錸(I)-188三羰基標誌Trastuzumab單株抗體作為乳癌造影及治療劑之研究

Study on [188]Re(I)-Tricarbonyl Labeled Trastuzumab Monoclonal Antibody as Imaging and Therapeutic Agent for Breast Cancer with HER2-overexpression

陳國庭(Kuo-Ting Chen)

指導教授 ： 羅建苗 ； 李德偉

國立清華大學/原子科學院/生醫工程與環境科學系/碩士(2007年)

https://doi.org/10.6843/NTHU.2007.00104

摘要

Herceptin®是近年來常見的抗乳癌藥物，其中的主成分trastuzumab抗體是一種經過基因重組的人類化單株抗體 (humanized monoclonal antibody)，其Fab端能辨識HER2，可取代生長因子結合HER2，終止其激酶信號功能，而抑制腫瘤細胞的分化與增生，臨床上用來治療有HER2大量表現的人類乳癌。
錸-188的半衰期長達16.9小時，且能釋放高能的β-粒子 (2.12MeV)及高解析度的γ射線 (0.155MeV)，用來標誌單株抗體，可兼具放射免疫治療及放射免疫造影之功效。本研究發展出新的錸-188標誌方式，先以無機化學合成方法在水相中製備錸-188(I)-三羰基離子，[188Re(OH2)3(CO)3]+，再將放射性核種錸-188標誌於trastuzumab單株抗體，作為HER2過量表現乳癌之造影及治療劑。
在本實驗中，以高效能液相層析法、分子大小排阻層析法及蛋白質去性沉澱法測試188Re(I)-trastuzumab的標誌效率及穩定度。並將188Re(I)-trastuzumab注入植有BT-474 (大量表現HER2)或MCF-7 (低表現HER2)腫瘤細胞的實驗裸鼠，經生物分佈及藥物動力學的分析，證實188Re(I)-trastuzumab保有trastuzumab本身的藥物專一性及活性。在SPECT/CT造影的實驗中，188Re(I)-trastuzumab因為與HER2有高度的親和力，使放射性標誌藥物能累積在BT-474腫瘤中，使之顯影。然而，將188Re(I)-trastuzumab注入已植有MCF-7腫瘤的實驗裸鼠，放射性藥物累積於腫瘤的量相對較低，亦無SPECT/CT之顯影。由此研究所得結果可推論188Re(I)-trastuzumab在未來有發展為放射免疫治療藥物之潛力。

關鍵字

錸-188 ； 單株抗體

並列摘要

Trastuzumab (Herceptin®), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. In this study, 188Re, an emitter with 2.12MeV β- and 0.155MeV γ and t1/2 = 16.9h, was labeled to trastuzumab aiming for radioimmunotherapy of HER2/neu-positive breast cancer. The 188Re(I)-tricarbonyl ion, [188Re(OH2)3(CO)3]+, was employed as a precursor for direct labeling 188Re to the monoclonal antibody. The resultant 188Re(I)-trastuzumab was found to be very stable even challenging with histidine. The tumor and normal tissues localization properties of 188Re(I)-trastuzumab in athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressing) and bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressing) were investigated. The in vivo biodistribution study demonstrated that 188Re(I)-trastuzumab was specifically accumulated in BT-474 tumor and the image of 188Re localized BT-474 tumor was clearly visualized within the useful lifetime of the radionuclide. By contrast, the 188Re(I)-trastuzumab uptakes in HER2-low expressing MCF-7 tumor was minimal so that the 188Re image localized at the tumor was not seen. It is revealed from the imaging study that 188Re(I)-trastuzumab may be a potential radioimmunotherapeutic agent for treatment of HER2/neu-overexpressing cancers.

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