Division of RI Application, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Department of Biomedical Laboratory Science, Yonsei University, Wonju, South Korea.
Clin Cancer Res. 2019 Oct 15;25(20):6148-6159. doi: 10.1158/1078-0432.CCR-19-1157. Epub 2019 Jul 23.
Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model.
We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with Cu or Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with Cu-/Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by Lu-cA10-A3 and F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67.
Radiolabeled cA10-A3 antibodies specifically recognized L1CAM , clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes ( < 0.05) and decreased glucose metabolism ( < 0.01). IHC analysis revealed Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or Lu-isotype.
Anti-L1CAM immuno-PET imaging using Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.
胆管癌是一种恶性胆管肿瘤，预后较差。常规化疗和放疗通常无效，手术切除是胆管癌唯一的治愈性治疗方法。L1 细胞黏附分子（L1CAM）已被认为是胆管癌的一种新的预后标志物和治疗靶点。本研究旨在评估基于免疫 PET 成像的放射性免疫治疗在胆管癌异种移植模型中使用放射性标记抗 L1CAM 抗体的可行性。
我们使用嵌合抗 L1CAM 抗体（cA10-A3）与 1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA）螯合剂偶联，并标记铜或镥，制备了一种治疗学融合的生物放射性药物，并用 Cu-/Lu-cA10-A3 在各种胆管癌异种移植模型中评估免疫 PET 或 SPECT/CT 成像和生物分布。通过 Lu-cA10-A3 和 F-FDG-PET 分别进行治疗效果和反应监测，并通过 TUNEL 和 Ki-67 进行免疫组化分析。
放射性标记的 cA10-A3 抗体特异性识别 L1CAM，在免疫 PET 和 SPECT/CT 成像中清晰地可视化胆管癌肿瘤，并区分了胆管癌异种移植模型中的 L1CAM 表达水平。Lu-cA10-A3（12.95 MBq/100 μg）显示肿瘤体积显著减小（<0.05），葡萄糖代谢降低（<0.01）。免疫组化分析显示，与生理盐水、cA10-A3 或 Lu 同型相比，Lu-cA10-A3 治疗增加了 TUNEL 阳性细胞，减少了 Ki-67 阳性细胞。
使用 Cu-cA10-A3 进行抗 L1CAM 免疫 PET 成像可以转化为临床，用于描述药代动力学并选择合适的放射免疫治疗患者。使用 Lu-cA10-A3 进行放射免疫治疗可能会为 L1CAM 表达的胆管癌肿瘤提供生存获益。治疗学融合生物放射性药物策略将作为基于成像生物标志物的个性化医学应用于 L1CAM 表达的胆管癌患者。
