Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Aug, 2004
Clinical and animal studies of chimeric monoclonal antibody G250 (moAb cG250) for the targeting of clear-cell renal cell carcinoma (RCC), to date, have been with the intact IgG form. To determine whether F(ab')2 fragments are more suited for radioimmunotherapy (RIT) than intact IgG, biodistribution experiments in nude mice were performed, and a pilot study in RCC patients was carried out. In these studies, the biodistribution, pharmacokinetics, and tumor-targeting characteristics of 131I-cG250-F(ab')2 fragments were determined.The biodistribution of intact IgG and F(ab')2 fragments (moAb cG250) was directly compared in mice with subcutaneous (s.c.) RCC xenografts that were coinjected with 125I-cG250-IgG and 131I-cG250-F(ab')2 fragments. Groups of 5 mice were dissected at 1, 2, 3, 5, and 7 days postinjection (p.i.). The activity in tumor and normal tissues was expressed as the percentage of the injected dose per gram (\%ID/g). Five (5) patients with evidence of primary RCC on computed tomography (CT) and scheduled for nephrectomy received a diagnostic infusion of 150 MBq 131I-cG250-F(ab')2. At various time points after injection of the antibody preparation (5 minutes, 3 hours, and 1, 2, 3, and 4 days), whole-body gamma camera images were acquired. After surgery, histology was determined and immunohistochemistry was performed. The scintigraphic images were analyzed visually and quantitatively. Radioactivity in whole-body, normal tissues and primary RCC was calculated and expressed as \%ID.In mice, 131I-cG250-F(ab')2 fragments cleared faster from the blood and other tissues, and absolute uptake in tumor (3.4 +/- 0.9 \%ID/g at 24 hours p.i.) and normal tissues was considerably lower compared to intact 125I-cG250. However, the tissue-to-blood ratios for both antibody preparations were similar for most tissues and at most time points. The results in patients corresponded with the results of the studies in mice. The 131I-cG250-F(ab')2 fragments cleared rapidly from the blood and body. The half-life of the distribution and elimination phase (t(1/2)alpha and t(1/2)beta) in blood of RCC patients were 4.8 +/- 0.9 hours and 29.0 +/- 3.3 hours, respectively. At 4 days p.i., whole-body activity was 20\%ID. Faint visualization of tumor was observed in only 2 of 5 patients.In mice, the tissue-to-blood ratios were similar for intact IgG and the 131I-cG250-F(ab')2 fragments for most tissues and at most time points, although absolute uptake in all tissues was considerably lower for the F(ab')2 fragments. In patients with primary RCC, tumorous kidney tissue was faintly visualized with 131I-cG250-F(ab')2 fragments. The intact IgG form of cG250 appears to be more suitable than cG250-F(ab')2 fragments for targeting clear-cell RCC.