期刊
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
卷 85, 期 2, 页码 304-315出版社
WILEY
DOI: 10.1111/bcp.13748
关键词
drug safety; immunology; monoclonal antibodies; pharmacodynamics; pharmacokinetics
资金
- GSK [NCT02293161]
- [GSK2681960]
Aim Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-alpha subunit (CD127) monoclonal antibody. Methods A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg(-1) or 2.0 mg kg(-1)) or placebo was carried out in 18 healthy subjects over 24 weeks. Results GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half-life was 5 (+/- 1) days (2.0 mg kg(-1)), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg(-1)) and day 22 (2.0 mg kg(-1)). Maximal inhibition of IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg(-1)). Mean circulating IL-7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg(-1)) and days 2 and 22 (2.0 mg kg(-1)). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL-6, tumour necrosis factor-alpha, interferon-gamma, IL-2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg(-1) (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg(-1) (neutralizing in 5/6). Conclusion GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据