A bispecific CD3×CD19 antibody for systemic lupus erythematosus: a phase 1 trial

Bispecific T cell engagers (TCEs) offer a potent, off-the-shelf approach to deep B cell depletion; however, controlled clinical evaluation in rheumatic disease remains limited. Here we report results from the intravenous treatment arm of an ongoing, first-in-disease, phase 1 trial of A-319, a next-generation CD3×CD19 TCE, in 12 patients with active systemic lupus erythematosus (SLE) with 52 weeks of follow-up. Patients received A-319 (0.3-1.2 μg kg-1) three times weekly for 3 weeks after 1 week of priming doses (0.05 μg kg-1). The primary endpoint was safety and tolerability. A-319 demonstrated a favorable safety profile, with no treatment-related serious adverse events, deaths, grade 3 or higher cytokine release syndrome (CRS) or neurotoxicity; CRS was predominantly grade 1 (91.6%, 11/12), and hematologic toxicity was minimal. Secondary endpoints (pharmacokinetics, pharmacodynamics and immunogenicity) demonstrated linear pharmacokinetics and dose-dependent B cell depletion, with complete peripheral depletion in higher-dose cohorts. Among exploratory efficacy endpoints, 80% (8/10) of patients achieved Lupus Low Disease Activity State (LLDAS), and 60% (6/10) achieved Definition of Remission in SLE (DORIS) at 12 months, accompanied by sustained reductions in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, autoantibody titers and proteinuria.