6cyf | pdb_00006cyf
PcrV fragment with bound Fab
Structural highlights
Publication Abstract from PubMedBackground: Bispecific antibody MEDI3902 targeting P. aeruginosa type-3-secretion system (PcrV) and Psl exopolysaccharide is currently in phase 2b development for prevention of nosocomial pneumonia in mechanically ventilated patients. 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 between 2003-2014. We conducted whole genome sequencing; PcrV and Psl expression analyses via immunoblotting and ELISA, respectively; crystallography to determine the MEDI3902 PcrV epitope using anti-PcrV Fab and PcrV components (resolved at 2.8 A); and evaluated MEDI3902 protective activity against selected 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 non-essential psl genes. We identified a total of 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. Pseudomonas aeruginosa PcrV and Psl, the molecular targets of bispecific antibody MEDI3902, are conserved among diverse global clinical isolates.,Tabor DE, Oganesyan V, Keller AE, Yu L, McLaughlin RE, Song E, Warrener P, Rosenthal K, Esser M, Qi Y, Ruzin A, Stover CK, DiGiandomenico A J Infect Dis. 2018 Jul 17. pii: 5054928. doi: 10.1093/infdis/jiy438. PMID:30016475[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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