Background/Purpose:  Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes stimulate plasmacytoid dendritic cells (pDCs) to secrete large amounts of IFN-I. BDCA2 is a pDC-specific surface receptor that has been demonstrated to inhibit the production of IFN-I when engaged. Targeting BDCA2 therefore represents an attractive therapeutic strategy for inhibiting pDC-derived IFN-I and may be an effective therapy for the treatment of SLE. BIIB059, an investigational anti-BDCA2 monoclonal antibody, has been shown to engage BDCA2, and this interaction leads to BDCA2 internalization and the consequent in vitro inhibition of TLR-induced IFN-I by pDCs (Pellerin et. al 2015). This first-in-human study aimed to assess the safety, tolerability, PK and PD profiles of single ascending doses of BIIB059 in healthy volunteers (HV).

Methods:  A randomized, double-blinded, placebo-controlled, single ascending dose-escalation study was conducted in adult HV. In cohorts 1-7 HV were randomized to receive single IV doses of 0.05, 0.3, 1, 3, 10, or 20 mg/kg or one 50 mg SC dose of BIIB059. Each cohort had an active:placebo ratio of 2:1 or 3:1. Blood samples were obtained before and after dose administration up to week 16. Target modulation of BDCA2 and serum BIIB059 concentrations were measured using flow cytometry, and an enzyme-linked immunosorbent assay (ELISA), respectively, and anti-drug antibodies (ADA) were measured using a bridging ELISA.

Results:  54 HV were assigned to cohorts 1-7 (38 BIIB059: 16 placebo). BIIB059 demonstrated non-linear PK consistent with target mediated drug disposition. Bioavailability of SC administration was ~50%. Treatment with BIIB059 led to rapid and complete down-modulation of BDCA2 on the surface of pDCs at all dose levels. Time to reappearance of BDCA2 on pDC cell surface correlated with circulating levels of BIIB059, establishing an in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship. Single dose administration of BIIB059 was well tolerated across all dose levels. All AEs were mild to moderate in severity with no serious AEs. There were no clinically significant changes in laboratory assessments, physical examinations, or electrocardiogram (ECG) values. Anti-drug antibodies were detected at low levels in a small number of BIIB059-treated subjects. Responses were largely transient and demonstrated no impact on BIIB059 exposure or association with any safety event.

Conclusion:  This first-in-human study demonstrated acceptable safety/tolerability and PK profile in healthy subjects and supports further multiple-dose studies with BIIB059. BIIB059 treatment showed dose-dependent target engagement and internalization of BDCA2 establishing a PK/PD correlation in vivo on circulating pDC. These data support further evaluation of clinical efficacy and safety of BIIB059 as a potential novel therapy in SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biib059-an-anti-bdca2-monoclonal-antibody-demonstrates-acceptable-safety-tolerability-pharmacokinetics-pk-and-pharmacodynamic-pd-effects-in-a-phase-1-study-with-single-ascending-doses-sad-in/