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

Early-phase studies of deep B cell depletion with anti-CD19 chimeric antigen receptor (CAR) T have produced prolonged, drug-free remission in refractory autoimmune disease. However, CAR T cell therapy requires lymphodepleting chemotherapy, autologous cell manufacturing and specialized infrastructure, limiting reach to a fraction of patients who might benefit. 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. Exploratory serial single-cell RNA sequencing revealed broad immune reprogramming mechanistically similar to that after CD19 CAR T cell therapy in SLE, including multi-lineage suppression of SLE-associated interferon response signatures across B cell, T cell and myeloid compartments and near-complete reconstitution of the B cell repertoire. Together, these findings demonstrate the feasibility, safety and preliminary efficacy of CD3×CD19 T cell engagement in SLE and support further clinical development of TCEs in controlled, pivotal studies. ClinicalTrials.gov identifier: NCT06400537.