Cole Erin L, Kim Joonyoung, Donnelly David J, Smith R Adam, Cohen Daniel, Lafont Virginie, Morin Paul E, Huang Richard Y-C, Chow Patrick L, Hayes Wendy, Bonacorsi Samuel
Radiochemistry Group, Bristol-Myers Squibb Company, Princeton, NJ, USA.
Imaging Group, Bristol-Myers Squibb Company, Princeton, NJ, USA.
Bioorg Med Chem. 2017 Oct 15;25(20):5407-5414. doi: 10.1016/j.bmc.2017.07.066. Epub 2017 Aug 4.
Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the Zr complex were shown to be acceptable for imaging. Three naïve NHPs were intravenously injected with tracer only or tracer co-injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver.
与传统的细胞毒性化疗不同，癌症免疫疗法通过激活免疫系统来识别癌细胞并刺激免疫反应。程序性死亡受体1（PD-1）蛋白是一种免疫抑制受体，由活化的细胞毒性T淋巴细胞（CTL）表达，CTL可寻找并破坏癌细胞。多种癌症类型会表达并上调程序性死亡配体1（PD-L1）和2（PD-L2），它们与PD-1结合，作为一种免疫逃逸机制。纳武单抗是一种全人源IgG4抗PD-1单克隆抗体（mAb），已被批准用于治疗多种癌症类型。本研究报告了在健康非人灵长类动物（NHP）中制备和体内评估锆标记的纳武单抗，作为生物分布和清除的初步研究。结果表明，锆配合物的放射化学稳定性和体内稳定性对于成像来说是可以接受的。对三只未经处理的NHP静脉注射示踪剂或示踪剂与纳武单抗共同注射，随后通过正电子发射断层扫描（PET）和磁共振成像（MRI）进行联合配准，在注射后八天内采集图像。通过感兴趣区域（ROI）分析对图像衍生的标准化摄取值（SUV）进行定量。与仅注射示踪剂的研究相比，在所有成像时间点，添加过量纳武单抗后脾脏中的放射性显著降低。放射性示踪剂在肝脏中的摄取作为清除器官是一致的，来自其他组织（肺、肌肉、脑、心脏和肾脏）的信号最小。结果表明，脾脏有特定的生物分布，过量纳武单抗共同给药可阻断这种分布。在其他器官中的分布与抗体的清除途径一致，主要通过肝脏清除。
