Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression
Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression
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DOI：
10.2967/jnumed.117.199596
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发表时间：
2018-03-01
影响因子：
9.3
通讯作者：
Hayes, Wendy
中科院分区：
文献类型：
--
作者：
Donnelly, David J.;Smith, R. Adam;Hayes, Wendy
程序性死亡蛋白(PD-1)及其配体(PD-L1)在癌细胞逃避免疫系统的检查点途径中发挥关键作用。一种用于检测原发灶和转移灶中PD-L1状态的同日PET显像剂对于优化药物治疗可能是重要的。在此，我们评价了F-18-氟标记后抗PD-L1黏附素的肿瘤靶向性。方法：用F-18分两步标记抗PD-L1粘附素。这种合成的特点是将一个新的假体基团氟化，然后无铜点击连接到修饰的粘附素上，生成F-18-BMS-986192。以双侧PD-L1阴性(PD-L1(-))和PD-L1阳性(PD-L1(+))皮下肿瘤小鼠为研究对象，采用体外放射自显影和正电子发射计算机断层扫描技术对F-18-BMS-986192进行了评价。评价了F-18-BMS-986192在一只健康食蟹猴体内的分布、结合和辐射剂量学。结果：表面等离子体共振法测得F-18-BMS-986192与人和食蟹猴PD-L1结合的解离常数小于35 pm。用18F标记这种粘附素，得到一种用于评估PD-L1在体内表达的PET放射性配基。F-18-BMS-986192通过免疫组织化学检测PD-L1的表达而与肿瘤组织结合。放射性配基结合以剂量依赖的方式被阻断。体内PET成像清楚地显示了植入PD-L1(1)、L2987异种移植瘤的小鼠的PD-L1表达。给药后2小时，摄取率为3.5倍(2.41+/-0.29比0.82+/-0.11%/g，P
The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after F-18-fluorine labeling. Methods: An anti-PD-L1 adnectin was labeled with F-18 in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate F-18-BMS-986192. F-18-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors. F-18-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results: F-18-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. F-18-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(1), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 +/- 0.29 vs. 0.82 +/- 0.11 percentage injected dose per gram, P