Pseudomonas aeruginosa is among the most formidable antibiotic-resistant pathogens and a leading cause of hospital-associated infections. With dwindling options for antibiotic resistant infections, a new paradigm for treatment and disease resolution is required. MEDI3902, a bispecific antibody targeting the P. aeruginosa type-3-secretion (T3S) protein PcrV and Psl exopolysaccharide, was previously shown to mediate potent protective activity in murine infection models. With the current challenges associated with clinical development of narrow-spectrum agents, robust preclinical efficacy data in multiple animal species are desirable. Here, we sought to develop a rabbit P. aeruginosa acute pneumonia model to further evaluate the activity of MEDI3902 intervention. In the rabbit model of acute pneumonia, prophylaxis with MEDI3902 exhibited potent dose-dependent protection whereas those receiving control IgG developed fatal, hemorrhagic, necrotizing pneumonia between 12 and 54 h after infection. Blood biomarkers (e.g. pO2, pCO2, base excess, lactate, creatinine) were grossly deranged for the vast majority of control IgG-treated animals, but remained within normal limits for MEDI3902-treated animals. In addition, MEDI3902-treated animals exhibited a profound reduction in P. aeruginosa organ burden and a marked reduction in expression of proinflammatory mediators from lung tissue, which correlated with reduced lung histopathology. These results confirm that targeting PcrV and Psl via MEDI3902 is a promising candidate for immunotherapy against P. aeruginosa pneumonia.
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