Russell H. Morgan Department of Radiology and Radiological Science , Sidney Kimmel Comprehensive Canter Center, Johns Hopkins University , Baltimore , Maryland 21287 , United States.
Mol Pharm. 2018 Sep 4;15(9):3946-3952. doi: 10.1021/acs.molpharmaceut.8b00399. Epub 2018 Aug 10.
Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy. Guidance of anti-PD-L1 therapy is currently effected through measurement of PD-L1 through biopsy and immunohistochemistry. Here, we report a peptide-based imaging agent, [Ga]WL12, to detect PD-L1 expression in tumors noninvasively by positron emission tomography (PET). WL12, a cyclic peptide comprising 14 amino acids, binds to PD-L1 with high affinity (IC50≈ 23 nM). Synthesis of [Ga]WL12 provided radiochemical purity >99% after purification. Biodistribution in immunocompetent mice demonstrated 11.56 ± 3.18, 4.97 ± 0.8, 1.9 ± 0.1, and 1.33 ± 0.21 percentage of injected dose per gram (%ID/g) in hPD-L1, MDAMB231, SUM149, and CHO tumors, respectively, at 1 h postinjection, with high binding specificity noted with coinjection of excess, nonradiolabeled WL12. PET imaging demonstrated high tissue contrast in all tumor models tested.
肿瘤会形成并维持免疫抑制微环境，促进癌细胞逃避免疫监视。免疫检查点蛋白程序性死亡配体 1（PD-L1）在许多癌症中表达，是维持免疫抑制肿瘤微环境的重要因素。PD-L1 是癌症免疫治疗的重要靶点。目前，通过活检和免疫组织化学来测量 PD-L1 来指导抗 PD-L1 治疗。在这里，我们报告了一种基于肽的成像剂 [Ga]WL12，可通过正电子发射断层扫描（PET）非侵入性地检测肿瘤中的 PD-L1 表达。WL12 是一种由 14 个氨基酸组成的环状肽，与 PD-L1 具有高亲和力（IC50≈23 nM）。[Ga]WL12 的合成在纯化后提供了 >99%的放射化学纯度。在免疫功能正常的小鼠中进行的生物分布研究表明，在注射后 1 小时，hPD-L1、MDAMB231、SUM149 和 CHO 肿瘤中的每克注射剂量百分比（%ID/g）分别为 11.56±3.18、4.97±0.8、1.9±0.1 和 1.33±0.21，与过量非放射性标记的 WL12 共注射时，观察到高结合特异性。PET 成像显示在所有测试的肿瘤模型中均具有高组织对比度。
