Daratumumab Depletes Pathogenic Antibody-Secreting Cells, Reduces Type-I Interferon Activity and Improves T Cell Function in Systemic Lupus Erythematosus

Jan Zernicke – Charité Universitätsmedizin Berlin; Jens Klotsche – German Rheumatology Research Center; Pawel Durek – German Rheumatology Research Center; Gabriela Maria Guerra – German Rheumatology Research Center; Frederik Heinrich – German Rheumatology Research Center; Laleh Khodadadi – German Rheumatology Research Center; Gerd-Rüdiger Burmester – Charité Universitätsmedizin Berlin; Anne Beenken – Charité Universitätsmedizin Berlin; Robert Biesen – Charité Universitätsmedizin Berlin; Qingyu Cheng – German Rheumatology Research Center; Robin Kempkens – German Rheumatology Research Center; Udo Schneider – Charité Universitätsmedizin Berlin; Gerhard Krönke – Charité Universitätsmedizin Berlin; Falk Hiepe – Charité Universitätsmedizin Berlin; Mir-Farzin Mashreghi – Charité Universitätsmedizin Berlin; Tobias Alexander – Charité Universitätsmedizin Berlin

Abstract Text:

Background:
Antibody-secreting cells (ASCs), including long-lived plasma cells (LLPCs) produce pathogenic autoantibodies in systemic lupus erythematosus (SLE). LLPCs are resistant to immunosuppressive therapies and contribute to tissue damage. Daratumumab is a CD38-targeting monoclonal antibody that depletes ASCs and is approved for the treatment of multiple myeloma.

Methods:
This single-arm, open-label, phase 2 clinical trial evaluated the safety, efficacy, and immunological effects of daratumumab in patients with moderate to severe SLE. Ten participants were included that received eight weekly subcutaneous injections of 1800mg daratumumab and were followed for 36 weeks. The primary endpoint was the reduction in anti-dsDNA antibody levels. Immunological changes were assessed using using flow cytometry and single-cell RNA and immune cell receptor sequencing of memory B and T cells.

Results:
Daratumumab treatment led to a significant reduction in serum anti-dsDNA levels as well as vaccine-induced antibodies, indicating depletion of both short-lived ASC and LLPCs. This was associated with marked clinical improvement, reflected by a reduction of the median disease activity index SLEDAI-2K from 12 to 4 at week 12. Immunological analyses demonstrated a depletion of mature ASCs and a reduction in type-I interferon activity. TCR analyses indicate that CD38+ memory T cells but instead CD8+ T cell and regulatory T cells had reduced dysfunction.

Discussion:
Daratumumab induced rapid and sustained clinical improvements across organ systems in refractory patients SLE. The observed reductions in autoantibody-production, type I interferon activity and normalization of T-cell functionality further support daratumumab as promising treatment option in SLE and potentially other systemic autoimmune diseases.