Abstract
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, 000μg/mouse produced plasma and lung tissue levels at 2hr of 61-507μg/ml and 4.3-150μg/g, respectively. The 1, 000μg MAb dose reduced bacterial counts in lung tissue (log10 cfu/g±S.D.) and blood (log10 cfu/ml±S.D.) 20hr post-treatment (18hr 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 125-500μg 2hr prior to a 3×50% lethal bacterial challenge produced significant protection against death, with a calculated 50% protective dose of 167μg. Protection was noted following administration of 1, 000μg of MAb up to 6hr 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.
