Zavvar Taraneh Sadat, Hörmann Anton Amadeus, Konijnenberg Mark, Kraihammer Martin, Mair Christian, Kronthaler Ariane, Joosten Lieke, Laverman Peter, Gruber Leonhard, di Santo Gianpaolo, Decristoforo Clemens, Virgolini Irene, von Guggenberg Elisabeth
Department of Nuclear Medicine, Medical University of Innsbruck, 6020, Innsbruck, Austria.
Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, the Netherlands.
Eur J Nucl Med Mol Imaging. 2025 Mar;52(4):1321-1331. doi: 10.1007/s00259-024-06979-1. Epub 2024 Dec 7.
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 [Lu]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.
Five individual batches of [Lu]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.
The automated cassette-based production of [Lu]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.
The radiopharmaceutical development and the preclinical/clinical results support the initiation of a first clinical trial to evaluate the therapeutic potential of [Lu]Lu-DOTA-MGS5 in PRRT.
靶向胆囊收缩素-2受体（CCK2R）的放射性标记小分子胃泌素（MG）类似物已被证明是肽受体放射性核素治疗（PRRT）的一种有前景的方法。在本研究中，我们报告了使用自动合成模块制备[¹⁷⁷Lu]Lu-DOTA-MGS5的放射性药物研发及制剂标准化情况。此外，我们还展示了推进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。
根据预定义的质量控制规范合成并分析了五批独立的[¹⁷⁷Lu]Lu-DOTA-MGS5。进行了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情况。在肿瘤异种移植小鼠中进行了临床前剂量学研究，并在一名小细胞肺癌患者中进行了首次剂量学研究。
基于自动盒式系统生产的[¹⁷⁷Lu]Lu-DOTA-MGS5产品具有>98%的高放射化学纯度和高稳定性。这种新型放射性药物在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，可描绘的肿瘤病灶的平均吸收剂量计算为12.5±10.2（1.2 - 28）Gy/GBq。
放射性药物研发以及临床前/临床结果支持开展首次临床试验，以评估[¹⁷⁷Lu]Lu-DOTA-MGS5在PRRT中的治疗潜力。
