Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus
Richard Furie, … , Dania Rabah, Nathalie Franchimont
Richard Furie, … , Dania Rabah, Nathalie Franchimont
Published January 15, 2019
Citation Information: J Clin Invest. 2019;129(3):1359-1371. https://doi.org/10.1172/JCI124466.
View: Text | PDF
Clinical Research and Public Health Immunology

Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus

Abstract

BACKGROUND. Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in healthy volunteers (HV) and patients with SLE with active cutaneous disease as well as proof of biological activity and preliminary clinical response in the SLE cohort. METHODS. A randomized, double-blind, placebo-controlled clinical trial was conducted in HV (n = 54) and patients with SLE (n = 12). All subjects were monitored for adverse events. Serum BIIB059 concentrations, BDCA2 levels on pDCs, and IFN-responsive biomarkers in whole blood and skin biopsies were measured. Skin disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A). RESULTS. Single doses of BIIB059 were associated with favorable safety and PK profiles. BIIB059 administration led to BDCA2 internalization on pDCs, which correlated with circulating BIIB059 levels. BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score. CONCLUSIONS. Single doses of BIIB059 were associated with favorable safety and PK/PD profiles and robust target engagement and biological activity, supporting further development of BIIB059 in SLE. The data suggest that targeting pDCs may be beneficial for patients with SLE, especially those with cutaneous manifestations. TRIAL REGISTRATION. ClinicalTrials.gov NCT02106897. FUNDING. Biogen Inc.

Authors

Richard Furie, Victoria P. Werth, Joseph F. Merola, Lauren Stevenson, Taylor L. Reynolds, Himanshu Naik, Wenting Wang, Romy Christmann, Agnes Gardet, Alex Pellerin, Stefan Hamann, Pavan Auluck, Catherine Barbey, Parul Gulati, Dania Rabah, Nathalie Franchimont

×

Figure 5

BIIB059 leads to decrease in the IFN response in the skin, which correlates with improvement in CLASI-A score.

Options: View larger image (or click on image) Download as PowerPoint
BIIB059 leads to decrease in the IFN response in the skin, which correla...
(A and B) Skin biopsies from active lesions were evaluated at baseline (day –1) and week 4 after treatment with 20 mg/kg BIIB059 for MxA protein expression using quantitative IHC on formalin-fixed 4 to 5 mm punch biopsies. Representative photomicrographs and percentage area of epidermal MxA-positive immunoreactivity are shown for each patient in the placebo group (A) and the BIIB059-treated group (B). CLASI-A scores were evaluated at day –1, week 4, and week 12 after treatment for placebo-treated (A) and BIIB059-treated (B) patients with SLE. Response is defined as a 4 or more point reduction from baseline in CLASI-A score at week 4 and/or week 12. Responders are depicted in green, nonresponders in red. (C) Correlation plot of percentage change in MxA expression from baseline and percentage CLASI-A score change from baseline for all patients (placebo treated, circles; BIIB059 treated, triangles). (D) CLASI-A response over time; CLASI-A responders are depicted in green, nonresponders in red. *Subject 1 initiated steroid treatment during the study. ACLE, acute CLE; DLE, discoid lupus erythematosus; ND, not determined; NR, no response; R, response; SCLE, subacute CLE.