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

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

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.

Figures
Products