RESULTS: rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3-0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6-11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively.
CONCLUSIONS: Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).
结果:rhPSMA-10.1和-10.2根据其他基于DOTA的PSMA配体的既定程序用lutium-177进行放射性标记,并在所有缓冲液和人血清中显示出较高且相当的稳定性(>97%,24h).生物分布研究显示,在48小时内从血池(1小时时0.3-0.6%ID/g)和其他背景组织中快速清除。在肾脏中发现了明显的差异,其中[177Lu]Lu-rhPSMA-10.1与[177Lu]Lu-rhPSMA-10.2相比,显示出较低的初始摄取和较快的排泄动力学,在健康动物中在1小时和24小时时表达的摄取值低1.5倍和九倍,分别。两种异构体的肿瘤摄取在24小时内具有可比性,在8.6-11.6%ID/g的范围内,对于[177Lu]Lu-rhPSMA-10.1和[177Lu]Lu-rhPSMA-10.2,分别保持在2.2±0.8和4.1±1.4%ID/g的水平长达168小时。
结论:我们关于生物分布和剂量学的临床前数据表明,与[177Lu]Lu-rhPSMA-10.2相比,[177Lu]Lu-rhPSMA-10.2对于PSMA靶向放射性配体治疗具有更有利的特征。[177Lu]Lu-rhPSMA-10.1显示出快速的肾脏清除动力学,从而在治疗相关的时间过程中产生优异的肿瘤与器官比率。同时,[177Lu]Lu-rhPSMA-10.1目前正在mCRPC患者的临床I/II期研究中进行研究(NCT05413850),在高风险的局部PC(NCT06066437,Nautilus试验)和外部束放疗后(NCT06105918)的患者中。