[^68Ga]Ga-AUNP-12 PET imaging to assess the PD-L1 status in preclinical and first-in-human study
[^68Ga]Ga-AUNP-12 PET imaging to assess the PD-L1 status in preclinical and first-in-human study
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DOI：
10.1007/s00259-023-06447-2
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发表时间：
2023-09
影响因子：
9.1
通讯作者：
M. Zhou;Shijun Xiang;Yajie Zhao;Yongxiang Tang;Jinhui Yang;X. Yin;Jie Tian;Shuo Hu;Yang Du
中科院分区：
文献类型：
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作者：
M. Zhou;Shijun Xiang;Yajie Zhao;Yongxiang Tang;Jinhui Yang;X. Yin;Jie Tian;Shuo Hu;Yang Du
目的PD-L1 PET显像作为一种无创性检查方法，可对肿瘤部位PD-L1表达进行实时、动态、定量分析。在这项研究中，我们开发了一种新的基于肽的PET示踪剂，[68 Ga]Ga-AUNP-12，用于临床前和首次的PD-L1在patient.MethodsRadiosynthesis成像的[68 Ga]Ga-AUNP-12进行。对PANC 02、CT 26和B16 F10细胞系进行细胞摄取和结合试验。临床前模型用于研究其生物分布，成像能力和药代动力学。此外，干扰素-γ（IFN-γ）用于开发具有高PD-L1表达的动物模型，用于靶向PET成像和PD-L1阻断治疗的疗效评价。在健康志愿者和癌症患者中，PD-L1成像，辐射剂量学，安全性和生物分布进行了进一步evaluated.ResultsIn体外和体内动物研究表明，[68 Ga]Ga-AUNP-12 PET成像在评估PD-L1的表达显示出较高的特异性。[68 Ga]Ga-AUNP-12的放化产率为71.7 ± 8.2%。此外，其摩尔活性和放化纯度也令人满意。在[68 Ga]Ga-AUNP-12注射后60分钟，B16 F10肿瘤以6.86 ± 0.71%ID/g的肿瘤摄取和6.83 ± 0.36的肿瘤-肌肉比可视化。此外，[68 Ga]Ga-AUNP-12 PET显像可灵敏地检测IFN-γ治疗调节的CT 26肿瘤异种移植模型中PD-L1的动态变化，从而有效地指导免疫治疗。关于辐射剂量测定，[68 Ga]Ga-AUNP-12对人类使用是安全的。第一项人体研究发现，[68 Ga]Ga-AUNP-12可以通过肾脏排泄从血液和其他非特异性器官中快速清除，从而在临床框架中形成清晰的成像对比。结论[68 Ga] Ga-AUNP-12可作为PD-L1特异性PET显像示踪剂，在临床前和首次人体研究中获得成功。
PurposePD-L1 PET imaging, as a non-invasive procedure, can perform a real-time, dynamic and quantitative analysis of PD-L1 expression at tumor sites. In this study, we developed a novel peptide-based PET tracer, [68Ga]Ga-AUNP-12, for preclinical and first-of-its-kind imaging of PD-L1 expression in patients.MethodsRadiosynthesis of [68Ga]Ga-AUNP-12 was conducted. Assays for cellular uptake and binding were conducted on the PANC02, CT26, and B16F10 cell lines. Preclinical models were used to investigate its biodistribution, imaging capacity, and pharmacokinetics. Furthermore, interferon-γ (IFN-γ) was used for development of an animal model with high PD-L1 expression for targeted PET imaging and efficacy evaluation of PD-L1 blocking therapy. In healthy volunteers and cancer patients, the PD-L1 imaging, radiation dosimetry, safety, and biodistribution were further evaluated.ResultsIn vitro and in vivo animal studies showed that [68Ga]Ga-AUNP-12 PET imaging displayed a high specificity in evaluating PD-L1 expression. The radiochemical yield of [68Ga]Ga-AUNP-12 was 71.7 ± 8.2%. Additionally, its molar activity and radiochemical purity were satisfactory. The B16F10 tumor was visualized with the tumor uptake of 6.86 ± 0.71% ID/g and tumor-to-muscle ratio of 6.83 ± 0.36 at 60 min after [68Ga]Ga-AUNP-12 injection. Furthermore, [68Ga]Ga-AUNP-12 PET imaging could sensitively detect the PD-L1 dynamic changes in CT26 tumor xenograft models regulated by IFN-γ treatment, and correspondingly can effectively guide immunotherapy. Regarding radiation dosimetry, [68Ga]Ga-AUNP-12 is safe for human use. The first human study found that [68Ga]Ga-AUNP-12 can be rapidly cleared from blood and other nonspecific organs through the kidney excretion, leading to form a clear imaging contrast in the clinical framework. The specificity of [68Ga]Ga-AUNP-12 was validated and tumor uptake strongly correlated with the high PD-L1 expression in patients with lung adenocarcinoma and oesophageal squamous cell carcinoma (OSCC).Conclusion[68Ga]Ga-AUNP-12 was successfully developed as a PD-L1-specific PET imaging tracer in preclinical and first-in-human studies.