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 Journal Article


Authors: Cheal, S. M.; Punzalan, B.; Doran, M. G.; Evans, M. J.; Osborne, J. R.; Lewis, J. S.; Zanzonico, P.; Larson, S. M.
Article 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: Purpose: The PET tracer, 124I-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 89Zr, however, may offer advantages as a surrogate PET nuclide over 124I 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 124I-cG250 and 89Zr-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 89Zr-cG250 and 124I-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 89Zr-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 124I/89Zr atoms released per unit time by tumor was 17.5. Conclusion: Pairwise evaluation of 89Zr-cG250 and 124I-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. 89Zr-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. © 2014 Springer-Verlag Berlin Heidelberg.
Keywords: controlled study; unclassified drug; human cell; nonhuman; positron emission tomography; cancer diagnosis; binding affinity; mouse; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; molecular imaging; kidney carcinoma; kinetics; drug uptake; isotope labeling; quantitative analysis; tumor cell; radiopharmaceutical agent; receptor; antigen binding; drug binding; zirconium-89; receptor binding; internalization; compartment model; cancer antibody; immunopet; turnover time; girentuximab i 124; g250; iodine-124; human; female; article; nonlinear kinetic model; carbonate dehydratase ix receptor; girentuximab zr 89
Journal Title: European Journal of Nuclear Medicine and Molecular Imaging
Volume: 41
Issue: 5
ISSN: 1619-7070
Publisher: Springer  
Date Published: 2014-05-01
Start Page: 985
End Page: 994
Language: English
DOI: 10.1007/s00259-013-2679-1
PROVIDER: scopus
PUBMED: 24604591
PMCID: PMC4120276
DOI/URL:
Notes: Eur. J. Nucl. Med. Mol. Imaging -- Export Date: 2 June 2014 -- CODEN: EJNMA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Joseph R Osborne
    57 Osborne
  2. Pat B Zanzonico
    247 Zanzonico
  3. Michael John Evans
    22 Evans
  4. Jason S Lewis
    248 Lewis
  5. Steven M Larson
    781 Larson
  6. Sarah Marie Cheal
    25 Cheal
  7. Michael G. Doran
    17 Doran