Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Cancer Biol Ther. 2010 Oct 15;10(8):767-74. doi: 10.4161/cbt.10.8.12879.
The utility of MORF/cMORF pretargeting for the radiotherapy of cancer requires further validation in tumored mice before clinical trials. We now report on a therapeutic study in mice pretargeted with MORF-CC49 (an anti-TAG-72 antibody CC49 conjugated with MORF, a phosphorodiamidate morpholino oligomer) and then targeted by 188Re-cMORF (a 188Re labeled complementary MORF). Before the dose-escalating therapeutic study, a pretargeting study in LS174T tumored mice was performed at tracer levels. By both necropsy and imaging, the tracer study showed that the whole body radioactivity was largely restricted to tumor in the mice pretargeted 48 h earlier with MORF-CC49 and the tumor radioactivity was retained over 90 h. After decay correction, a best-fit to the biodistribution provided the areas under the radioactivity curves (AUCs) used for the radiation dose estimates. The tumor to normal organ AUC ratios in all cases were greater than unity and ranged from 3 (kidneys) to 48 (muscle). Tumor growth was inhibited in the therapy study. At the highest 188Re dose of 1.40 mCi, a complete but temporary tumor remission was evident in 3 out of the 5 animals. Histological examination of tissues from these animals showed no evidence of cytotoxicity to normal tissues but obvious radiation damage to tumor. In conclusion, effective radiotherapy was achieved in a mouse model by MORF/cMORF pretargeting using 188Re as the therapeutic radionuclide and CC49 as the pretargeting antibody.
MORF/cMORF 前靶向在癌症放射治疗中的应用需要在肿瘤小鼠中进一步验证，然后才能进行临床试验。我们现在报告了一项在经 MORF-CC49（一种与 MORF 缀合的抗 TAG-72 抗体 CC49，MORF 是一种磷酰胺二酯吗啉寡聚物）预处理的小鼠中进行的治疗研究，然后用 188Re-cMORF（一种用 188Re 标记的互补 MORF）进行靶向。在进行剂量递增治疗研究之前，在 LS174T 肿瘤小鼠中进行了一项示踪剂研究。通过尸检和成像，示踪研究表明，在预先用 MORF-CC49 预处理 48 小时的小鼠中，全身放射性主要局限于肿瘤，肿瘤放射性在 90 小时以上保持不变。经衰变校正后，对生物分布进行最佳拟合，提供用于辐射剂量估计的放射性曲线下面积 (AUC)。在所有情况下，肿瘤与正常器官 AUC 比值均大于 1，范围从 3（肾脏）到 48（肌肉）。在治疗研究中，肿瘤生长受到抑制。在最高的 188Re 剂量为 1.40 mCi 时，5 只动物中有 3 只出现明显的肿瘤完全缓解，但暂时缓解。对这些动物组织的组织学检查显示，对正常组织没有细胞毒性，但对肿瘤有明显的辐射损伤。总之，用 188Re 作为治疗放射性核素和 CC49 作为前靶向抗体，通过 MORF/cMORF 前靶向，在小鼠模型中实现了有效的放射治疗。
