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 IFNresponsive 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.

A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection

“…Although trials targeting TLRs have yielded inconclusive results, a recent study looking at the attenuation of pDC response using an antibody that targets the human pDC-specific BDCA2 in systemic lupus erythematosus (SLE) patients suggests that pDCs are responsible, at least partially, for the presence of the chronic IFN signature in the blood of patients (Furie et al, 2019). Interestingly, blocking pDCs in these patients had a dramatic effect on the skin, with a sustained inhibition of IFNinducible markers in the skin of patients that correlated with amelioration of symptoms (Furie et al, 2019).…”

“…Thus, focusing on the skin to evaluate pDC-targeting drugs would take advantage of a strong scientific rationale and less complex clinical designs. The recent report showing that attenuation of pDCs using BIIB059, a humanized mAb that binds the pDC marker BDCA2, led to reduced IFN signals and cellular infiltration in skin lesions with decreased CLASI-A score (Furie et al, 2019) is a strong indication that an organ-specific approach with a primary focus on the skin may be a promising strategy with such drugs. One can argue that pDCs can be defined as "professional adjuvant cells," which would explain the potent adjuvant effect of CpG-containing oligonucleotides in humans.…”

Targeting human Plasmacytoid dendritic cells through BDCA2 prevents inflammation and fibrosis in xenotransplant mouse model of Scleroderma

“…BDCA2 signals through an associated transmembrane adaptor, the FcϵRγ, which recruits the protein tyrosine kinase Syk, inducing protein tyrosine phosphorylation and calcium mobilization [17] , which, in turn, interferes with TLR induced activation of pDC, inhibiting type I IFN secretion and other inflammatory mediators [15,[17][18][19]. For this reason, antibodies binding BDCA2 have been explored for their potential to block pDC activation in some IFN-associated autoimmune conditions, such as Systemic lupus erythematosus (SLE) [20,21]. Recently, Ah Kioon and colleagues suggested that this could also be applicable to fibrotic disease such as SSc as mouse pDC enhance pathogenesis of bleomycininduced skin fibrosis [10].…”

A promising approach to targeting type 1 IFN in systemic lupus erythematosus

“…These and similar mechanistic studies cited in the paper help inform the rationale for the development of a humanized BDCA-2-binding mAb (BIIB059). Furie et al conducted a multicenter, randomized, double-blind, placebo-controlled phase 1b study (18) assessing the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of BIIB059 in healthy volunteers and patients with SLE with active cutaneous disease. The authors also evaluated the biological activity and clinical response among these cutaneous lupus patients.…”

“…In contrast to the above referenced studies, a unique means of inhibiting the production of type 1 IFN at the level of the plasmacytoid DCs (pDCs) ( Figure 1) was undertaken by Furie et al (18) and reported in this issue. We know that pDCs are the primary cell source of the type 1 IFN signal in SLE.…”