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Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET
European Journal of Nuclear Medicine and Molecular Imaging ( IF 9.1 ) Pub Date : 2022-07-14 , DOI: 10.1007/s00259-022-05876-9
Ming Zhou 1 , Xiaobo Wang 2 , Bei Chen 1 , Shijun Xiang 1 , Wanqian Rao 1 , Zhe Zhang 2 , Huanhuan Liu 2 , Jianyang Fang 2 , Xiaoqin Yin 1 , Pengbo Deng 3 , Xianzhong Zhang 2 , Shuo Hu 1, 4, 5
Affiliation  

Purpose

PD-L1 PET imaging allows for the whole body measuring its expression across primary and metastatic tumors and visualizing its spatiotemporal dynamics before, during, and after treatment. In this study, we reported a novel 18F-labeled D-peptide antagonist, 18F-NOTA-NF12, for PET imaging of PD-L1 status in preclinical and first-in-human studies.

Methods

Manual and automatic radiosynthesis of 18F-NOTA-NF12 was performed. Cell uptake and binding assays were completed in MC38, H1975, and A549 cell lines. The capacity for imaging of PD-L1 status, biodistribution, and pharmacokinetics were investigated in preclinical models. The PD-L1 status was verified by western blotting, immunohistochemistry/fluorescence, and flow cytometry. The safety, radiation dosimetry, biodistribution, and PD-L1 imaging potential were evaluated in healthy volunteers and patients.

Results

The radiosynthesis of 18F-NOTA-NF12 was achieved via manual and automatic methods with radiochemical yields of 41.7 ± 10.2 % and 70.6 ± 4.2 %, respectively. In vitro binding assays demonstrated high specificity and affinity with an IC50 of 78.35 nM and KD of 85.08 nM. The MC38 and H1975 tumors were clearly visualized with the optimized tumor-to-muscle ratios of 5.36 ± 1.17 and 7.13 ± 1.78 at 60 min after injection. Gemcitabine- and selumetinib-induced modulation of PD-L1 dynamics was monitored by 18F-NOTA-NF12. The tumor uptake correlated well with their PD-L1 expression. 18F-NOTA-NF12 exhibited renal excretion and rapid clearance from blood and other non-specific organs, contributing to high contrast imaging in the clinical time frame. In NSCLC and esophageal cancer patients, the specificity of 18F-NOTA-NF12 for PD-L1 imaging was confirmed. The 18F-NOTA-NF12 PET/CT and 18F-FDG PET/CT had equivalent findings in patients with high PD-L1 expression.

Conclusion

18F-NOTA-NF12 was developed successfully as a PD-L1-specific tracer with promising results in preclinical and first-in-human trials, which support the further validation of 18F-NOTA-NF12 for PET imaging of PD-L1 status in clinical settings.

Graphical abstract



中文翻译:

18F 标记的 D 肽拮抗剂用于 PET PD-L1 状态成像的临床前和首次人体评估

目的

PD-L1 PET 成像允许全身测量其在原发性和转移性肿瘤中的表达,并在治疗之前、期间和之后可视化其时空动态。在这项研究中,我们报道了一种新型18 F 标记的 D 肽拮抗剂18 F-NOTA-NF12,用于在临床前和首次人体研究中对 PD-L1 状态进行 PET 成像。

方法

进行了18 F-NOTA-NF12的手动和自动放射合成。在 MC38、H1975 和 A549 细胞系中完成细胞摄取和结合测定。在临床前模型中研究了 PD-L1 状态、生物分布和药代动力学的成像能力。通过蛋白质印迹、免疫组织化学/荧光和流式细胞术验证 PD-L1 状态。在健康志愿者和患者中评估了安全性、辐射剂量测定、生物分布和 PD-L1 成像潜力。

结果

18 F-NOTA-NF12的放射合成通过手动和自动方法实现,放射化学产率分别为 41.7 ± 10.2 % 和 70.6 ± 4.2 %。体外结合测定显示出高特异性和亲和力,IC 50为 78.35 nM,K D为 85.08 nM。注射后 60 分钟,MC38 和 H1975 肿瘤清晰可见,优化的肿瘤与肌肉比率为 5.36 ± 1.17 和 7.13 ± 1.78。吉西他滨和司美替尼诱导的 PD-L1 动力学调节由18 F-NOTA-NF12 监测。肿瘤摄取与其 PD-L1 表达密切相关。18F-NOTA-NF12 表现出肾排泄和从血液和其他非特异性器官中快速清除,有助于在临床时间范围内进行高对比度成像。在 NSCLC 和食管癌患者中,18 F-NOTA-NF12 对 PD-L1 成像的特异性得到证实。18 F-NOTA-NF12 PET/CT 和18 F -FDG PET/CT 在 PD-L1 高表达患者中具有相同的发现。

结论

18 F-NOTA-NF12 被成功开发为 PD-L1 特异性示踪剂,在临床前和首次人体试验中取得了可喜的结果,这支持进一步验证18 F-NOTA-NF12 用于 PD-L1 状态的 PET 成像在临床环境中。

图形概要

更新日期:2022-07-15
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