Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.

Autor: Ellis J; GlaxoSmithKline, Stevenage, Herts, UK., van Maurik A; GlaxoSmithKline, Stevenage, Herts, UK., Fortunato L; GlaxoSmithKline, Stevenage, Herts, UK., Gisbert S; GlaxoSmithKline, Uxbridge, Middlesex, UK., Chen K; GlaxoSmithKline, King of Prussia, PA, USA., Schwartz A; GlaxoSmithKline, King of Prussia, PA, USA., McHugh S; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Want A; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Santos Franco S; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Oliveira JJ; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Price J; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Coles A; Clinical Neurosciences, University of Cambridge, UK., Brown K; GlaxoSmithKline, Stevenage, Herts, UK., Su D; GlaxoSmithKline, Shanghai, China.; Shanghai Henlius Biotech, Inc., Shanghai, China., Craigen JL; GlaxoSmithKline, Stevenage, Herts, UK.; Crescendo Biologics, Cambridge, UK., Yang J; GlaxoSmithKline, Shanghai, China.; Mosim Co. Ltd, Shanghai, China., Brett S; GlaxoSmithKline, Stevenage, Herts, UK., Davis B; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK., Cheriyan J; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK.; Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK., Kousin-Ezewu O; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK.; Clinical Neurosciences, University of Cambridge, UK., Gray F; Indivior, Slough, Berks, UK., Thompson PW; Mission Therapeutics Ltd, Babraham Research Campus, Cambridge, UK., Fernando D; GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2019 Feb; Vol. 85 (2), pp. 304-315. Date of Electronic Publication: 2018 Dec 03.
DOI: 10.1111/bcp.13748
Abstrakt: 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.
(© 2018 GlaxoSmithKline. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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