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

• Published in: British journal of clinical pharmacology Vol. 85; no. 2; pp. 304 - 315
• Main Authors: Ellis, Joanne, Maurik, Andre, Fortunato, Lea, Gisbert, Sophie, Chen, Keguan, Schwartz, Ann, McHugh, Simon, Want, Andrew, Santos Franco, Sara, Oliveira, Joao‐Joaquim, Price, Jeffrey, Coles, Alasdair, Brown, Kim, Su, Donggang, Craigen, Jenny L., Yang, Jiansong, Brett, Sara, Davis, Bill, Cheriyan, Joseph, Kousin‐Ezewu, Onajite, Gray, Frank, Thompson, Paul W., Fernando, Disala
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.02.2019
• Subjects: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Double-Blind Method; drug safety; Female; Half-Life; Healthy Volunteers; Humans; immunology; Infusions, Intravenous; Interleukin-7 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-7 Receptor alpha Subunit - immunology; Male; Middle Aged; monoclonal antibodies; Original; pharmacodynamics; pharmacokinetics; Placebos - administration & dosage; Placebos - adverse effects; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Young Adult; pharmacokinetics; immunology; pharmacodynamics; drug safety; monoclonal antibodies
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13748

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.