title: Placental growth factor (PlGF)-specific uptake in tumor microenvironment of 89Zr-labeled PlGF antibody RO5323441.
abstract: Placental growth factor (PlGF) is a member of the proangiogenic vascular endothelial growth factor family, which is upregulated in many tumors. RO5323441, a humanized monoclonal antibody against PlGF, showed antitumor activity in human tumor xenografts. We therefore aimed to radiolabel RO5323441 and preclinically validate this tracer to study drug tumor uptake and organ distribution by PET imaging. (89)Zr-RO5323441 was tested for stability and immunoreactivity in vitro.
  
  
  METHODS
  The tumor uptake and organ distribution for 10, 50, and 500 μg of (89)Zr-RO5323441 was assessed in mice bearing human PlGF-expressing hepatocellular cancer (Huh7) xenografts or human renal cell carcinoma (ACHN) xenografts without detectable human PlGF expression. The effect of pretreatment with RO5323441 (20 mg/kg) on (89)Zr-RO5323441 tumor uptake was analyzed in Huh7 xenografts. (111)In-IgG served as a control for nonspecific tumor uptake and organ distribution. Cy5-RO5323441 was injected to study the intratumor distribution of RO5323441 with fluorescence microscopy.
  
  
  RESULTS
  (89)Zr-RO5323441 showed a time- and dose-dependent tumor accumulation. Uptake in Huh7 xenografts at 10 μg of (89)Zr-RO5323441 was 8.2% ± 1.7% injected dose (ID)/cm(3) at 144 h after injection, and in ACHN xenografts it was 5.5 ± 0.3 %ID/cm(3) (P = 0.03). RO5323441 pretreatment of Huh7 xenograft-bearing mice reduced (89)Zr-RO5323441 tumor uptake to the level of nonspecific (111)In-IgG uptake. Cy5-RO5323441 was present in the tumors mainly in the microenvironment.
  
  
  CONCLUSIONS
  The findings show that RO5323441 tumor uptake is PlGF-specific and time- and dose-dependent.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Thijs H
authors.initials: TH
authors.lastname: Oude Munnink
authors.forename: Karin R
authors.initials: KR
authors.lastname: Tamas
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.forename: Silke R
authors.initials: SR
authors.lastname: Vedelaar
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: Annemiek M E
authors.initials: AM
authors.lastname: Walenkamp
authors.forename: K Michael
authors.initials: KM
authors.lastname: Weidner
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.forename: Jean
authors.initials: J
authors.lastname: Tessier
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001692:Biological Transport / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007553:Isotope Labeling; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000276:immunology* / Q000378:metabolism*; D011868:Radioisotopes; D059016:Tumor Microenvironment / Q000187:drug effects; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011868:Radioisotopes; D000072483:Placenta Growth Factor; C569915:TB-403; D015040:Zirconium
keywords: 89Zr; RO5323441; angiogenesis; placental growth factor; positron emission tomography