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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

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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 × 1012 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.

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Acknowledgments

We thank Ms. Rebekah Cesar and Mr. Ashraf Elzanie for technical assistance, under the City College of New York-Memorial Sloan Kettering Cancer Center Research Training Program in Molecular Imaging, Nanotechnology (ET-CURE). This study was supported in part by The Center for Targeted Radioimmunotherapy and Diagnosis, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, a training grant from the National Institutes of Health (R25-CA096945), the Geoffrey Beene Cancer Research Center of Memorial Sloan Kettering Cancer Center, and the Center to Reduce Cancer Health Disparity (R21 CA153177-03) (J.O.), and P50 CA 086438-13 (S.M.L.). Technical services provided by the Memorial Sloan Kettering Cancer Center Small-Animal Imaging Core Facility were supported by the National Institutes of Health (R24-CA83084, P30-CA08748, and P50-CA92629).

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Sarah M. Cheal, Blesida Punzalan, Michael G. Doran, Joseph R. Osborne, Jason S. Lewis, Pat Zanzonico & Steven M. Larson

  2. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Michael J. Evans

  3. Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jason S. Lewis & Steven M. Larson

  4. Radiochemistry and Imaging Sciences Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jason S. Lewis

  5. Molecular Pharmacology and Therapy Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Pat Zanzonico & Steven M. Larson

  6. Memorial-Sloan Kettering Cancer Center, 415 E. 68th Street, New York, NY, 10065, USA

    Pat Zanzonico

  7. Memorial-Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10021, USA

    Pat Zanzonico

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  1. Sarah M. Cheal
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Correspondence to Pat Zanzonico.

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Cheal, S.M., Punzalan, B., Doran, M.G. et al. 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. Eur J Nucl Med Mol Imaging 41, 985–994 (2014). https://doi.org/10.1007/s00259-013-2679-1

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