Lesniak Wojciech G, Chatterjee Samit, Gabrielson Matthew, Lisok Ala, Wharram Bryan, Pomper Martin G, Nimmagadda Sridhar
Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
Bioconjug Chem. 2016 Sep 21;27(9):2103-10. doi: 10.1021/acs.bioconjchem.6b00348. Epub 2016 Aug 9.
The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [(64)Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET-CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [(64)Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [(64)Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [(64)Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO-hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [(64)Cu]atezolizumab for the detection of PD-L1 expression in different tumor types.
程序性死亡蛋白1（PD-1）与程序性死亡配体1（PD-L1）配对是癌细胞用来建立和维持免疫耐受的主要免疫检查点途径。随着抗PD-1和抗PD-L1治疗性抗体最近获得批准，迫切需要非侵入性检测方法来量化肿瘤中动态PD-L1表达，并评估肿瘤对免疫调节疗法的反应。为满足这一需求，我们评估了[（64）Cu]阿特珠单抗用于检测肿瘤中的PD-L1表达。阿特珠单抗（MPDL3208A）是一种人源化、人鼠交叉反应性治疗性PD-L1抗体，正在多种癌症中进行研究。阿特珠单抗与DOTAGA偶联并用铜-64进行放射性标记。对所得的[（64）Cu]阿特珠单抗在多种具有不同PD-L1表达的细胞系和肿瘤中进行体外和体内特异性评估。我们在携带组成性PD-L1表达肿瘤（CHO-hPD-L1）的NSG小鼠和对照组（CHO）中进行了PET-CT成像、生物分布和阻断研究。[（64）Cu]阿特珠单抗的特异性在人乳腺癌原位肿瘤模型（MDAMB231和SUM149）以及同基因小鼠乳腺癌模型（4T1）中得到进一步证实。我们观察到[（64）Cu]阿特珠单抗在体外与肿瘤细胞的特异性结合，这与PD-L1表达水平相关。与低PD-L1表达的肿瘤（CHO、SUM149）相比，在高PD-L1表达的肿瘤（CHO-hPD-L1和MDAMB231）中也观察到了[（64）Cu]阿特珠单抗的特异性蓄积。总体而言，这些研究证明了使用[（64）Cu]阿特珠单抗检测不同肿瘤类型中PD-L1表达的可行性。
