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

Abstract

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-inhuman 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.

Clinical landscape of LAG-3-targeted therapy

“…Preliminary results showed that GSK2831781 is pharmacologically active with a tolerable safety profile, and provides early evidence of improvement in psoriasis. 59 GSK2831781 treatment reduced pro-inflammatory gene expression (IL-17A, IL-17F, IFNg, and S100A12), and upregulated genes associated with skin barrier functions (CDHR1). TSR-033.…”

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

“…GSK2831781 , derived from IMP731 Immunetep’s antibody, developed in monotherapy by GlaxoSmithKline in 3 clinical trials (2 phase I and 1 phase II) for psoriasis and ulcerative colitis. The ulcerative colitis phase II trial was terminated after an interim analysis [ 83 ], but phase I results show good tolerability, safety and inflammation regulation profiles [ 84 ].…”

Co-Inhibitory Molecules – Their Role in Health and Autoimmunity; Highlighted by Immune Related Adverse Events

“…Moreover, a cytotoxic LAG-3 Ab has been evaluated in a nonhuman primate model of delayed-type hypersensitivity ( 109 ). Contrarily, in a phase I clinical trial investigating psoriasis the depletion of LAG-3–positive T cells was linked to a reduced Th1-driven skin inflammation, lasting even in the absence of the depleting antibody ( 110 ).…”