Chatterjee Samit, Lesniak Wojciech G, Gabrielson Matthew, Lisok Ala, Wharram Bryan, Sysa-Shah Polina, Azad Babak Behnam, Pomper Martin G, Nimmagadda Sridhar
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Oncotarget. 2016 Mar 1;7(9):10215-27. doi: 10.18632/oncotarget.7143.
Antibodies targeting the PD-1/PD-L1 immune checkpoint lead to tumor regression and improved survival in several cancers. PD-L1 expression in tumors may be predictive of response to checkpoint blockade therapy. Because tissue samples might not always be available to guide therapy, we developed and evaluated a humanized antibody for non-invasive imaging of PD-L1 expression in tumors. Radiolabeled [111In]PD-L1-mAb and near-infrared dye conjugated NIR-PD-L1-mAb imaging agents were developed using the mouse and human cross-reactive PD-L1 antibody MPDL3280A. We tested specificity of [111In]PD-L1-mAb and NIR-PD-L1-mAb in cell lines and in tumors with varying levels of PD-L1 expression. We performed SPECT/CT imaging, biodistribution and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO). Results were confirmed in triple negative breast cancer (TNBC) (MDAMB231 and SUM149) and non-small cell lung cancer (NSCLC) (H2444 and H1155) xenografts with varying levels of PD-L1 expression. There was specific binding of [111In]PD-L1-mAb and NIR-PD-L1-mAb to tumor cells in vitro, correlating with PD-L1 expression levels. In mice bearing subcutaneous and orthotopic tumors, there was specific and persistent high accumulation of signal intensity in PD-L1 positive tumors (CHO-PDL1, MDAMB231, H2444) but not in controls. These results demonstrate that [111In]PD-L1-mAb and NIR-PD-L1-mAb can detect graded levels of PD-L1 expression in human tumor xenografts in vivo. As a humanized antibody, these findings suggest clinical translation of radiolabeled versions of MPDL3280A for imaging. Specificity of NIR-PD-L1-mAb indicates the potential for optical imaging of PD-L1 expression in tumors in relevant pre-clinical as well as clinical settings.
靶向PD-1/PD-L1免疫检查点的抗体可使多种癌症出现肿瘤消退并改善生存率。肿瘤中的PD-L1表达可能预示着对检查点阻断疗法的反应。由于并非总能获得组织样本以指导治疗，我们研发并评估了一种用于对肿瘤中PD-L1表达进行非侵入性成像的人源化抗体。使用小鼠与人交叉反应性PD-L1抗体MPDL3280A，研发了放射性标记的[111In]PD-L1单克隆抗体和近红外染料偶联的NIR-PD-L1单克隆抗体成像剂。我们在具有不同PD-L1表达水平的细胞系和肿瘤中测试了[111In]PD-L1单克隆抗体和NIR-PD-L1单克隆抗体的特异性。我们在携带组成性PD-L1表达肿瘤（CHO-PDL1）的NSG小鼠和对照（CHO）小鼠中进行了SPECT/CT成像、生物分布和阻断研究。在具有不同PD-L1表达水平的三阴性乳腺癌（TNBC）（MDAMB231和SUM149）和非小细胞肺癌（NSCLC）（H2444和H1155）异种移植模型中证实了结果。[111In]PD-L1单克隆抗体和NIR-PD-L1单克隆抗体在体外与肿瘤细胞有特异性结合，与PD-L1表达水平相关。在携带皮下和原位肿瘤的小鼠中，PD-L1阳性肿瘤（CHO-PDL1、MDAMB231、H2444）中有特异性且持续的高信号强度聚集，而对照中则没有。这些结果表明，[111In]PD-L1单克隆抗体和NIR-PD-L1单克隆抗体可在体内检测人肿瘤异种移植模型中不同程度的PD-L1表达。作为一种人源化抗体，这些发现提示MPDL3280A放射性标记版本用于成像的临床转化。NIR-PD-L1单克隆抗体的特异性表明在相关临床前及临床环境中对肿瘤中PD-L1表达进行光学成像的潜力。
