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-mu-g/mouse produced plasma and lung tissue levels at 2 hr of 61-507-mu-g/ml and 4.3-150-mu-g/g, respectively. The 1,000-mu-g MAb dose reduced bacterial counts in lung tissue (log10 cfu/g +/- SD.) and blood (log10 cfu/ml +/- SD.) 20 hr post-treatment (18 hr post-challenge) from 10.00 +/-0.66 to 7.66 +/- 0.91 (P < 0.01) and from 4.39 +/- 0.81 to < 3.0, respectively. Administration of MAb to mice in doses of 125-500-mu-g 2 hr prior to a 3 X 50% lethal bacterial challenge produced significant protection against death, with a calculated 50% protective dose of 167-mu-g. Protection was noted following administration of 1,000-mu-g of MAb up to 6 hr after bacterial challenge (P < 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.