Brouwers Adrienne H, van Eerd Julliëtte E M, Frielink Cathelijne, Oosterwijk Egbert, Oyen Wim J G, Corstens Frans H M, Boerman Otto C
Department of Nuclear Medicine, University Medical Center Nijmegen, NL-6500 HB Nijmegen, The Netherlands.
J Nucl Med. 2004 Feb;45(2):327-37.
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.
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.
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.
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.
放射免疫疗法（RIT）可使用多种放射性核素进行。我们在患有皮下肾细胞癌（RCC）肿瘤的裸鼠中测试了嵌合抗肾细胞癌单克隆抗体G250（mAb cG250）的各种放射免疫缀合物（（131）I、（88/90）Y、（177）Lu和（186）Re）的稳定性、生物分布和治疗效果。
对与环状二乙烯三胺五乙酸酐（cDTPA）、异硫氰酸苄基-DTPA（SCN-Bz-DTPA）或1,4,7,10-四氮杂环十二烷四乙酸（DOTA）偶联的cG250的（88/90）Y和（177）Lu标记程序进行了表征。评估了标记缀合物在37℃血浆中的稳定性。在患有SK-RC-52人RCC异种移植瘤的裸鼠中比较了标记cG250的生物分布和治疗效果。
当用于将（88）Y或（177）Lu标记到cG250上时，SCN-Bz-DTPA和DOTA在体外（孵育14天和21天期间放射性标记释放<5%）和体内（注射后7天骨摄取≤1.5%注射剂量每克[％ID/g]）均稳定。注射后7天，DOTA缀合物比SCN-Bz-DTPA略微但显著更稳定。在体内，这些cG250制剂显示出高肿瘤摄取（注射后7天为70±15％ID/g±SD）。（125）I-cG250和（186）Re-巯基乙酰三甘氨酸-（MAG3）-cG250的最大肿瘤摄取（<20±3％ID/g±SD）在注射后3天达到，与用残留放射性核素标记的cG250相比要低得多。由于使用SCN-Bz-DTPA可以制备最高的比活，并且可以在不使肿瘤饱和的情况下给予相对低蛋白剂量的cG250，因此cG250-SCN-Bz-DTPA缀合物用于RIT研究。在最大耐受剂量的RIT实验中，用（177）Lu标记的cG250最有效地延迟了肿瘤生长，其次是（90）Y和（186）Re（两者大致相等），而（131）I最不有效（分别延迟约185、125、90和25天）。观察到（177）Lu-SCN-Bz-DTPA-cG250的最佳中位生存期为300天。对照组的中位生存期<150天。
DOTA偶联的放射性标记抗体在体外和体内是最稳定的放射免疫缀合物，表现为最低的骨摄取。然而，SCN-Bz-DTPA的比活更高。RIT研究清楚地表明，用（177）Lu、（90）Y或（186）Re标记的mAb cG250的治疗效果优于（131）I-cG250。残留放射性核素（177）Lu和（90）Y对肿瘤产生更高的辐射剂量，并且对于RCC患者用cG250进行RIT而言，它们很可能比传统放射性标记的（131）I更适合。
