Govindan S V, Shih L B, Goldenberg D M, Sharkey R M, Karacay H, Donnelly J E, Losman M J, Hansen H J, Griffiths G L
Immunomedics, Inc., 300 American Road, Morris Plains, New Jersey 07950, and Garden State Cancer Center, Belleville, New Jersey 07109, USA.
Bioconjug Chem. 1998 Nov-Dec;9(6):773-82. doi: 10.1021/bc980040g.
90Yttrium-labeled monoclonal antibodies (mAbs) are likely to be important to radioimmunotherapy (RAIT) of a variety of cancers. The goal of this study was to select and evaluate a form of [90Y]mAb suitable for RAIT and determine conditions for high-yield, reproducible radiolabelings. 90Y-Labelings, at 2-40 mCi levels, of cdr-grafted versions of anti-B-cell lymphoma (hLL2) and anti-CEA (hIMMU-14) mAbs were optimized to >90% incorporations using the macrocyclic chelator DOTA as the metal carrier. In in vitro challenge assays, the stability of mAbs labeled with [90Y]DOTA was better than that of the corresponding [90Y]benzyl-DTPA conjugates. The retention of [90Y]DOTA-hLL2 on Raji tumor cells in vitro was similar to that of the same mAb labeled with [90Y]benzyl-DTPA and was about twice as much as with [125I]hLL2, indicating residualization of metalated mAb. Both [90Y]hLL2 conjugates, prepared using DOTA and Bz-DTPA, had similar maximum tolerated doses of 125 muCi in BALB/c mice and showed no discernible chelator-induced immune responses. Animal biodistribution studies in nude mice bearing Ramos human B-cell lymphoma xenografts revealed similar tumor and tissue uptake over a 10 day period, with the exception of bone uptake which was up to 50% lower for [88Y]DOTA-hLL2 compared to [88Y]Bz-DTPA-hLL2 at time points beyond 24 h. With [90Y]DOTA-hLL2 fragments, in vivo animal tumor dosimetries were inferior to those for the IgG, and kidney uptake was relatively high even with D-lysine administration. The ability of [111In]DOTA-hLL2 to accurately predict [90Y]DOTA-hLL2 biodistribution was established. These preclinical findings demonstrate that [90Y]DOTA-(CDR-grafted) mAbs are suitable for examination in clinical RAIT.
90钇标记的单克隆抗体（mAb）可能对多种癌症的放射免疫疗法（RAIT）具有重要意义。本研究的目的是选择并评估一种适用于RAIT的[90Y]mAb形式，并确定高产率、可重复放射性标记的条件。使用大环螯合剂DOTA作为金属载体，将抗B细胞淋巴瘤（hLL2）和抗癌胚抗原（hIMMU-14）mAb的互补决定区移植版本在2 - 40毫居里水平进行90Y标记，优化后的掺入率>90%。在体外挑战试验中，用[90Y]DOTA标记的mAb的稳定性优于相应的[90Y]苄基二乙三胺五乙酸（benzyl-DTPA）缀合物。[90Y]DOTA-hLL2在体外Raji肿瘤细胞上的保留情况与用[90Y]苄基-DTPA标记的相同mAb相似，约为[125I]hLL2的两倍，表明金属化mAb发生了残留。使用DOTA和Bz-DTPA制备的两种[90Y]hLL2缀合物在BALB/c小鼠中的最大耐受剂量均为125微居里，且未显示出明显的螯合剂诱导的免疫反应。在携带Ramos人B细胞淋巴瘤异种移植物的裸鼠中进行的动物生物分布研究显示，在10天内肿瘤和组织摄取情况相似，但在24小时后的时间点，[88Y]DOTA-hLL2的骨摄取比[88Y]Bz-DTPA-hLL2低多达50%。对于[90Y]DOTA-hLL2片段，体内动物肿瘤剂量测定结果不如IgG，即使给予D-赖氨酸，肾脏摄取仍相对较高。已证实[111In]DOTA-hLL2能够准确预测[90Y]DOTA-hLL2的生物分布。这些临床前研究结果表明，[90Y]DOTA-（互补决定区移植）mAb适用于临床RAIT检查。
