PO.ET07.02 · 实验与分子治疗
人血微核网织红细胞：作为肿瘤药物开发中DNA双链断裂药效学生物标志物的应用
Human blood micronucleated reticulocytes: Application as a pharmacodynamic biomarker for DNA double strand breaks in oncology drug development
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摘要 Abstract
中文摘要
引言：微核网织红细胞（MN-RET）是一种成熟的染色体损伤生物标志物，其评估传统上作为临床前开发期间基于法规的产品安全性测试的一部分。将该方法学改进为高通量流式细胞术分析拓展了该检测的应用范围，并使其能够切实转化应用于人类受试者。最近，该方法学已被用于在开发靶向DNA双链断裂修复通路的疗法期间，通过诱导MN-RET作为疗效生物标志物来证明靶点结合。
方法：为支持这一应用，我们在临床模型中开展研究以确定基本的方法学参数。为更好地理解随时间/受试者间的基线值及可重复性，我们基于14名受试者的血液标本评估了MN-RET频率的技术重复变异性。受试者内变异性基于6名受试者的连续采血，受试者间变异基于多达344名年龄0至73岁的受试者。
结果：人类模型显示在暴露于已知DNA损伤剂后MN-RET频率增加。受试者间变异（≥77%）远大于受试者内和技术重复变异性。相对较大的受试者间变异从MN-RET的均值和标准差值中可见一斑（0.15 ± 0.10%）。年龄和性别均未影响MN-RET频率的受试者间变异。在临床环境中，以标签剂量接受PARP抑制剂治疗的患者显示MN-RET升高，表明未修复的DNA损伤增加，作为治疗诱导的靶点结合指标。
总结：这一染色体损伤的转化生物标志物代表了一种独特而强大的工具，可用于开发引发DNA双链断裂的癌症疗法。
查看英文原文 English abstract
Introduction: Micronucleated reticulocytes (MN-RET) are a well-established biomarker of chromosomal damage, and their assessment is traditionally included as part of regulatory-based, product safety testing during preclinical development. Adaptation of the methodology to high-throughput flow cytometric analysis broadened the utility of the assay and enabled practical translation to human subjects. Most recently, this methodology has been used to demonstrate target engagement via the induction of MN-RET as a biomarker of efficacy during the development of therapies targeting DNA double strand break-repair pathways.
Methods: To support this application, we have conducted studies in clinical models to define basic methodological parameters. In an effort to better understand baseline values over time/between subjects and reproducibility, we evaluated technical replicate variability in MN-RET frequencies based on blood specimens from 14 subjects. Intra-subject variability was based on serial blood draws from 6 subjects, and inter-subject variation was based on up to 344 subjects age 0 to 73 years.
Results: Human models demonstrate increased MN-RET frequencies following exposure to known DNA damaging agents. Inter-subject variation (≥77%) was much greater than intra-subject and technical replicate variability. The relatively large inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%). Neither age nor sex affected inter-subject variation of the MN-RET frequency. In a clinical setting, patients treated with PARP inhibitors at a labelled dose showed elevated MN-RETs, demonstrating the increased unrepaired DNA damage as an indicator of target engagement induced by treatment.
Summary: This translational biomarker of chromosomal damage represents a unique and powerful tool for use in the development of cancer therapies that elicit DNA double strand breaks.
利益披露 Disclosure
J. C. Bemis,
Litron Laboratories Employment, Patent.
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Artios Pharma Limited Employment, Stock.
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Gilead Biosciences Other, Consulting.
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S. Avlasevich,
Litron Laboratories Employment.
D. Torous,
Litron Laboratories Employment.
S. Dertinger,
Litron Laboratories Employment, Patent.