Evaluation of 177Lu[Lu]-CHX-A"-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII
Evaluation of 177Lu[Lu]-CHX-A"-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII
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DOI：
10.1016/j.nucmedbio.2018.02.004
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发表时间：
2018-05-01
影响因子：
3.1
通讯作者：
Gildehaus, F. J.
中科院分区：
文献类型：
--
作者：
Fiedler, L.;Kellner, M.;Gildehaus, F. J.
由于胶质瘤的浸润性生长，即使在手术切除后，也有很高的复发率。腔内放射免疫治疗（RIT）的目的是通过直接给药到切除腔（RC）来抑制肿瘤的再生长。直接将放射性缀合物应用于RC具有绕过血脑屏障的优点，这使得比全身应用的辐射剂量更高。碳酸酐酶XII （CA XII）在胶质瘤细胞中高表达，而在正常大脑中不存在，因此是RIT的一个有吸引力的靶分子。我们评估了一种带有lu177标记的caxii特异性6A10 Fab（片段抗原结合）作为RIT的药物。方法：对6A10 Fab片段进行修饰，用Lu-177对其进行放射性标记，并采用MALDI-TOF、流式细胞术和放射性薄层色谱对其进行鉴定。在生理条件下测定其体外稳定性。对移植人类胶质瘤的scid小鼠进行生物分布研究、放射自显影检查和平面闪烁成像。结果：证实了修饰Fab的体外CA - XII结合能力。生理条件下孵育72小时后，放射化学纯度测定为> - 90%。放射自显影实验证实了Fab与CA XII在肿瘤细胞上的特异性结合。生物分布研究显示，6小时后肿瘤摄取为3.0%ID/g，未检测到脑摄取。定量平面显像证实肿瘤与对侧的比值为10/1。结论：放射化学稳定性和成功的体内肿瘤摄取表明6A10 Fab在未来的RIT应用中具有潜在的适用性。(C) 2018爱思唯尔公司版权所有。
Introduction: Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with Lu-177 as an agent for RIT.Methods: 6A10 Fab fragment was modified and radiolabelled with Lu-177 and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts.Results: The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy.Conclusion: The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab. (C) 2018 Elsevier Inc. All rights reserved.