title: Optical Imaging of Renal Cell Carcinoma with Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab.
abstract: Near-infrared dye-tagged antibodies can be used for the sensitive detection of tumor tissue in vivo. Surgery for clear-cell renal cell carcinoma (ccRCC) might benefit from the use of optical imaging to facilitate the intraoperative detection of carbonic anhydrase IX (CAIX)-expressing tumor lesions with chimeric monoclonal antibody (mAb) girentuximab, which has been shown to have excellent imaging capabilities for ccRCC. Here we studied the potential of fluorescence imaging to detect ccRCC tumors in nude mice with RCC xenografts by using mAb girentuximab conjugated with IRDye800CW; SPECT imaging was used as a reference.
  
  
  METHODS
  Groups of athymic BALB/c mice with subcutaneous CAIX-positive SK-RC-52 ccRCC tumors were injected intravenously with (125)I-labeled girentuximab-IRDye800CW or (125)I-labeled girentuximab. For determination of the specificity of the accumulation of the anti-CAIX antibody conjugate in ccRCC, separate groups of mice bearing a CAIX-positive tumor (SK-RC-52) and a CAIX-negative tumor (SK-RC-59) received (125)I-girentuximab-IRDye800CW or (125)I-labeled MOPC21-IRDye800CW (control mAb). Optical images and micro-SPECT images were acquired until 3 d after injection. Mice were euthanized after the last imaging session, and the biodistribution of the radiolabeled antibody preparations was determined.
  
  
  RESULTS
  Optical imaging and micro-SPECT imaging at 1 d after the injection of (125)I-girentuximab-IRDye800CW showed clear delineation of the CAIX-expressing ccRCC xenografts, and image contrast improved with time. Fluorescence imaging and biodistribution studies showed high and specific uptake of (125)I-girentuximab-IRDye800CW in CAIX-positive ccRCC xenografts (SK-RC-52, 31.5 ± 9.6 percentage injected dose per gram [%ID/g] at 72 h after injection). Tumor uptake was specific, as very low uptake of (125)I-girentuximab-IRDye800CW was noted in the CAIX-negative SK-RC-59 tumor (4.1 ± 1.5 %ID/g), and no uptake of (125)I-MOPC21-IRDye800CW (control mAb) was noted in the CAIX-positive SK-RC-52 tumor (1.2 ± 0.1 %ID/g).
  
  
  CONCLUSIONS
  Subcutaneous CAIX-expressing ccRCC xenografts were visualized by optical imaging with (125)I-girentuximab-IRDye800CW. Optical images showed good concordance with micro-SPECT images. The accumulation of (125)I-girentuximab-IRDye800CW in ccRCC tumors was high and specific. Girentuximab-IRDye800CW potentially could be used for the intraoperative detection of CAIX-expressing tumors and the assessment of residual tumor in resection margins or metastatic lesions in patients with ccRCC.
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands stijn.muselaers@radboudumc.com.
authors.forename: Constantijn H J
authors.initials: CH
authors.lastname: Muselaers
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Stillebroer
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Rijpkema
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000737:chemistry; D001692:Biological Transport; D002256:Carbonic Anhydrases / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D061848:Optical Imaging / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; C106533:G250 monoclonal antibody; C562366:IRDye 800CW; D007211:Indoles; D002256:Carbonic Anhydrases
keywords: CAIX; girentuximab; monoclonal antibody; optical imaging; renal cell carcinoma