Translational Biomarkers, Merck & Co., Inc., WP 44D, 770 Sumneytown Pike, West Point, PA, 19486, USA.
PPDM Bioanalysis, MRL South San Francisco, 213 East Grand Blvd, South San Francisco, CA, 94080, USA.
Mol Imaging Biol. 2021 Apr;23(2):250-259. doi: 10.1007/s11307-020-01558-w. Epub 2020 Oct 26.
Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1-positive immune cells.
Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal-Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis.
Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (> 99 %) and acceptable molar activity (> 7 MBq/nmol). In animals dosed with tracer only, Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation.
Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.
ClinicalTrials.gov Identifier: NCT02760225.
程序性死亡受体-1（PD-1）及其配体（PD-L1）是许多癌症类型免疫治疗的靶点。虽然 PD-1 阻断具有治疗效果，但疗效在患者之间存在差异。导致这种变异性的因素包括 PD-L1 表达水平和肿瘤中的免疫细胞。然而，PD-1 在肿瘤微环境中的表达如何影响免疫治疗反应尚不清楚。因此，对表达 PD-1 的免疫细胞进行成像具有重要意义。本研究旨在评估锆-89（Zr）标记的 pembrolizumab（一种针对 PD-1 的人源化 IgG4 kappa 单克隆抗体）在健康食蟹猴中的分布，作为跟踪 PD-1 阳性免疫细胞的转化模型。
将 pembrolizumab 与四氟苯酚-N-琥珀酰去铁胺-Fe(III)酯（TFP-N-sucDf）缀合，然后用 Zr 标记。四只未接触过人源化单克隆抗体的食蟹猴静脉注射示踪剂或示踪剂与 pembrolizumab 共注射 5 分钟。此后，在第 0、2、5 和 7 天，以每个床位 10 分钟的速度进行静态全身正电子发射断层扫描（PET）扫描。通过感兴趣区（ROI）分析定量图像衍生的标准化摄取值（SUV）。
Zr-N-sucDf-pembrolizumab 的放射性化学纯度（>99%）高，摩尔活性（>7MBq/nmol）可接受。在仅给予示踪剂的动物中，Zr-N-sucDf-pembrolizumab 在肠系膜淋巴结、脾脏和扁桃体等淋巴组织中的分布随时间增加。除肝脏外，所有非淋巴组织（包括肺、肌肉、大脑、心脏和肾脏）中的放射性示踪剂分布均较低。当与放射性示踪剂一起给予大量 pembrolizumab 时，淋巴结、脾脏和扁桃体的积聚减少，提示存在靶向介导的积聚。
Zr-N-sucDf-pembrolizumab 优先在包括淋巴结、脾脏和扁桃体在内的淋巴组织中摄取。Zr-N-sucDf-pembrolizumab 可能有助于在非人类灵长类动物和人类中追踪免疫细胞亚群的分布。
ClinicalTrials.gov 标识符：NCT02760225。
