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.

Keywords: Dendritic cells; Immunology; Lupus; Pharmacology.

Conflict of interest statement

Conflict of interest: RF is a consultant and investigator for Biogen. VPW is a consultant for and has received research grants from Biogen. JFM is a consultant and/or investigator for Biogen, AbbVie, Amgen, Eli Lilly, Novartis, Pfizer, Janssen, UCB, Samumed, Science 37, Celgene, Sanofi Regeneron, Merck, and GSK. LS, TLR, HN, WW, RC, AG, AP, SH, CB, PG, DR, and NF are employees and shareholders of Biogen. PA is currently affiliated with the National Institute of Mental Health, NIH, is not a Biogen shareholder, and has no financial interests to report. The University of Pennsylvania owns the copyright for the Cutaneous Lupus Activity and Severity Index.

Figures

Figure 1. Study design.

Single ascending dose in the HV cohorts and single dose in the SLE cohort.

Figure 2. BIIB059 PK profile in HV and a cohort of patients with SLE with active cutaneous lupus.

BIIB059 serum levels were measured using ELISA. (A) PK of single ascending dose of BIIB059 in HV (n = 38) and (B) PK of 20 mg/kg BIIB059 in HV (black line) (n = 6) and patients with SLE (red line) (n = 8). Arithmetic mean values are represented. conc., concentrations.

Figure 3. BII059 demonstrates PK and PD correlations in both HV and a cohort of patients with SLE.

(A and B) BDCA2 levels on pDCs as the median percentage change in BDCA2 levels normalized to baseline level in HV placebo (PBO) cohort (n = 16), HV BIIB059-treated cohort (n = 38), SLE PBO (n = 4), SLE BIIB059-treated cohort (n = 8). Fluorescent-labeled noncrossblocking anti-BDCA2 mAb (2D6) was used to label surface BDCA2 on the pDC population (CD123+ HLA-DR+) in whole blood using flow cytometry. (C and D) PK/PD relationship between BIIB059 serum concentrations (red triangles, left axis) and BDCA2 expression on pDCs (black squares, right axis, normalized to baseline levels). Panel C depicts a representative HV from the 3 mg/kg dose group (n = 6). Panel D depicts a representative patient with SLE (20 mg/kg) (n = 8).

Figure 4. Single dose of BIIB059 in patients with SLE dampens the expression of IRG in whole blood.

Whole blood was collected in PAXgene Blood RNA Tubes. After RNA isolation, the expression of IRG was analyzed using the Fluidigm BioMark HD System. The ratio from baseline is shown for (A) placebo and (B) BIIB059 treatment of patients with SLE (C). Percentage change from baseline of the IFN score based on the 9 IRGs in individual patients. *Subject 1 initiated steroid treatment during the study.

Figure 5. BIIB059 leads to decrease in the IFN response in the skin, which correlates with improvement in CLASI-A score.

(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.

Figure 6. BIIB059 normalizes MxA expression and reduces cellular infiltration in skin lesions of patients with SLE.

Representative photomicrographs of IHC from patient 5 (A) MxA protein (also shown in Figure 5B) and (C) CD45+ cells. HV (top panel), predose patient 5 (lower left panel), week 4 after BIIB059 treatment (lower right panel). (B and D) Percentage area of immunoreactivity of MxA protein and CD45 in placebo- and BIIB059-treated patients before (day –1) and 4 weeks after BIIB059 administration. Healthy range was determined using biopsies from 8 HV; dotted lines delineate the healthy range. Responders are depicted with a black line, nonresponders with a red line.

Figure 7. Model of BIIB059 mechanism of action in CLE.

(A) In CLE, pDCs accumulate in skin lesions and produce IFN-I and IFN-λ (large arrow), as detected by the upregulation of the IFN-responsive protein MxA in the epidermis. pDCs also secrete a broad range of cytokines and chemokines, which in addition to IFN-I, may support the recruitment of inflammatory cells into the lesions (depicted by CD45+ cells). (B) Treatment with BIIB059 leads to the functional inhibition of pDCs and the dampening of IFN-I and likely other inflammatory mediators, resulting in decreased MxA expression, reduction in immune cellular infiltrates, and amelioration of disease activity in CLE lesions.