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Deutscher Rheumatologiekongress 2020, 48. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 34. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh)

09.09. - 12.09.2020, virtuell

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Targeting CD38 in Systemic Lupus erythematosus

Meeting Abstract

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  • Lennard Ostendorf - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin; Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Marie Urbicht - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Pawel Durek - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Gitta Anne Heinz - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Frederik Heinrich - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Panagiotis Garantziotis - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
  • Philipp Enghard - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Nephrologie und internistische Intensivmedizin, Berlin
  • Robert Biesen - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
  • Udo Schneider - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
  • Gerd-Rüdiger Burmester - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
  • Andreas Radbruch - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Henrik Mei - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Mir-Farzin Mashereghi - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Falk Hiepe - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin; Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Tobias Alexander - Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin; Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Deutscher Rheumatologiekongress 2020, 48. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 34. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh). sine loco [digital], 09.-12.09.2020. Düsseldorf: German Medical Science GMS Publishing House; 2020. DocVK.33

doi: 10.3205/20dgrh182, urn:nbn:de:0183-20dgrh1824

Veröffentlicht: 9. September 2020

© 2020 Ostendorf et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

Introduction: Depletion of long-lived plasma cells (PC) represents a novel therapeutic concept for the treatment systemic lupus erythematosus (SLE), which derived from preclinical models and our experiences with autologous stem-stem cell transplantation and proteasome inhibition. However, these are limited by significant treatment-related toxicity. A novel target for depleting PC is CD38, a surface protein that is highly expressed on PCs. The CD38-targeting monoclonal antibody daratumumab is approved for the treatment of multiple myeloma and efficiently depleted PCs isolated from SLE patients ex vivo.

Methods: We treated two patients with life-threatening and refractory SLE “off-label” with four weekly infusions of 16 mg/kg Daratumumab. We investigated the clinical and serologic responses and performed integrative analyses to evaluate immunological changes upon treatment for a follow-up period of 6 months. Using flow cytometry and single-cell RNA and T-cell receptor (TCR) sequencing, we followed CD38 expression and composition of peripheral blood leukocytes.

Results: Patient 1, a 50-year old woman, suffered from active biopsy-proven class III/V lupus nephritis (LN) with nephrotic syndrome, pericarditis, arthritis and skin rash. Upon daratumumab treatment, her glomerular filtration rate normalized within 3 months and proteinuria gradually declined from 6.4 to 1.9 g/g Creatinine. Pericarditis, arthritis and skin rash completely resolved. Patient 2, a 32-year-old woman, presented with transfusion-dependent autoimmune hemolytic anemia, immune thrombocytopenia and cutaneous vasculitis. Her direct antiglobulin test normalized within 66 days and remained negative throughout follow-up with consecutive recovery of the hemolytic anemia. Immune thrombocytopenia stabilized and vasculitic skin lesions completely resolved. Infusions were well tolerated without severe adverse drug reactions. NK cells and plasmacytoid dendritic cells (pDCs) were transiently depleted, while numbers of T- and B-cells in peripheral blood remained stable although CD38 was downregulated. Single-cell transcription analysis demonstrated a vast modulation of their inflammatory transcriptional profile with reduction of genes associated with recent activation and repeated antigenic-stimulation.

Conclusion: Daratumumab treatment promoted therapeutic clinical and serologic responses and was well tolerated. Integrative analysis revealed a depletion of PCs by 50%, reduction of type-I interferon activity and downregulation of genes associated with chronic inflammation in T-cells. Collectively, these data identify CD38 as a promising treatment target in SLE.

Disclosures: The authors do not declare any conflicts of interest related to the study. No commercial sponsor has been involved.