Departments of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
Cancer Res. 2015 Jul 15;75(14):2928-36. doi: 10.1158/0008-5472.CAN-14-3477. Epub 2015 May 14.
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti-PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3.1 was radiolabeled with Indium-111 ((111)In) and characterized using PD-L1-expressing MDA-MB-231 cells. Subsequently, the optimal antibody dose and time point for imaging was determined in mice with MDA-MB-231 xenografts. Finally, SPECT/CT imaging was performed in xenograft models with different PD-L1 expression levels and tumor sections were analyzed for PD-L1 expression using IHC. The optimal antibody dose of (111)In-PD-L1.3.1 (Kd = 1 nmol/L) for SPECT/CT imaging was ≤1 μg. Highest tumor-to-normal tissue contrast was obtained at days 3 and 7 after injection. (111)In-PD-L1.3.1 SPECT/CT showed efficient accumulation in high PD-L1-expressing tumors (MDA-MB-231 and SK-Br-3), whereas no specific uptake was observed in tumors with low or no detectable levels of PD-L1 (SUM149, BT474, and MCF-7). SPECT/CT and autoradiography showed a very heterogeneous distribution of (111)In-PD-L1.3.1 within the tumor. In conclusion, this is the first study showing the feasibility of noninvasive in vivo imaging of PD-L1 expression in tumors. (111)In-PD-L1.3.1 showed efficient and specific uptake in PD-L1 expressing xenografts. This technique may enable patient selection for PD-1 and PD-L1-targeted therapy.
阻断程序性死亡配体 1（PD-L1）与 PD-1 相互作用的抗体显示出令人印象深刻的抗肿瘤活性。表达 PD-L1 的肿瘤患者最有可能对此治疗产生反应。我们的研究旨在开发一种非侵入性成像技术，以在体内确定肿瘤 PD-L1 表达。这可以允许选择最有可能从抗 PD-1/PD-L1 治疗中受益的患者，并在治疗过程中监测 PD-L1 表达。单克隆抗体 PD-L1.3.1 用铟-111（(111)In）标记并使用表达 PD-L1 的 MDA-MB-231 细胞进行了表征。随后，在 MDA-MB-231 异种移植小鼠中确定了用于成像的最佳抗体剂量和时间点。最后，在具有不同 PD-L1 表达水平的异种移植模型中进行 SPECT/CT 成像，并使用免疫组织化学分析肿瘤切片中的 PD-L1 表达。用于 SPECT/CT 成像的（111)In-PD-L1.3.1（Kd = 1 nmol/L）的最佳抗体剂量≤1μg。在注射后 3 天和 7 天获得了最高的肿瘤与正常组织对比。（111)In-PD-L1.3.1 SPECT/CT 显示在高 PD-L1 表达肿瘤（MDA-MB-231 和 SK-Br-3）中有效积聚，而在 PD-L1 水平低或无法检测到的肿瘤（SUM149、BT474 和 MCF-7）中未观察到特异性摄取。SPECT/CT 和放射自显影显示（111)In-PD-L1.3.1 在肿瘤内的分布非常不均匀。总之，这是第一项研究表明，非侵入性体内成像 PD-L1 表达在肿瘤中的可行性。（111)In-PD-L1.3.1 在表达 PD-L1 的异种移植瘤中显示出高效和特异性摄取。这项技术可能使患者能够选择接受 PD-1 和 PD-L1 靶向治疗。
