1 Molecular Imaging Program, National Cancer Institute, Bethesda, MD, USA.
2 Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD, USA.
Mol Imaging. 2019 Jan-Dec;18:1536012119829986. doi: 10.1177/1536012119829986.
The goal is to evaluate avelumab, an anti-PD-L1 monoclonal immunoglobulin G antibody labeled with zirconium-89 in human PD-L1-expressing cancer cells and mouse xenografts for clinical translation.
[Zr]Zr-DFO-PD-L1 monoclonal antibody (mAb) was synthesized using avelumab conjugated to desferrioxamine. In vitro binding studies and biodistribution studies were performed with PD-L1+MDA-MB231 cells and MDA-MB231 xenograft mouse models, respectively. Biodistributions were determined at 1, 2, 3, 5, and 7 days post coinjection of [Zr]Zr-DFO-PD-L1 mAb without or with unlabeled avelumab (10, 20, 40, and 400 µg).
[Zr]Zr-DFO-PD-L1 mAb exhibited high affinity (K ∼ 0.3 nM) and detected moderate PD-L1 expression levels in MDA-MB231 cells. The spleen and lymph nodes exhibited the highest [Zr]Zr-DFO-PD-L1 mAb uptakes in all time points, while MDA-MB231 tumor uptakes were lower but highly retained. In the unlabeled avelumab dose escalation studies, spleen tissue-muscle ratios decreased in a dose-dependent manner indicating specific [Zr]Zr-DFO-PD-L1 mAb binding to PD-L1. In contrast, lymph node and tumor tissue-muscle ratios increased 4- to 5-fold at 20 and 40 µg avelumab doses.
[Zr]Zr-DFO-PD-L1 mAb exhibited specific and high affinity for PD-L1 in vitro and had target tissue uptakes correlating with PD-L1 expression levels in vivo. [Zr]Zr-DFO-PD-L1 mAb uptake in PD-L1+tumors increased with escalating doses of avelumab.
评估在人 PD-L1 表达癌细胞和小鼠异种移植瘤中表达 PD-L1 的avelumab（一种抗 PD-L1 单克隆免疫球蛋白 G 抗体），以期将其转化用于临床。
使用与去铁胺偶联的avelumab 合成[Zr]Zr-DFO-PD-L1 单克隆抗体（mAb）。分别在 PD-L1+MDA-MB231 细胞和 MDA-MB231 异种移植瘤小鼠模型中进行体外结合研究和生物分布研究。在不使用或使用未标记的 avelumab（10、20、40 和 400μg）的情况下，在[Zr]Zr-DFO-PD-L1 mAb 注射后 1、2、3、5 和 7 天，测定生物分布。
[Zr]Zr-DFO-PD-L1 mAb 表现出高亲和力（K∼0.3 nM），并在 MDA-MB231 细胞中检测到中等水平的 PD-L1 表达。在所有时间点，脾脏和淋巴结的摄取最高，而 MDA-MB231 肿瘤的摄取较低，但保留率高。在未标记的 avelumab 剂量递增研究中，脾脏组织-肌肉比呈剂量依赖性下降，表明 PD-L1 特异性结合[Zr]Zr-DFO-PD-L1 mAb。相比之下，在 20 和 40μg avelumab 剂量下，淋巴结和肿瘤组织-肌肉比增加了 4 到 5 倍。
[Zr]Zr-DFO-PD-L1 mAb 在体外对 PD-L1 表现出特异性和高亲和力，并且在体内与 PD-L1 表达水平相关的靶组织摄取。随着 avelumab 剂量的增加，[Zr]Zr-DFO-PD-L1 mAb 在 PD-L1+肿瘤中的摄取增加。
