Fu Jie, Wang Fang, Dong Li-Hou, Xing Mei-Jing, Cheng Xue, Wei Su, Xu Jing-Zhi, Han Min, Dong Kelly, Song Hai-Feng
State Key Laboratory of Proteomics, Beijing Institute of Lifeomics, Beijing 102206, PR China.
New Drug Evaluation Platform, National Engineering Research Center for Protein Drugs, Beijing 102206, PR China.
Bioanalysis. 2019 Jul;11(14):1347-1358. doi: 10.4155/bio-2019-0090. Epub 2019 Aug 8.
The reliable measurement of receptor occupancy (RO) provides informative data for efficacy and safety evaluation. This study aimed to assess factors affecting RO measurement of anti-PD-1 antibodies in clinical studies. RO performance was assessed using different T-cell activation markers measured by flow cytometry. The validated methodology was then used in support of a clinical study. The optimized active cell population was comprised of CD45RO or CD45RA T cells. The bioanalytical method was validated for inter- and intra-assay precision (coefficient of variation ≤30%) and sample storage stability for 3 days. Consistent RO saturation was observed in Phase Ia clinical trial, although receptor regulation appeared to be different. The formation of anti-drug antibodies had markedly influenced pharmacokinetics and RO. RO measurement in combination with pharmacokinetics and anti-drug antibodies data could allow the integrated evaluation and better understanding of efficacy and safety.
受体占有率（RO）的可靠测量可为疗效和安全性评估提供有用数据。本研究旨在评估临床研究中影响抗PD-1抗体RO测量的因素。使用流式细胞术测量的不同T细胞活化标志物评估RO性能。然后将经过验证的方法用于支持一项临床研究。优化的活性细胞群体由CD45RO或CD45RA T细胞组成。生物分析方法经验证具有批间和批内精密度（变异系数≤30%）以及3天的样品储存稳定性。在Ia期临床试验中观察到一致的RO饱和度，尽管受体调节似乎有所不同。抗药抗体的形成显著影响了药代动力学和RO。结合药代动力学和抗药抗体数据进行RO测量可以实现疗效和安全性的综合评估并更好地理解。
