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-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.

Figure 1

Clinical study design. *Cohort 5 included a pre‐treatment delayed‐type hypersensitivity challenge. Dosing with GSK2831781 occurred on day 29, hence, follow‐up is correspondingly longer relative to study day 1. ADA, anti‐drug antibodies; n, total participants (GSK2831781:placebo).

Figure 2

Characterization of GSK2831781, an affinity‐enhanced and ADCC‐enhanced afucosylated IgG1 LAG‐3‐specific mAb. Fold change in the proliferation of CD4⁺ antigen‐specific T cells in the presence of GSK2831781 alone and with anti‐CD16, relative to untreated antigen stimulation controls. ADCC, antibody‐dependent cellular cytotoxicity; IgG1, immunoglobulin G1; mAb, monoclonal antibody; PBMC, peripheral blood mononuclear cell.

Figure 3

Pharmacokinetics and pharmacodynamics of GSK2831781 in blood. (a) Plasma concentration‐time profile of GSK2831781. (b) Individual serum concentration‐time profiles of total sLAG‐3. (c) Depletion of LAG‐3⁺ T cells over time in blood following dosing with GSK2831781*. Only data up to 84 days after dose are shown. *Due to high variability in the data, all CD4⁺CD45RA⁻ data > 2 times the individual baseline is shown at 200%. Dashed line in a represents lower limit of quantification of assay (10 ng/mL), b represents the individual’s baseline shown at 200%. Dashed line in a represents lower limit of quantification of assay (10 ng/mL), in b it represents the individual’s baseline count normalized to 100%.

Figure 4

GSK2831781 depletes LAG‐3⁺ and CD3⁺ T cells in psoriatic skin lesions. (a) Observed mean (±SE) LAG‐3⁺ and (±SE) CD3⁺ cell counts in the dermis and epidermis following administration of GSK2831781 or placebo. (b) Representative IHC photomicrographs of LAG‐3⁺ (×20 magnification; arrows point to LAG‐3⁺ cells) and CD3⁺ (×10 magnification) stained psoriatic skin biopsies. IHC, immunohistochemistry.

Figure 5

PLSS and PASI scores over time in patients with psoriasis. (a) Observed mean (±SE) change from baseline* in PLSS and PASI following administration of GSK2831781 or placebo to patients with psoriasis. (b) Illustrative photograph of one participant showing a response following a GSK2831781 1.5 mg/kg. *No assessment at day 85 for 0.5 mg/kg treatment group. PASI, Psoriasis Activity Severity Index; PLSS, Psoriasis Lesion Severity Score.