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

  • Br J Clin Pharmacol. 2019 Feb;85(2):304-315. doi: 10.1111/bcp.13748.
Joanne Ellis  1 ,  Andre van Maurik  1 ,  Lea Fortunato  1 ,  Sophie Gisbert  2 ,  Keguan Chen  3 ,  Ann Schwartz  3 ,  Simon McHugh  4 ,  Andrew Want  4 ,  Sara Santos Franco  4 ,  Joao-Joaquim Oliveira  4 ,  Jeffrey Price  4 ,  Alasdair Coles  5 ,  Kim Brown  1 ,  Donggang Su  6  7 ,  Jenny L Craigen  1  8 ,  Jiansong Yang  6  9 ,  Sara Brett  1 ,  Bill Davis  4 ,  Joseph Cheriyan  4  10 ,  Onajite Kousin-Ezewu  4  5 ,  Frank Gray  11 ,  Paul W Thompson  12 ,  Disala Fernando  4
Affiliations
  • 1. GlaxoSmithKline, Stevenage, Herts, UK.
  • 2. GlaxoSmithKline, Uxbridge, Middlesex, UK.
  • 3. GlaxoSmithKline, King of Prussia, PA, USA.
  • 4. GlaxoSmithKline R&D, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK.
  • 5. Clinical Neurosciences, University of Cambridge, UK.
  • 6. GlaxoSmithKline, Shanghai, China.
  • 7. Shanghai Henlius Biotech, Inc., Shanghai, China.
  • 8. Crescendo Biologics, Cambridge, UK.
  • 9. Mosim Co. Ltd, Shanghai, China.
  • 10. Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK.
  • 11. Indivior, Slough, Berks, UK.
  • 12. Mission Therapeutics Ltd, Babraham Research Campus, Cambridge, UK.
PMID: 30161291 DOI: 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.
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