Department of Radiology, University of Louisville, Louisville, Kentucky, USA.
Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA.
Cancer Biother Radiopharm. 2020 Oct;35(8):549-557. doi: 10.1089/cbr.2019.3056. Epub 2020 Apr 21.
The rise of programmed death-1 (PD-1)/PD-L1 immune checkpoint inhibitor therapy has been one of the most promising developments in melanoma research. However, not all the melanoma patients respond to such immune checkpoint blockade. There is a great need of biomarkers for appropriate melanoma patient selection and therapeutic efficacy monitoring. The objective of this study is to develop a novel radiolabeled anti-PD-L1 antibody fragment, as an imaging biomarker, for evaluating the PD-L1 levels in melanoma. The Df-conjugated F(ab') fragment of the anti-mouse PD-L1 antibody was successfully synthesized and radiolabeled with Zr. Both Df-F(ab') and Zr-Df-F(ab') maintained the nano-molar murine PD-L1 targeting specificity and affinity. Zr-Df-F(ab') showed less uptake in normal liver tissue in mice compared with its full antibody counterpart Zr-Df-anti-PD-L1. Positron emission tomography (PET)/computed tomography images clearly showed that Zr-Df-F(ab') possessed superior pharmacokinetics and imaging contrast over the radiolabeled full antibody, with much earlier and higher tumor uptake (5.5 times more at 2 h post injection) and much lower liver background (51% reduction at 2 h post injection). The specific and high murine PD-L1-targeting uptake at tumor foci coupled with fast clearance of Zr-Df-F(ab') highlighted its potential for PET imaging of murine PD-L1 levels and future development of radiolabeled anti-human PD-L1 fragment for potential application in melanoma patients.
程序性死亡受体-1（PD-1）/PD-L1 免疫检查点抑制剂治疗的兴起是黑色素瘤研究中最有前途的进展之一。然而，并非所有黑色素瘤患者对这种免疫检查点阻断都有反应。因此，非常需要生物标志物来进行适当的黑色素瘤患者选择和治疗效果监测。本研究旨在开发一种新型放射性标记的抗 PD-L1 抗体片段，作为一种成像生物标志物，用于评估黑色素瘤中的 PD-L1 水平。成功合成了抗小鼠 PD-L1 抗体的 Df 缀合 F(ab')片段，并对其进行了 Zr 放射性标记。Df-F(ab')和 Zr-Df-F(ab')均保持了纳米摩尔级的抗 PD-L1 靶向特异性和亲和力。与完整抗体 Zr-Df-anti-PD-L1 相比，Zr-Df-F(ab')在小鼠正常肝脏组织中的摄取较少。正电子发射断层扫描（PET）/计算机断层扫描图像清楚地表明，Zr-Df-F(ab')在药代动力学和成像对比度方面优于放射性标记的完整抗体，具有更早和更高的肿瘤摄取（注射后 2 小时增加 5.5 倍）和更低的肝脏背景（注射后 2 小时减少 51%）。肿瘤病灶中特异性和高的小鼠 PD-L1 靶向摄取，加上 Zr-Df-F(ab')的快速清除，突出了其用于 PET 成像的潜力，可用于检测小鼠 PD-L1 水平，并为未来开发用于黑色素瘤患者的放射性标记抗人 PD-L1 片段奠定基础。
