Background/Purpose:  Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). BDCA2 is a plasmacytoid dendritic cell (pDC)-specific receptor that, upon engagement, inhibits the production of IFN-I and other inflammatory mediators produced by human pDCs. Targeting BDCA2, therefore, represents an attractive therapeutic strategy for inhibiting pDC-driven inflammation that is such a prominent feature of SLE. BIIB059 is an investigational humanized anti-BDCA2 monoclonal antibody. This first-in-patient study aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects and clinical activity of BIIB059 in adult SLE patients with active cutaneous disease following administration of a single BIIB059 dose.

Methods:  A phase 1b randomized, double-blinded, placebo-controlled, multicenter clinical trial was conducted in 12 adult SLE subjects (meeting 1997 ACR criteria) with active cutaneous manifestations [including acute, sub-acute and/or chronic cutaneous forms of cutaneous lupus erythematosus (CLE)]. Subjects received a single IV administration of either BIIB059 20 mg/kg (n=8) or placebo (n=4). A panel of IFN-responsive genes (IRG) was assessed from whole blood by qPCR at baseline and several post-dose time points. Skin biopsies from active lesions were obtained and evaluated at baseline and week 4 for IFN-regulated proteins, including MxA using quantitative immunohistochemistry. CLE disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI™), and safety data, including adverse events (AEs) and laboratory tests, were also collected.

Results:  Most SLE subjects had high IRG signatures in the blood and/or skin biopsies demonstrating features of inflammation consistent with active CLE, including elevated expression of MxA and other IFN-regulated proteins. A single dose of BIIB059 led to reversible inhibition of IRG in the blood. A marked decrease in skin expression of MxA at week 4 was observed in 5 of the 6 subjects treated with BIIB059 who had elevated MxA at baseline compared to less pronounced effects in the 4 placebo subjects (all with elevated baseline MxA). In addition, CLASI-activity at week 12 was also notably decreased in 6 of 8 BIIB059-treated subjects compared to the 4 placebo subjects (2/4 non-responders, 1/4 lost to follow-up and 1/4 treated with IV steroids for SLE flare). BIIB059 was generally well tolerated; the incidence of AEs was similar between BIIB059- and placebo-treated SLE subjects, and most AEs were mild or moderate in severity. There were no withdrawals due to AEs.

Conclusion:  A single dose of BIIB059 resulted in inhibition of the IRG in peripheral blood and MxA expression in lesional skin of SLE subjects, consistent with BIIB059’s proposed mechanism of action. The clinical and biomarker data together confirm the role of human pDCs in SLE skin pathology, and support further development of BIIB059 in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biib059-a-monoclonal-antibody-targeting-bdca2-shows-evidence-of-biological-activity-and-early-clinical-proof-of-concept-in-subjects-with-active-cutaneous-sle/