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 positron-emitting tomography (PET) tracer, 124I-cG250, directed against carbonic anhydrase IX (CAIX) shows promise for pre-surgical diagnosis of clear renal cell carcinoma (cRCC) [1, 2]. The radiometal zirconium-89 (89Zr), however, may offer advantages as a surrogate PET nuclide over 124I in terms of greater tumor uptake and retention [3]. In the current report, we have developed a non-linear immunokinetic model to facilitate a quantitative comparison of absolute uptake and antibody turnover between 124I-cG250 and 89Zr- cG250 using a human cRCC xenograft tumor model in mice. We believe that his unique model better relates quantitative imaging data to the salient biologic 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 sub-cutaneous cRCC 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 tumor were derived from the PET images using non-linear compartmental modeling. Results The two tracers demonstrate virtually identical tumor-cell binding and internalization but with 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 wash-out 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. Conclusions Pairwise evaluation of 89Zr-cG250 and 124I-cG250 provided the basis for a non-linear 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 non-invasively in man.

ImmunoPET of Malignant and Normal B Cells with 89Zr- and 124I-Labeled Obinutuzumab Antibody Fragments Reveals Differential CD20 Internalization In Vivo

“…(30) The 124 I-labeled antibody fragments undergo intracellular catabolism and dehalogenation upon internalization and 124 I-iodotyrosine diffuses rapidly from the cell. 89 Zr-antibody fragments show identical target cell binding but noticeable differences in retention because the residualizing 89 Zr radio-metabolites are trapped intracellularly.…”

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

“…However, to our knowledge, CLI had not previously been used to evaluate, in a head-to-head manner, the performance of different antibody-based radiotracers, a strategy that has routinely been performed with PET (24)(25)(26)(27). Therefore, the focus of these studies was to determine whether CLI can be used to distinguish between the preclinical performance of immuno-PET radiotracers that carry the same radioisotope and are targeted at the same tumor antigen but are predicted to have different clearance and tumor uptake properties.…”

PET/Computed Tomography in Renal, Bladder, and Testicular Cancer

“…Moreover, it is unclear whether the niche applications of this agent would make it economically sustainable. Suggestions have been made to exchange the I-124 with Zr-89, which may result in better imaging, but this does not clarify the actual clinical role of this agent 6,16 …”