Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2004
Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Brouwers Adrienne H, van Eerd Julliëtte E M, Frielink Cathelijne, Oosterwijk Egbert, Oyen Wim J G, Corstens Frans H M, Boerman Otto C
Аннотация
UNLABELLED: Radioimmunotherapy (RIT) can be performed with various radionuclides. We tested the stability, biodistribution, and therapeutic efficacy of various radioimmunoconjugates ((131)I, (88/90)Y, (177)Lu, and (186)Re) of chimeric antirenal cell cancer monoclonal antibody G250 (mAb cG250) in nude mice with subcutaneous renal cell cancer (RCC) tumors.
METHODS: The (88/90)Y and (177)Lu 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 degrees 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 (88)Y or (177)Lu 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 (125)I-cG250 and (186)Re-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 (177)Lu, next most effectively by (90)Y and (186)Re (which were approximately equal), and least by (131)I (delayed by approximately 185, 125, 90, and 25 d, respectively). The best median survival (300 d) was observed for (177)Lu-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 (177)Lu, (90)Y, or (186)Re was superior to that of (131)I-cG250. The residualizing radionuclides (177)Lu and (90)Y led to higher radiation doses to the tumor and most likely are better candidates than conventionally radiolabeled (131)I for RIT with cG250 in patients with RCC.
METHODS: The (88/90)Y and (177)Lu 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 degrees 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 (88)Y or (177)Lu 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 (125)I-cG250 and (186)Re-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 (177)Lu, next most effectively by (90)Y and (186)Re (which were approximately equal), and least by (131)I (delayed by approximately 185, 125, 90, and 25 d, respectively). The best median survival (300 d) was observed for (177)Lu-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 (177)Lu, (90)Y, or (186)Re was superior to that of (131)I-cG250. The residualizing radionuclides (177)Lu and (90)Y led to higher radiation doses to the tumor and most likely are better candidates than conventionally radiolabeled (131)I for RIT with cG250 in patients with RCC.