Daratumumab in systemic lupus erythematosus: a phase 2 trial

Antibody-secreting cells (ASCs) play a central role in the pathophysiology of systemic lupus erythematosus (SLE). This single-arm, open-label, phase 2 clinical trial aimed to evaluate the safety and efficacy of the ASC-depleting anti-CD38 monoclonal antibody daratumumab in patients with refractory SLE. The primary endpoint was a significant reduction in serum anti-double-stranded DNA (anti-dsDNA) antibody levels. Ten female patients with active disease and inadequate responses to at least two disease-modifying drugs received eight weekly subcutaneous injections of 1800 mg daratumumab. By week 12, anti-dsDNA antibody levels were significantly reduced (p=0.002), accompanied by rapid and sustained clinical improvements across all patients and organ domains. Adverse events were mild to moderate. Daratumumab treatment depleted circulating ASCs, reduced type I interferon activity, and profoundly modulated T-cell responses. These findings highlight the pivotal role of ASCs in SLE pathogenesis and support daratumumab as a promising therapeutic option for refractory SLE. ClinicalTrials.gov identifier: NCT04810754.