Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study
| العنوان: | Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study |
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| المؤلفون: | Simon M. McHugh, Paul W. Thompson, Frank A Gray, Onajite Kousin-Ezewu, Jenny L Craigen, Disala Fernando, Alasdair Coles, Donggang Su, Joanne Ellis, Keguan Chen, Sara Santos Franco, Joao-Joaquim Oliveira, Kim Brown, Lea Fortunato, André van Maurik, Ann M. Schwartz, Sophie Gisbert, Jiansong Yang, Sara Brett, Bill Davis, Joseph Cheriyan, Andrew Want, Jeffrey Price |
| المصدر: | British Journal of Clinical Pharmacology |
| بيانات النشر: | John Wiley and Sons Inc., 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Adult, Male, drug safety, Adolescent, medicine.medical_treatment, T cell, T-Lymphocytes, Pharmacology, Antibodies, Monoclonal, Humanized, 030226 pharmacology & pharmacy, Autoimmune Diseases, immunology, Interleukin-7 Receptor alpha Subunit, Placebos, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pharmacokinetics, Double-Blind Method, medicine, pharmacodynamics, Humans, Pharmacology (medical), 030212 general & internal medicine, Interleukin-7 receptor, Receptor, Infusions, Intravenous, Aged, biology, business.industry, Interleukin, Original Articles, Middle Aged, Healthy Volunteers, Cytokine, medicine.anatomical_structure, Pharmacodynamics, biology.protein, Original Article, Female, monoclonal antibodies, Antibody, business, pharmacokinetics, Half-Life |
| الوصف: | 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-α 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-α, interferon-γ, 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. |
| اللغة: | English |
| تدمد: | 1365-2125 0306-5251 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af326e175e6773cbef32639a120f87e8Test http://europepmc.org/articles/PMC6339973Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....af326e175e6773cbef32639a120f87e8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652125 03065251 |
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