Purpose

Radiolabelled minigastrin (MG) analogues targeting the cholecystokinin-2 receptor (CCK2R) have proven to be a promising approach for peptide receptor radionuclide therapy (PRRT). In this study, we report on the radiopharmaceutical development and standardization of the preparation of [¹⁷⁷Lu]Lu-DOTA-MGS5 using an automated synthesis module. Furthermore, we present the preclinical tests required to move forward towards a first therapeutic clinical trial as well as preliminary clinical dosimetry data.

Methods

Five individual batches of [¹⁷⁷Lu]Lu-DOTA-MGS5 were synthesized and analysed according to predefined quality control specifications. Cell-based experiments and biodistribution studies were performed to evaluate the specific receptor binding and tumour uptake of the radiopharmaceutical formulation. A preclinical dosimetry study was carried out in tumour xenografted mice and a first dosimetry study was performed in a patient with small cell lung cancer.

Results

The automated cassette-based production of [¹⁷⁷Lu]Lu-DOTA-MGS5 resulted in a product with high radiochemical purity of > 98% and high stability. The new radiopharmaceutical showed a favourable biodistribution profile in A431-CCK2R xenografted BALB/c nude mice. Pharmacokinetic data obtained in mice and dosimetry extrapolation demonstrated the feasibility of PRRT. In the preliminary patient-specific dosimetry study, a low risk of toxicity was shown and a mean absorbed dose of 12.5 ± 10.2 (1.2–28) Gy/GBq was calculated for delineable tumour lesions.

Conclusion

The radiopharmaceutical development and the preclinical/clinical results support the initiation of a first clinical trial to evaluate the therapeutic potential of [¹⁷⁷Lu]Lu-DOTA-MGS5 in PRRT.

中文翻译：

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[177Lu]Lu-DOTA-MGS5 在肽受体放射性核素治疗中的应用放射性药物制剂和初步临床剂量测定

 目的

靶向胆囊收缩素-2 受体 （CCK2R） 的放射性同位素 （MG） 类似物已被证明是肽受体放射性核素治疗 （PRRT） 的一种有前途的方法。在本研究中，我们报告了使用自动合成模块制备 [¹⁷⁷Lu]Lu-DOTA-MGS5 的放射性药物开发和标准化。此外，我们还提供了迈向首次治疗性临床试验所需的临床前测试以及初步临床剂量学数据。

 方法

合成了五个单独的批次的 [¹⁷⁷Lu]Lu-DOTA-MGS5，并根据预定义的质量控制规范进行了分析。进行基于细胞的实验和生物分布研究，以评估放射性药物制剂的特异性受体结合和肿瘤摄取。在肿瘤异种移植小鼠中进行临床前剂量学研究，并在小细胞肺癌患者中进行第一次剂量学研究。

 结果

[¹⁷⁷Lu]Lu-DOTA-MGS5 基于盒式自动化生产，生产出具有 > 98% 的高放射化学纯度和高稳定性的产品。新的放射性药物在 A431-CCK2R 异种移植的 BALB/c 裸鼠中显示出良好的生物分布特征。在小鼠中获得的药代动力学数据和剂量学外推证明了 PRRT 的可行性。在初步的患者特异性剂量学研究中，显示出低毒性风险，并且计算出可描绘的肿瘤病灶的平均吸收剂量为 12.5 ± 10.2 （1.2-28） Gy/GBq。

 结论

放射性药物开发和临床前/临床结果支持启动首次临床试验，以评估 [¹⁷⁷Lu]Lu-DOTA-MGS5 在 PRRT 中的治疗潜力。