Byun Joo-Yun, Koh Yi T, Jang Sun Young, Witcher Jennifer W, Chan Jason R, Pustilnik Anna, Daniels Mark J, Kim Young Hoon, Suh Kwee Hyun, Linnik Matthew D, Lee Young-Mi
Hanmi Research Center, Hanmi Pharm. Co. Ltd., 14 Wiryeseong-daero, Songpa-gu, Seoul, 05545, Korea.
Lilly Biotechnology Center, 10290 Campus Point Drive, San Diego, 92121, USA.
Sci Rep. 2021 Sep 21;11(1):18671. doi: 10.1038/s41598-021-98255-7.
The selective Bruton tyrosine kinase (BTK) inhibitor poseltinib has been shown to inhibit the BCR signal transduction pathway and cytokine production in B cells (Park et al. Arthritis Res. Ther. 18, 91, https://doi.org/10.1186/s13075-016-0988-z , 2016). This study describes the translation of nonclinical research studies to a phase I clinical trial in healthy volunteers in which pharmacokinetics (PKs) and pharmacodynamics (PDs) were evaluated for dose determination. The BTK protein kinase inhibitory effects of poseltinib in human peripheral blood mononuclear cells (PBMCs) and in rats with collagen-induced arthritis (CIA) were evaluated. High-dimensional phosphorylation analysis was conducted on human immune cells such as B cells, CD8 + memory cells, CD4 + memory cells, NK cells, neutrophils, and monocytes, to map the impact of poseltinib on BTK/PLC and AKT signaling pathways. PK and PD profiles were evaluated in a first-in-human study in healthy donors, and a PK/PD model was established based on BTK occupancy. Poseltinib bound to the BTK protein and modulated BTK phosphorylation in human PBMCs. High-dimensional phosphorylation analysis of 94 nodes showed that poseltinib had the highest impact on anti-IgM + CD40L stimulated B cells, however, lower impacts on anti-CD3/CD-28 stimulated T cells, IL-2 stimulated CD4 + T cells and NK cells, M-CSF stimulated monocytes, or LPS-induced granulocytes. In anti-IgM + CD40L stimulated B cells, poseltinib inhibited the phosphorylation of BTK, AKT, and PLCγ2. Moreover, poseltinib dose dependently improved arthritis disease severity in CIA rat model. In a clinical phase I trial for healthy volunteers, poseltinib exhibited dose-dependent and persistent BTK occupancy in PBMCs of all poseltinib-administrated patients in the study. More than 80% of BTK occupancy at 40 mg dosing was maintained for up to 48 h after the first dose. A first-in-human healthy volunteer study of poseltinib established target engagement with circulating BTK protein. Desirable PK and PD properties were observed, and a modeling approach was used for rational dose selection for subsequent trials. Poseltinib was confirmed as a potential BTK inhibitor for the treatment of autoimmune diseases.Trial registration: This article includes the results of a clinical intervention on human participants [NCT01765478].
选择性布鲁顿酪氨酸激酶（BTK）抑制剂泊昔替尼已被证明可抑制B细胞中的BCR信号转导通路和细胞因子产生（Park等人，《关节炎研究与治疗》18卷，91页，https://doi.org/10.1186/s13075-016-0988-z，2016年）。本研究描述了将非临床研究转化为在健康志愿者中进行的I期临床试验，其中评估了药代动力学（PK）和药效学（PD）以确定剂量。评估了泊昔替尼在人外周血单核细胞（PBMC）和胶原诱导性关节炎（CIA）大鼠中的BTK蛋白激酶抑制作用。对人免疫细胞如B细胞、CD8 + 记忆细胞、CD4 + 记忆细胞、NK细胞、中性粒细胞和单核细胞进行了高维磷酸化分析，以绘制泊昔替尼对BTK/PLC和AKT信号通路的影响。在健康供体的首次人体研究中评估了PK和PD谱，并基于BTK占有率建立了PK/PD模型。泊昔替尼与人PBMC中的BTK蛋白结合并调节BTK磷酸化。对94个节点的高维磷酸化分析表明，泊昔替尼对抗IgM + CD40L刺激的B细胞影响最大，然而，对抗CD3/CD-28刺激的T细胞、IL-2刺激的CD4 + T细胞和NK细胞、M-CSF刺激的单核细胞或LPS诱导的粒细胞影响较小。在抗IgM + CD40L刺激的B细胞中，泊昔替尼抑制BTK、AKT和PLCγ2的磷酸化。此外，泊昔替尼剂量依赖性地改善了CIA大鼠模型中的关节炎疾病严重程度。在针对健康志愿者的临床I期试验中，泊昔替尼在该研究中所有接受泊昔替尼治疗的患者的PBMC中表现出剂量依赖性和持续性的BTK占有率。首次给药后长达48小时，40 mg剂量下超过80%的BTK占有率得以维持。泊昔替尼在首次人体健康志愿者研究中确定了与循环BTK蛋白的靶点结合。观察到了理想的PK和PD特性，并采用建模方法进行合理的剂量选择以用于后续试验。泊昔替尼被确认为治疗自身免疫性疾病的潜在BTK抑制剂。试验注册：本文包括对人类参与者进行临床干预的结果[NCT01765478]。
