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http://purl.uniprot.org/citations/30016475http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30016475http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30016475http://www.w3.org/2000/01/rdf-schema#comment"

Background

Bispecific antibody MEDI3902, targeting the Pseudomonas aeruginosa type 3 secretion system (PcrV) and Psl exopolysaccharide, is currently in phase 2b development for prevention of nosocomial pneumonia in patients undergoing mechanical ventilation. We surveyed a diverse collection of isolates to study MEDI3902 epitope conservation and protective activity.

Methods

P. aeruginosa clinical isolates (n = 913) were collected from diverse patients and geographic locations during 2003-2014. We conducted whole-genome sequencing; performed PcrV and Psl expression analyses via immunoblotting and enzyme-linked immunosorbent assay, respectively; performed crystallography to determine the MEDI3902 PcrV epitope, using anti-PcrV Fab and PcrV components (resolved at 2.8 Å); and evaluated MEDI3902 protective activity against select isolates in vitro and in vivo.

Results

Intact psl operon and pcrV genes were present in 94% and 99% of isolates, respectively, and 99.9% of isolates contained at least one of the genetic elements. Anti-Psl binding was confirmed in tested isolates harboring a complete Psl operon or lacking nonessential psl genes. We identified 46 PcrV variant sequences, and MEDI3902-PcrV contact residues were preserved. MEDI3902 maintained potent in vivo activity against various strains, including strains expressing only a single target.

Conclusions

Psl and PcrV are highly prevalent in global clinical isolates, suggesting MEDI3902 can mediate broad coverage against P. aeruginosa."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.org/dc/terms/identifier"doi:10.1093/infdis/jiy438"xsd:string
http://purl.uniprot.org/citations/30016475http://purl.org/dc/terms/identifier"doi:10.1093/infdis/jiy438"xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"McLaughlin R.E."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"McLaughlin R.E."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Qi Y."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Qi Y."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Stover C.K."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Stover C.K."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Yu L."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Yu L."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Warrener P."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Warrener P."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Oganesyan V."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Oganesyan V."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Song E."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Song E."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Ruzin A."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Ruzin A."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Rosenthal K."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"Rosenthal K."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"DiGiandomenico A."xsd:string
http://purl.uniprot.org/citations/30016475http://purl.uniprot.org/core/author"DiGiandomenico A."xsd:string
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