Background: Long-lived antibody-secreting cells (ASC) contribute to the pathogenesis of systemic lupus erythematosus (SLE) by the continuous secretion of autoantibodies, but they are unresponsive to immunosuppressive or B-cell depleting therapies. Daratumumab, a monoclonal antibody targeting CD38, depletes ASCs and has demonstrated efficacy in cases of SLE and other autoimmune diseases.

Objectives: To evaluate the long-term safety and efficacy of daratumumab in adult patients with SLE.

Methods: In this single-center, open-label Phase 2 trial (DARALUP), patients with moderate to severe SLE were enrolled to receive eight weekly subcutaneous injections of 1800 mg daratumumab, administered alongside stable background therapy. 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: Ten female patients with active disease and inadequate response to at least two disease-modifying drugs, including belimumab in 6 patients, were enrolled. 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. Serum IgG and vaccine-induced anti-tetanus toxoid antibody levels declined by approximately 40%, indicating depletion of long-lived ASC. Clinically, 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 were reported; the most common adverse events included hypogammaglobulinemia, infections and gastrointestinal symptoms. Flow cytometry and single-cell RNA sequencing demonstrated depletion of circulating ASCs, preferentially affecting those with a mature IgG ⁺ phenotype, along with a reduction in type-I interferon activity. 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 84 weeks.

Conclusions: Our findings identify CD38 as novel therapeutic target in SLE and support daratumumab as a promising therapeutic option for patients with refractory and serologically active SLE. Short-term daratumumab treatment induced rapid clinical and serologic improvements through depletion of ASC. The treatment was generally well tolerated; however, disease flares may occur despite ongoing immunosuppressive therapy, which could potentially be mitigated by repeated daratumumab injections. Future randomized studies are warranted to further evaluate these findings and optimize dosing regimens.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Lennard Ostendorf: None declared, Jan Zernicke: None declared, Jens Klotsche: None declared, Anne Elisabeth Beenken: None declared, Robert Biesen: None declared, Robin Kempkens: None declared, Qingyu Cheng: None declared, Laleh Khodadadi: None declared, Gabriela Guerra: None declared, Frederik Heinrich: None declared, Pawel Durek: None declared, Mir-Farzin Mashreghi: None declared, Gerd R. Burmester: None declared, Gerhard Krönke: None declared, Falk Hiepe: None declared, Tobias Alexander Study Support from Johnson & Johnson.