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

Joanne Ellis, Andre van Maurik, Lea Fortunato, Sophie Gisbert, Keguan Chen, Ann Schwartz, Simon McHugh, Andrew Want, Sara Santos Franco, Joao-Joaquim Oliveira, Jeffrey Price, Alasdair Coles, Kim Brown, Donggang Su, Jenny L Craigen, Jiansong Yang, Sara Brett, Bill Davis, Joseph Cheriyan, Onajite Kousin-Ezewu, Frank Gray, Paul W Thompson, Disala Fernando, Joanne Ellis, Andre van Maurik, Lea Fortunato, Sophie Gisbert, Keguan Chen, Ann Schwartz, Simon McHugh, Andrew Want, Sara Santos Franco, Joao-Joaquim Oliveira, Jeffrey Price, Alasdair Coles, Kim Brown, Donggang Su, Jenny L Craigen, Jiansong Yang, Sara Brett, Bill Davis, Joseph Cheriyan, Onajite Kousin-Ezewu, Frank Gray, Paul W Thompson, Disala Fernando

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.

Trial registration: ClinicalTrials.gov NCT02293161.

Keywords: drug safety; immunology; monoclonal antibodies; pharmacodynamics; pharmacokinetics.

© 2018 GlaxoSmithKline. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
Subject disposition. PK, pharmacokinetic
Figure 2
Figure 2
GSK2618960 plasma concentrations in individual subjects following a single intravenous infusion. Symbols represent individual subjects. The dashed horizontal line represents the lower limit of quantification (LLQ = 50 ng ml–1). BLQ, below the limit of quantification
Figure 3
Figure 3
Receptor occupancy of interleukin‐7 receptor subunit‐α (IL‐7Rα) following a single administration of GSK2618960. Mean (± standard deviation) values
Figure 4
Figure 4
Extent and duration of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) signal inhibition in individual subjects following a single 2.0 mg kg–1 intravenous infusion of GSK2618960. Percentage inhibition of pSTAT5 signal upon ex vivo interleukin‐7 exposure. Coloured symbols represent individual subjects
Figure 5
Figure 5
Circulating (A) interleukin‐7 (IL‐7) and (B) soluble IL‐7 receptor‐α subunit (CD127) in plasma following a single intravenous infusion of GSK2618960. Mean (± standard deviation) values
Figure 6
Figure 6
GSK2618960 plasma concentrations vs. receptor occupancy of interleukin‐7 receptor subunit‐α, for subjects in each treatment group with the fitted locally estimated scatterplot smoothing curve (post hoc analysis). Coloured symbols represent individual subjects. The vertical line represents the lower limit of quantification (50 ng ml–1). BLQ, below the lower limit of quantification

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