PET/CT Imaging of 89 Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys,Molecular Imaging and Biology

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PET/CT Imaging of 89 Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys
Molecular Imaging and Biology ( IF 3.1 ) Pub Date : 2020-10-26 , DOI: 10.1007/s11307-020-01558-w
Wenping Li ₁ , Yuchuan Wang ₁ , Daniel Rubins ₁ , Idriss Bennacef ₁ , Marie Holahan ₁ , Hyking Haley ₁ , Mona Purcell ₁ , Liza Gantert ₁ , SuChun Hseih ₂ , Michael Judo ₂ , Wolfgang Seghezzi ₂ , Shuli Zhang ₂ , Elly L van der Veen ₃ , Marjolijn N Lub-de Hooge ₃ , Elisabeth G E de Vries ₃ , Jeffrey L Evelhoch ₁ , Michael Klimas ₁ , Eric D Hostetler ₁

Affiliation

Purpose

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 (⁸⁹Zr)-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.

Procedures

Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal-Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with ⁸⁹Zr. 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_mean) were quantified by region of interest (ROI) analysis.

Results

⁸⁹Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (> 99 %) and acceptable molar activity (> 7 MBq/nmol). In animals dosed with tracer only, ⁸⁹Zr-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.

Conclusions

⁸⁹Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. ⁸⁹Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.

Trial Registration

ClinicalTrials.gov Identifier: NCT02760225

中文翻译：

89 Zr-N-sucDf-Pembrolizumab 在健康食蟹猴中的 PET/CT 成像

目的

程序性细胞死亡 1 受体 (PD-1) 及其配体 (PD-L1) 是许多癌症类型的免疫治疗靶点。尽管 PD-1 阻断剂具有治疗作用，但疗效因患者而异。导致这种变异性的因素是肿瘤中存在的 PD-L1 表达水平和免疫细胞。然而，目前尚不清楚肿瘤微环境中 PD-1 的表达如何影响免疫治疗反应。因此，对表达 PD-1 的免疫细胞进行成像是很有意义的。本研究旨在评估 Zirconium-89 ( ⁸⁹ Zr) 标记的 pembrolizumab（一种靶向 PD-1 的人源化 IgG4 kappa 单克隆抗体）在健康食蟹猴中的生物分布，作为跟踪 PD-1 阳性免疫细胞的转化模型。

程序

派姆单抗与四氟苯酚-N-琥珀酰去铁醛-Fe(III) 酯 (TFP-N-sucDf) 结合，随后用⁸⁹ Zr进行放射性标记。四只之前没有接触过人源化单克隆抗体的食蟹猴只接受了示踪剂或示踪剂与派姆单抗联合注射超过 5 分钟。此后，在第 0、2、5 和 7 天以每个床位 10 分钟获取静态全身正电子发射断层扫描 (PET) 扫描。图像衍生的标准化摄取值（SUV_平均值）按感兴趣区域进行量化（投资回报率）分析。

结果

⁸⁹ Zr-N-sucDf-pembrolizumab 以高放射化学纯度 (> 99 %) 和可接受的摩尔活性 (> 7 MBq/nmol) 合成。在仅给予示踪剂的动物中，⁸⁹ Zr-N-sucDf-pembrolizumab 在淋巴组织（如肠系膜淋巴结、脾脏和扁桃体）中的分布随时间增加。除肝脏外，在包括肺、肌肉、脑、心脏和肾脏在内的所有非淋巴组织中均观察到放射性示踪剂的低分布。当大量过量的 pembrolizumab 与放射性示踪剂共同给药时，淋巴结、脾脏和扁桃体中的积聚减少，提示靶介导的积聚。