Ventilator-associated pneumonia due to Pseudomonas aeruginosa(PA) is associated with high rates of mortality, morbidity, increased intensive care unit length of stay and substantial economic burden. MEDI3902 is a bivalent, bispecific human IgG1κ mAb that selectively binds to both the type 3 secretion (T3S) injectisome protein PcrV and Psl exopolysaccharide on the surface of PA and is being developed for the prevention of nosocomial pneumonia caused by PA. MEDI3902 binding to PcrV prevents T3S injectisome-mediated host cell cytotoxicity, while binding to Psl mediates opsonophagocytic killing (OPK) of PA by host phagocytic cells and may also inhibit attachment of the bacterium to host epithelial cells.
To better understand the prevalence of the pcrV gene and psl operon (expression of Psl is mediated via a 20 KB operon) in PA clinical isolates, we performed whole genome sequencing on 648 isolates collected from diverse patient populations and geographical locations in 43 countries from 2004-2014. Whole genome sequence data was analyzed for the presence of the pcrV gene and psl operon (pslA to pslO). The predicted amino acid sequence changes in the PcrV protein was compared to PA reference strain PAO1. Psl expression from select isolates lacking one or more genes from the psloperon was evaluated by anti-Psl mAb ELISA.
Analysis showed that the pcrV and psl genes were present in 99% and 96% of the isolates, respectively. PcrV amino acid sequence variation revealed >35 genotypes that were mapped to PcrV in relation to the MEDI3902 epitope, which are not expected to effect the binding of PcrV by MEDI3902. Anti-Psl ELISAs were performed on selected isolates that were negative for one or more genes in the psloperon and thusly defined the set of genes required for exopolysaccharide synthesis and binding by MEDI3902.
This study provides compelling data that PcrV and Psl are highly conserved in diverse PA isolates collected from around the world and suggests that they are good targets for prophylactic mAb and vaccine development.
D. E. Tabor,
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