Miwa
H
H
Tanaka
H
H
Watanabe
K
K
Matsumoto
K
K
Pollack
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000502:physiology / Q000627:therapeutic use*; D000918:Antibody Specificity; D015169:Colony Count, Microbial; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000502:physiology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000737:chemistry / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D011014:Pneumonia / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D011552:Pseudomonas Infections / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D008070:Lipopolysaccharides