Zhou Ming, Xiang Shijun, Zhao Yajie, Tang Yongxiang, Yang Jinhui, Yin Xiaoqin, Tian Jie, Hu Shuo, Du Yang
Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No. 95 Zhongguancun East Road, Beijing, 100190, China.
Eur J Nucl Med Mol Imaging. 2024 Jan;51(2):369-379. doi: 10.1007/s00259-023-06447-2. Epub 2023 Sep 28.
PD-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, [ Ga]Ga-AUNP-12, for preclinical and first-of-its-kind imaging of PD-L1 expression in patients.
Radiosynthesis of [ Ga]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.
In vitro and in vivo animal studies showed that [ Ga]Ga-AUNP-12 PET imaging displayed a high specificity in evaluating PD-L1 expression. The radiochemical yield of [ Ga]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 [ Ga]Ga-AUNP-12 injection. Furthermore, [ Ga]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, [ Ga]Ga-AUNP-12 is safe for human use. The first human study found that [ Ga]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 [ Ga]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).
[ Ga]Ga-AUNP-12 was successfully developed as a PD-L1-specific PET imaging tracer in preclinical and first-in-human studies.
作为一种非侵入性检查，PD-L1正电子发射断层显像（PET）成像可对肿瘤部位的PD-L1表达进行实时、动态和定量分析。在本研究中，我们开发了一种新型的基于肽的PET示踪剂[68Ga]Ga-AUNP-12，用于临床前及首例患者PD-L1表达成像。
进行了[68Ga]Ga-AUNP-12的放射性合成。对PANC02、CT26和B16F10细胞系进行了细胞摄取和结合试验。采用临床前模型研究其生物分布、成像能力和药代动力学。此外，使用干扰素-γ（IFN-γ）建立高PD-L1表达动物模型，用于靶向PET成像及PD-L1阻断治疗的疗效评估。在健康志愿者和癌症患者中，进一步评估了PD-L1成像、辐射剂量测定、安全性和生物分布。
体外和体内动物研究表明，[68Ga]Ga-AUNP-12 PET成像在评估PD-L1表达方面具有高特异性。[68Ga]Ga-AUNP-12的放射化学产率为71.7±8.2%。此外，其摩尔活度和放射化学纯度令人满意。注射[68Ga]Ga-AUNP-12后60分钟，B16F10肿瘤可视化，肿瘤摄取率为6.86±0.71%ID/g，肿瘤与肌肉比值为6.83±0.36。此外，[68Ga]Ga-AUNP-12 PET成像可灵敏检测IFN-γ治疗调控的CT26肿瘤异种移植模型中PD-L1的动态变化，并相应有效指导免疫治疗。关于辐射剂量测定，[68Ga]Ga-AUNP-12对人体使用安全。首例人体研究发现，[68Ga]Ga-AUNP-12可通过肾脏排泄从血液和其他非特异性器官快速清除，在临床框架内形成清晰的成像对比。[68Ga]Ga-AUNP-12的特异性得到验证，肿瘤摄取与肺腺癌和食管鳞状细胞癌（OSCC）患者的高PD-L1表达密切相关。
在临床前和首例人体研究中，[68Ga]Ga-AUNP-12已成功开发为一种PD-L1特异性PET成像示踪剂。
