Yang Yanling, Wang Chao, Wang Yan, Sun Yan, Huang Xing, Huang Minzhou, Xu Hui, Fan Huaying, Chen Daquan, Zhao Feng
Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai, 264005, People's Republic of China.
SmartNuclide Biopharma Co. Ltd, 218 Xinghu St., BioBAY A4-202, Suzhou Industrial Park, Suzhou, 215123, People's Republic of China.
EJNMMI Res. 2021 Oct 30;11(1):113. doi: 10.1186/s13550-021-00854-y.
Immunotherapy is a valuable option for cancer treatment, and the curative effect of anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using Ga-NOTA-Nb109 nanobody. Ga-NOTA-Nb109 was generated by radionuclide (Ga) labeling of Nb109 using a NOTA chelator. To facilitate clinical trials, we explored the optimal dose range of Ga-NOTA-Nb109 in BALB/c A375-hPD-L1 tumor-burdened nude mice and C57-hPD-L1 transgenic MC38-hPD-L1 tumor-burdened mice by administration of a single intravenous dose of Ga-NOTA-Nb109 and confirmed the dose in cynomolgus monkeys. The biodistribution data of cynomolgus monkey PET images were extrapolated to estimate the radiation dose for the adult male and female using OLINDA2.1 software.
Ga-NOTA-Nb109 was stable in physiologic media and human serum. Ex vivo biodistribution studies showed rapid and specific uptake in A375-hPD-L1 or MC38-hPD-L1 tumors. The estimated ED was approximately 5.4 µg in humanized mice. The injected mass (0.3-100 µg in nude mice and approximately 1-100 µg in humanized mice) greatly influenced the general biodistribution, with a better tumor-to-background ratio acquired at lower doses of Nb109 (0.3-10 µg in nude mice and approximately 1 µg in humanized mice), indicating maximum uptake in tumors at administered mass doses below the estimated ED Therefore, a single 15-μg/kg dose was adopted for the PET/CT imaging in the cynomolgus monkey. The highest specific and persistent uptake of the tracer was detected in the spleen, except the levels in the kidney and urine bladder, which was related to metabolism and excretion. The spleen-to-muscle ratio of the tracer exceeded 10 from immediately to 4 h after administration, indicating that the dose was appropriate. The estimated effective dose was calculated to yield a radiation dose of 4.1 mSv to a patient after injecting 185 MBq of Ga-NOTA-Nb109.
Ga-NOTA-Nb109 showed specific accumulation in hPD-L1 xenografts in ex vivo biodistribution studies and monkey PET/CT imaging. The dose escalation distribution data provided a recommended dose range for further use, and the safety of the tracer was confirmed in dosimetry studies.
免疫疗法是癌症治疗的一种有价值的选择，抗PD-1/PD-L1疗法的疗效与PD-L1表达水平密切相关。使用Ga-NOTA-Nb109进行PD-L1表达的正电子发射断层扫描（PET）成像是可行的。Ga-NOTA-Nb109是通过使用NOTA螯合剂对Nb109进行放射性核素（Ga）标记而产生的。为了促进临床试验，我们通过单次静脉注射Ga-NOTA-Nb109，在荷BALB/c A375-hPD-L1肿瘤的裸鼠和荷C57-hPD-L1转基因MC38-hPD-L1肿瘤的小鼠中探索了Ga-NOTA-Nb109的最佳剂量范围，并在食蟹猴中确定了该剂量。使用OLINDA2.1软件外推食蟹猴PET图像的生物分布数据，以估计成年男性和女性的辐射剂量。
Ga-NOTA-Nb109在生理介质和人血清中稳定。体外生物分布研究表明，其在A375-hPD-L1或MC38-hPD-L1肿瘤中快速且特异性摄取。在人源化小鼠中估计的有效剂量约为5.4μg。注射质量（裸鼠中为0.3 - 100μg，人源化小鼠中约为1 - 100μg）对总体生物分布有很大影响，在较低剂量的Nb109（裸鼠中为0.3 - 10μg，人源化小鼠中约为1μg）下可获得更好的肿瘤与背景比值，表明在低于估计有效剂量的给药质量剂量下肿瘤摄取最大。因此，在食蟹猴的PET/CT成像中采用了15μg/kg的单次剂量。除了肾脏和膀胱中的水平与代谢和排泄有关外，在脾脏中检测到示踪剂的最高特异性和持续性摄取。给药后立即至4小时，示踪剂的脾脏与肌肉比值超过10，表明剂量合适。计算得出，注射185MBq的Ga-NOTA-Nb109后，估计有效剂量会使患者产生4.1mSv的辐射剂量。
在体外生物分布研究和猴PET/CT成像中，Ga-NOTA-Nb109在hPD-L1异种移植瘤中显示出特异性积聚。剂量递增分布数据提供了进一步使用的推荐剂量范围，并且在剂量学研究中证实了示踪剂的安全性。
