title: In vivo visualization of MET tumor expression and anticalin biodistribution with the MET-specific anticalin 89Zr-PRS-110 PET tracer.
abstract: Anticalins are a novel class of biopharmaceuticals, displaying highly desirable attributes as imaging agents. The anticalin PRS-110 was rationally engineered to target the oncogene MET with high affinity and specificity. The aim of this study was to visualize MET expression and analyze biodistribution of (89)Zr-labeled PRS-110 in human tumor-bearing mice.
  
  
  METHODS
  (89)Zr-PRS-110 was generated. For biodistribution studies (96 h after injection of tracer) 10 μg of (89)Zr-PRS-110 (with 0-490 μg of unlabeled PRS-110) were injected into BALB/c mice bearing high MET-expressing H441 non-small cell lung cancer xenografts. Further characterization with PET imaging was performed at 6, 24, 48, and 96 h after injection of 50 μg of (89)Zr-PRS-110 into mice bearing H441, primary glioblastoma U87-MG (intermediate MET), or ovarian cancer A2780 (low MET) xenografts. Drug distribution was also analyzed ex vivo using fluorescently labeled PRS-110.
  
  
  RESULTS
  Biodistribution analyses showed a dose-dependent tumor uptake of (89)Zr-PRS-110, with the highest fractional tumor uptake at 10 μg of (89)Zr-PRS-110, with no unlabeled PRS-110. Small-animal PET imaging supported by biodistribution data revealed specific tumor uptake of (89)Zr-PRS-110 in the MET-expressing H441 and U87-MG tumors whereas the MET-negative A2780 tumor model showed a lower uptake similar to a non-MET binder anticalin control. Tumor uptake increased up to 24 h after tracer injection and remained high, whereas uptake in other organs decreased over time. Ex vivo fluorescence revealed intracellular presence of PRS-110.
  
  
  CONCLUSIONS
  (89)Zr-PRS-110 specifically accumulates in MET-expressing tumors in a receptor density-dependent manner. PET imaging provides real-time noninvasive information about PRS-110 distribution and tumor accumulation in preclinical models.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.forename: Marlon J
authors.initials: MJ
authors.lastname: Hinner
authors.forename: Remy B
authors.initials: RB
authors.lastname: Verheijen
authors.forename: Andrea
authors.initials: A
authors.lastname: Allersdorfer
authors.forename: Martin
authors.initials: M
authors.lastname: Hülsmeyer
authors.forename: Wouter B
authors.initials: WB
authors.lastname: Nagengast
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Laurent
authors.initials: L
authors.lastname: Audoly
authors.forename: Shane A
authors.initials: SA
authors.lastname: Olwill
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D007553:Isotope Labeling; D054834:Lipocalins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011506:Proteins; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D011786:Quality Control; D019275:Radiopharmaceuticals; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054834:Lipocalins; C000588668:PRS-110; D011506:Proteins; D019275:Radiopharmaceuticals; D000068258:Bevacizumab; D019859:Proto-Oncogene Proteins c-met
keywords: 89Zr; MET; PET; anticalins