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Objectives Antibody-secreting cells (ASC) produce autoantibodies in Systemic Lupus erythematosus (SLE), thereby contributing to the pathogenesis. Some ASC are long-lived and resistant to standard immunosuppressive therapies. Daratumumab, a monoclonal antibody targeting CD38, depletes ASCs and has demonstrated efficacy in cases of SLE and other autoimmune diseases.Methods In this single-arm, open-label phase 2 trial of daratumumab in patients with moderate to severe SLE (DARALUP), we evaluate the safety, efficacy, and immunological effects in 10 female patients with active disease and failure of at least 2 prior immunosuppressants, including belimumab in 6 patients. Participants received eight weekly subcutaneous injections of 1800 mg daratumumab. The primary endpoint was reduction in anti-dsDNA antibody levels at week 12; the primary endpoint of the long-term extension phase (up to week 84) was safety.Results Daratumumab treatment resulted in a significant reduction in serum anti-dsDNA levels (median 61.5%, p=0.002) at week 12, meeting the primary endpoint. IgG and vaccine-induced anti-tetanus toxoid antibody levels declined by approximately 40%, indicating depletion of long-lived ASC. All patients experienced improvements across major organ domains, with median SLEDAI-2K scores decreasing from 12 to 4 at week 12, and a SRI-4 response achieved in 100% of patients. No severe adverse events occurred; the most common adverse events included hypogammaglobulinemia, infections and gastrointestinal symptoms. During follow-up, 6 of 10 patients experienced disease flares between week 20 and 61, all of which responded to belimumab treatment, resulting in a SRI-4 response rate of 100% at the last follow-up at week 84.Conclusions Short-term daratumumab treatment induced rapid clinical improvements across multiple organ domains in patients with refractory SLE; however, relapses occurred despite ongoing immunosuppressive therapy. Future studies are needed to explore strategies to prevent the resurgence of pathogenic ASCs and sustain low disease activity following daratumumab treatment.