Depletion of LAG-3 + T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.

Autor: Ellis J; GlaxoSmithKline, Stevenage, Hertfordshire, UK., J B Marks D; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Srinivasan N; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Barrett C; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Hopkins TG; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Richards A; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Fuhr R; Parexel International, Berlin, Germany., Albayaty M; Parexel International, London, UK., Coenen M; Study Center Bonn (SZB), Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Liefaard L; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Leavens K; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Nevin KL; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Tang S; GlaxoSmithKline, Upper Providence, Pennsylvania, USA., Hughes SA; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Fortunato L; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Edwards K; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Cui Y; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Anselm R; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Delves CJ; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Charles E; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Feeney M; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Webb TM; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Brett SJ; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Schmidt TS; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Stone J; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Savage COS; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Wisniacki N; GlaxoSmithKline, Stevenage, Hertfordshire, UK., Tarzi RM; GlaxoSmithKline, Stevenage, Hertfordshire, UK.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 May; Vol. 109 (5), pp. 1293-1303. Date of Electronic Publication: 2020 Nov 24.
DOI: 10.1002/cpt.2091
Abstrakt: Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 + and CD8 + T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3 + cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3 + and CD3 + T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.
(© 2020 GlaxoSmithKline. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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