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首页> 外文期刊>Journal of Pharmaceutical and Biomedical Analysis: An International Journal on All Drug-Related Topics in Pharmaceutical, Biomedical and Clinical Analysis >Insights in the application of research-grade diagnostic kits for biomarker assessments in support of clinical drug development: Bioanalysis of circulating concentrations of soluble receptor activator of nuclear factor kappaB ligand.
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Insights in the application of research-grade diagnostic kits for biomarker assessments in support of clinical drug development: Bioanalysis of circulating concentrations of soluble receptor activator of nuclear factor kappaB ligand.

机译：用于生物标志物评估的研究级诊断试剂盒在支持临床药物开发中的应用见解：核因子kappaB配体的可溶性受体激活剂循环浓度的生物分析。

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Application of research-grade diagnostic kits in clinical drug development has grown commensurate with the increased interest in utilization of biomarkers as drug development tools. Since novel biomarkers are frequently macromolecular, immunoassay methodology comprises the 'technology-of-choice' for biomarker quantification. In particular, commercial research-grade immunoassay kits are appealing for use in biomarker quantification during clinical phase drug development because of their ready availability, ease of operation and perceived convenience. However, bioanalytical validation issues arise often during the application of commercial kits, as GLP regulatory-compliant application places greater demands on kit design and performance. In this review, we have used the receptor activator of nuclear factor kappaB ligand (RANKL) as a model system to offer some insights into the challenges that can be encountered in the application of 'research-grade' diagnostic kits in support of clinical drug development. Currently only a few assays are available commercially for the determination of circulating concentrations of sRANKL. Of these, two immunoassay designs have been most often. The first design employs human osteoprotegerin to capture unbound sRANKL from serum and, thereby, provides a measure of circulating free concentrations. In contrast, the other common assay design first involves preincubation of serum samples with human osteoprotegerin to convert the free fraction of sRANKL to the osteoprotegerin-bound complex. The bound fraction is subsequently captured by an anti-osteoprotegerin antibody. In both immunoassay designs, detection is accomplished with an anti-sRANKL enzyme conjugation system. In this report we review these sRANKL immunoassay designs critically from the perspective of their potential suitability as drug development biomarker tools. In addition, analytical challenges relevant to the application of these 'research-grade' diagnostic kits for regulatory-compliant determination of sRANKL concentrations are discussed.
机译：研究级诊断试剂盒在临床药物开发中的应用与生物标志物作为药物开发工具的兴趣日益增长相称。由于新型生物标志物通常是大分子，因此免疫分析方法包括生物标志物定量的“选择技术”。尤其是，商业研究级的免疫分析试剂盒因其易于获得，易于操作和方便的感觉而吸引了临床阶段药物开发过程中用于生物标记定量的需求。但是，由于符合GLP法规的应用对试剂盒的设计和性能提出了更高的要求，因此在商业化试剂盒的应用中经常会出现生物分析验证问题。在本综述中，我们已使用核因子κB配体的受体激活剂（RANKL）作为模型系统，以对应用“研究级”诊断试剂盒支持临床药物开发时可能遇到的挑战提供一些见解。 。目前，仅有几种测定可用于测定sRANKL的循环浓度。其中，最常见的是两种免疫测定设计。第一种设计采用人骨保护素从血清中捕获未结合的sRANKL，从而提供了一种测量循环游离浓度的方法。相反，另一种常见的测定设计首先涉及将血清样品与人骨保护素进行预孵育，以将sRANKL的游离部分转化为骨保护素结合的复合物。结合的级分随后被抗骨保护蛋白抗体捕获。在这两种免疫测定设计中，检测都是通过抗sRANKL酶结合系统完成的。在本报告中，我们从其作为药物开发生物标志物工具的潜在适用性的角度出发，对这些sRANKL免疫测定设计进行了严格审查。此外，还讨论了与这些“研究级”诊断试剂盒的应用相关的分析难题，这些试剂盒可用于法规要求的sRANKL浓度测定。

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