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Optimization of Radioimmunotherapy of Renal Cell Carcinoma: Labeling of Monoclonal Antibody cG250 with ¹³¹I, ⁹⁰Y, ¹⁷⁷Lu, or ¹⁸⁶Re

¹ Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
² Department of Urology, University Medical Center Nijmegen, Nijmegen, The Netherlands

Radioimmunotherapy (RIT) can be performed with various radionuclides. We tested the stability, biodistribution, and therapeutic efficacy of various radioimmunoconjugates (¹³¹I, ^88/90Y, ¹⁷⁷Lu, and ¹⁸⁶Re) of chimeric antirenal cell cancer monoclonal antibody G250 (mAb cG250) in nude mice with subcutaneous renal cell cancer (RCC) tumors. Methods: The ^88/90Y and ¹⁷⁷Lu labeling procedures of cG250 conjugated with cyclic diethylenetriaminepentaacetic acid anhydride (cDTPA), isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), or 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) were characterized. Stability of the labeled conjugates in plasma at 37°C was assessed. Biodistribution and therapeutic efficacy of labeled cG250 were compared in nude mice with SK-RC-52 human RCC xenografts. Results: Both SCN-Bz-DTPA and DOTA were stable in vitro (<5% release of the radiolabel during 14 and 21 d of incubation) and in vivo (uptake in bone 1.5 percentage injected dose per gram [%ID/g] at 7 d after injection) when used to label ⁸⁸Y or ¹⁷⁷Lu to cG250. The DOTA conjugate was slightly but significantly more stable than SCN-Bz-DTPA at 7 d after injection. In vivo, these cG250 preparations showed high tumor uptake (70 ± 15 %ID/g ± SD at 7 d after injection). Maximum tumor uptake for ¹²⁵I-cG250 and ¹⁸⁶Re-mercaptoacetyltriglycine-(MAG3)-cG250 (<20 ± 3 %ID/g ± SD) was reached at 3 d after injection and was much lower in comparison with cG250 labeled with the residualizing radionuclides. Because the highest specific activities could be prepared using SCN-Bz-DTPA, and relatively low protein doses of cG250 could be administered without saturating the tumor, cG250-SCN-Bz-DTPA conjugates were used in RIT studies. In RIT experiments at maximum tolerated dose, tumor growth was delayed most effectively by cG250 labeled with ¹⁷⁷Lu, next most effectively by ⁹⁰Y and ¹⁸⁶Re (which were approximately equal), and least by ¹³¹I (delayed by approximately 185, 125, 90, and 25 d, respectively). The best median survival (300 d) was observed for ¹⁷⁷Lu-SCN-Bz-DTPA-cG250. Median survival for control groups was <150 d. Conclusion: DOTA-conjugated radiolabeled antibodies were the most stable radioimmunoconjugates in vitro and in vivo as manifested by the lowest bone uptake. However, specific activity was higher for SCN-Bz-DTPA. The RIT studies clearly showed that the therapeutic efficacy of mAb cG250 labeled with ¹⁷⁷Lu, ⁹⁰Y, or ¹⁸⁶Re was superior to that of ¹³¹I-cG250. The residualizing radionuclides ¹⁷⁷Lu and ⁹⁰Y led to higher radiation doses to the tumor and most likely are better candidates than conventionally radiolabeled ¹³¹I for RIT with cG250 in patients with RCC.

Key Words: renal cell carcinoma • monoclonal antibody cG250 • experimental radioimmunotherapy • radionuclides • chelates

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