抗 EGFRvIII 单克隆抗体与 177Lu 偶联：大环和非环配体的体内比较。
Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.
机构信息
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
出版信息
Nucl Med Biol. 2010 Oct;37(7):741-50. doi: 10.1016/j.nucmedbio.2010.04.020.
INTRODUCTION
Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with (177)Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors.
MATERIALS AND METHODS
L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.ΔEGFR glioma xenografts over a period of 1 to 8 days to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB).
RESULTS
Except with C-DOTA, tumor uptake for the (177)Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for (177)Lu-1B4M-DTPA-L8A4 and, to an even greater extent, (177)Lu-MeO-DOTA-L8A4 were higher than those for [(125)I]SGMIB-L8A4 in most other tissues.
CONCLUSIONS
Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for (177)Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application.
简介
单克隆抗体（mAb）L8A4 特异性结合表皮生长因子受体变体 III（EGFRvIII），该蛋白存在于神经胶质瘤中，而不存在于正常组织中，在与受体结合后迅速被内吞。由于其 β 射线的射程较短，因此用（177）Lu 标记这种 mAb 用于治疗脑肿瘤手术切除后残留的肿瘤边缘是一种很有吸引力的方法。
材料与方法
使用非环状配体[（R）-2-氨基-3-（4-异硫氰酸根合苯丙基）-反式-（S，S）-环己烷-1,2-二胺-五乙酸（CHX-A″-DTPA）和 2-（4-异硫氰酸根合苄基）-6-甲基二乙烯三胺五乙酸（1B4M-DTPA）和环状配体 S-2-（4-异硫氰酸根合苄基）-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（C-DOTA）和α-（5-异硫氰酸根合-2-甲氧基苯基）-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（MeO-DOTA）对 L8A4 mAb 进行（177）Lu 标记。在表达 EGFRvIII 的 U87.ΔEGFR 神经胶质瘤异种移植的皮下荷瘤裸鼠中进行了为期 1 至 8 天的配对标记组织分布实验，以直接比较（177）Lu 标记的 L8A4 与使用 N-琥珀酰亚胺基 4-胍基甲基-3-[[125I]碘代苯甲酸（[（125）I]SGMIB）标记的 L8A4。
结果
除了 C-DOTA 之外，（177）Lu 标记的 mAb 的肿瘤摄取率明显高于同时给予的放射性碘标记制剂；但是，脾、肝、骨和肾也是如此。与（125）I]SGMIB-L8A4 相比，（177）Lu-1B4M-DTPA-L8A4 和（177）Lu-MeO-DOTA-L8A4 的肿瘤/正常组织比值在大多数其他组织中更高。
结论
这种抗 EGFRvIII mAb 的肿瘤和正常组织分布模式取决于用于（177）Lu 标记的双功能螯合剂的性质。使用 1B4M-DTPA 和 MeO-DOTA 可获得最佳结果，这表明对于这种应用，环状配体与非环状配体相比没有明显优势。
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