Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.
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Authors
Ellis, Joanne
van Maurik, Andre
Fortunato, Lea
Gisbert, Sophie
Chen, Keguan
Schwartz, Ann
McHugh, Simon
Want, Andrew
Santos Franco, Sara
Oliveira, Joao-Joaquim
Price, Jeffrey
Brown, Kim
Su, Donggang
Craigen, Jenny L
Yang, Jiansong
Brett, Sara
Davis, Bill
Kousin-Ezewu, Onajite
Gray, Frank
Thompson, Paul W
Fernando, Disala
Publication Date
2019-01-20Journal Title
British Journal of Clinical Pharmacology
ISSN
1365-2125
Publisher
Blackwell Publishing Inc.
Volume
85
Issue
2
Pages
304-315
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ellis, J., van Maurik, A., Fortunato, L., Gisbert, S., Chen, K., Schwartz, A., McHugh, S., et al. (2019). Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.. British Journal of Clinical Pharmacology, 85 (2), 304-315. https://doi.org/10.1111/bcp.13748
Abstract
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.
Keywords
drug safety, immunology, monoclonal antibodies, pharmacodynamics, pharmacokinetics
Sponsorship
GSK
Identifiers
External DOI: https://doi.org/10.1111/bcp.13748
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292709
Rights
Attribution-NonCommercial 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc/4.0/
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