title: Pairwise comparison of 89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcinoma.
abstract: OBJECTIVE
  The PET tracer, (124)I-cG250, directed against carbonic anhydrase IX (CAIX) shows promise for presurgical diagnosis of clear-cell renal cell carcinoma (ccRCC) (Divgi et al. in Lancet Oncol 8:304-310, 2007; Divgi et al. in J Clin Oncol 31:187-194, 2013). The radiometal (89)Zr, however, may offer advantages as a surrogate PET nuclide over (124)I in terms of greater tumor uptake and retention (Rice et al. in Semin Nucl Med 41:265-282, 2011). We have developed a nonlinear immunokinetic model to facilitate a quantitative comparison of absolute uptake and antibody turnover between (124)I-cG250 and (89)Zr-cG250 using a human ccRCC xenograft tumor model in mice. We believe that this unique model better relates quantitative imaging data to the salient biological features of tumor antibody-antigen binding and turnover.
  
  
  METHODS
  We conducted experiments with (89)Zr-cG250 and (124)I-cG250 using a human ccRCC cell line (SK-RC-38) to characterize the binding affinity and internalization kinetics of the two tracers in vitro. Serial PET imaging was performed in mice bearing subcutaneous ccRCC tumors to simultaneously detect and quantify time-dependent tumor uptake in vivo. Using the known specific activities of the two tracers, the equilibrium rates of antibody internalization and turnover in the tumors were derived from the PET images using nonlinear compartmental modeling.
  
  
  RESULTS
  The two tracers demonstrated virtually identical tumor cell binding and internalization but showed markedly different retentions in vitro. Superior PET images were obtained using (89)Zr-cG250, owing to the more prolonged trapping of the radiolabel in the tumor and simultaneous washout from normal tissues. Estimates of cG250/CAIX complex turnover were 1.35 - 5.51 × 10(12) molecules per hour per gram of tumor (20 % of receptors internalized per hour), and the ratio of (124)I/(89)Zr atoms released per unit time by tumor was 17.5.
  
  
  CONCLUSIONS
  Pairwise evaluation of (89)Zr-cG250 and (124)I-cG250 provided the basis for a nonlinear immunokinetic model which yielded quantitative information about the binding and internalization of radioantibody bound to CAIX on tumor cells in vivo. (89)Zr-cG250 is likely to provide high-quality PET images and may be a useful tool to quantify CAIX/cG250 receptor turnover and cG250-accessible antigen density noninvasively in humans.
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cheal
authors.forename: Blesida
authors.initials: B
authors.lastname: Punzalan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Doran
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Osborne
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007700:Kinetics; D051379:Mice; D049268:Positron-Emission Tomography; D011485:Protein Binding; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C106533:G250 monoclonal antibody; D007457:Iodine Radioisotopes; D015040:Zirconium; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases