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

Purpose 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 of...

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Published in:European journal of nuclear medicine and molecular imaging 2014-05, Vol.41 (5), p.985-994
Main Authors: Cheal, Sarah M., Punzalan, Blesida, Doran, Michael G., Evans, Michael J., Osborne, Joseph R., Lewis, Jason S., Zanzonico, Pat, Larson, Steven M.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacokinetics
Antigens, Neoplasm - immunology
Antigens, Neoplasm - metabolism
Carbonic Anhydrase IX
Carbonic Anhydrases - immunology
Carbonic Anhydrases - metabolism
Carcinoma, Renal Cell - diagnostic imaging
Cardiology
Cell Line, Tumor
Humans
Imaging
Iodine Radioisotopes - pharmacokinetics
Kinetics
Medicine
Medicine & Public Health
Mice
Nuclear Medicine
Oncology
Original Article
Orthopedics
Positron-Emission Tomography
Protein Binding
Radiology
Tissue Distribution
Xenograft Model Antitumor Assays
Zirconium - pharmacokinetics
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Summary:Purpose 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. Conclusion 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.
ISSN:1619-7070
1619-7089
DOI:10.1007/s00259-013-2679-1