Pharmacodynamic and Protective Properties of a Murine Lipopolysaccharide‐Specific Monoclonal Antibody in Experimental Pseudomonas aeruginosa Pneumonia in Mice

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 125–1,000 μg/mouse produced plasma and lung tissue levels at 2 hr of 61–507 μg/ml and 4.3–150 μg/g, respectively. The 1,000 μg MAb dose reduced bacterial counts in lung tissue (logio cfu/g±S.D.) and blood (log10cfu/ml+S.D.) 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 μg 2 hr prior to a 3 × 50% lethal bacterial challenge produced significant protection against death, with a calculated 50% protective dose of 167 μg. Protection was noted following administration of 1,000 μg 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. © owned by Center for Academic Publications Japan (Publisher)