一种（90）Y 标记的抗 ROBO1 单克隆抗体在 ROBO1 靶向放射免疫治疗期间表现出针对肝癌异种移植物的抗肿瘤活性。
A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy.
机构信息
Department of Radiology, Graduate School of Medicine, The University of Tokyo, 3-1, Hongo 7-Chome, Bunkyo-ku 113-8655, Tokyo, Japan.
SANKYO LABO SERVICE Co., Ltd., 2-13-16, Nishiichinoe, Edogawaku 132-0023, Tokyo, Japan.
出版信息
EJNMMI Res. 2014 Jun 1;4:29. doi: 10.1186/s13550-014-0029-3. eCollection 2014.
BACKGROUND
ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models.
METHODS
ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with (111)In and (90)Y. To study biodistribution, the (111)In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the (90)Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out.
RESULTS
The tumour uptake of (111)In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection. Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of (90)Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow.
CONCLUSIONS
These results suggest that RIT with (90)Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular carcinoma.
背景
ROBO1 是一种在轴突导向中起作用的膜蛋白。ROBO1 有助于肿瘤转移和血管生成，并且可能具有作为免疫治疗靶蛋白的潜力，因为 ROBO1 在肝癌中特异性高水平表达。在这项研究中，我们使用放射性同位素标记的抗 ROBO1 单克隆抗体（MAb）检查了针对肝癌模型的生物分布和放射免疫治疗（RIT）。
方法
本研究使用 ROBO1 阳性 HepG2 人肝癌异种移植裸鼠。我们将抗 ROBO1 MAb 与 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）缀合，并用（111）In 和（90）Y 标记缀合物。为了研究生物分布，将（111）In-DOTA-抗 ROBO1 MAb 通过尾静脉注射到 HepG2 异种移植小鼠中。为了评估任何抗肿瘤作用，通过尾静脉注射（90）Y-DOTA-抗 ROBO1 MAb 进行 RIT 研究。在整个实验过程中定期测量肿瘤体积、小鼠体重和血细胞计数。收集小鼠的肿瘤和器官，并进行组织病理学分析。
结果
在 HepG2 异种移植小鼠中，（111）In-抗 ROBO1 MAb 的肿瘤摄取率为注射后 48 小时每克 15.0%±0.69% 注入剂量。用冷抗 ROBO1 MAb（70μg）进行免疫治疗没有引起明显的抗肿瘤作用。用 6.7MBq 的（90）Y-抗 ROBO1 MAb 进行 RIT 导致肿瘤生长明显抑制。观察到短暂的体重减轻和骨髓抑制。肿瘤的组织病理学分析显示肿瘤细胞致命变性、Ki-67 指数显著降低和凋亡指数增加。正常器官没有明显损伤，但脾和胸骨骨髓中的造血细胞短暂减少。
结论
这些结果表明，用（90）Y-抗 ROBO1 MAb 进行 RIT 是治疗 ROBO1 阳性肝癌的一种有前途的方法。
Zotero 插件