Improved iodine radiolabels for monoclonal antibody therapy.
Improved iodine radiolabels for monoclonal antibody therapy.
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
R. Stein;S. Govindan;M. Mattes;Susan S. Chen;L. Reed;G. Newsome;B. Mcbride;G. Griffiths;H. Hansen;D. Goldenberg
中科院分区：
文献类型：
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作者：
R. Stein;S. Govindan;M. Mattes;Susan S. Chen;L. Reed;G. Newsome;B. Mcbride;G. Griffiths;H. Hansen;D. Goldenberg
用于放射免疫治疗的（131）碘（I）标记的单克隆抗体（MAb）的主要缺点是在放射性碘标记的MAb的内化和催化后碘酪氨酸从靶细胞快速扩散。我们最近报道了一种放射性碘标记的二亚乙基三胺五乙酸附加肽，称为免疫医学的残留肽1（IMP-R1），是一种残留碘标记物，克服了许多阻碍残留碘临床应用发展的限制。为了确定控制标记单克隆抗体治疗指数的因素，以及以高产率和高比活性生产放射性碘标记单克隆抗体所需的因素，评价了IMP-R1肽结构的变化。比较了一系列放射性碘标记的二亚乙基三胺五乙酸附加肽部分（IMP-R1至IMP-R8），这些肽部分在总体亲水性和电荷方面不同。放射性碘标记的肽，然后通过共轭二硫化物还原RS7（抗上皮糖蛋白-1单克隆抗体）提供放射性免疫共轭物在良好的整体性能，与直接放射性碘标记的RS7的免疫反应。已实现高达8 mCi/mg的比活性和> 80%的产率。在体外处理实验表明，放射性碘保留与所有的加合物显着增加;在45小时的放射性碘保留高达86%以上的细胞比直接碘化RS7。在携带人肺肿瘤异种移植物的裸鼠中的配对标记生物分布研究中，将每种（125）I-肽-RS7缀合物与（131）I-RS7（通过氯胺-T方法标记）进行比较。与直接放射性碘标记的RS7相比，所有残留底物在肿瘤中的保留显著增强，但非靶向摄取在残留标记之间存在显著差异。最好的标记是IMP-R4和IMP-R8，由于高肿瘤摄取和保留以及低正常器官摄取以及上级的放射化学性质，显示出上级的肿瘤与非肿瘤比率。在裸鼠肺癌模型上比较了（131）I-IMP-R4-RS7与常规（131）I标记RS7和（90）钇-RS7的治疗效果。（131）I-IMP-R4-RS7和（90）钇-RS7的治疗效果相当，与传统的（131）I-标记RS7相比，两种药物对肿瘤生长的控制均显著改善。
A major disadvantage of (131)iodine (I)-labeled monoclonal antibodies (MAbs) for radioimmunotherapy has been the rapid diffusion of iodotyrosine from target cells after internalization and catabolism of the radioiodinated MAbs. We recently reported that a radioiodinated, diethylenetriaminepentaacetic acid-appended peptide, designated immunomedics' residualizing peptide 1 (IMP-R1), was a residualizing iodine label that overcame many of the limitations that had impeded the development of residualizing iodine for clinical use. To determine the factors governing the therapeutic index of the labeled MAb, as well as the factors required for production of radioiodinated MAb in high yield and with high specific activity, variations in the peptide structure of IMP-R1 were evaluated. A series of radioiodinated, diethylenetriaminepentaacetic acid-appended peptide moieties (IMP-R1 through IMP-R8) that differed in overall hydrophilicity and charge were compared. Radioiodinations of the peptides followed by conjugations to disulfide-reduced RS7 (an anti-epithelial glycoprotein-1 MAb) furnished radioimmunoconjugates in good overall incorporations, with immunoreactivities comparable to that of directly radioiodinated RS7. Specific activities of up to 8 mCi/mg and yields > 80% have been achieved. In vitro processing experiments showed marked increases in radioiodine retention with all of the adducts; radioiodine retention at 45 h was up to 86% greater in cells than with directly iodinated RS7. Each of the (125)I-peptide-RS7 conjugates was compared with (131)I-RS7 (labeled by the chloramine-T method) in paired-label biodistribution studies in nude mice bearing human lung tumor xenografts. All of the residualizing substrates exhibited significantly enhanced retention in tumor in comparison to directly radioiodinated RS7, but the nontarget uptakes differed significantly among the residualizing labels. The best labels were IMP-R4 and IMP-R8, showing superior tumor-to-non-tumor ratios by virtue of high tumor uptake and retention and low normal organ uptake, as well as superior radiochemical properties. The therapeutic efficacy of (131)I-IMP-R4-RS7 was compared with that of conventionally (131)I-labeled RS7 and (90)yttrium-RS7 in the nude mice lung cancer model. The therapeutic efficacy of (131)I-IMP-R4-RS7 and (90)yttrium-RS7 were equivalent, and both agents yielded significantly improved control of tumor growth compared with conventional (131)I-labeled RS7.