Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus

Ostendorf, Lennard; Burns, Marie; Durek, Pawel; Heinz, Gitta Anne; Heinrich, Frederik; Garantziotis, Panagiotis; Enghard, Philipp; Richter, Ulrich; Biesen, Robert; Schneider, Udo; Knebel, Fabian; Burmester, Gerd R; Radbruch, Andreas; Mei, Henrik E.; Mashreghi, Mir‐Farzin; Hiepe, Falk; Alexander, Tobias

doi:10.1056/nejmoa2023325

Cited by 216 publications

(159 citation statements)

References 24 publications

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“…This heterogeneity was detectable at levels of low-and high-resolution analyses of different cells types, indicating that the capacity to express CD38 is not restricted to certain immune cell lineages. Initial studies already indicated increased CD38 expression levels on peripheral blood leukocyte cells isolated from SLE patients [9][10][11][12]15]. Our data confirm and extend these findings.…”

Section: Discussionsupporting

confidence: 89%

“…Instead, the ability to identify patients with increased CD38 expression or abundance of CD38-expressing cells might be relevant in the context of emerging CD38-directed treatments with approved or preclinical candidate compounds, including CD38 CAR T cells, daratumumab, isatuximab, GBR 1342, TAK169, and TAK079. In that regard, our previous report of two SLE patients who underwent anti-CD38 targeted treatment with the monoclonal antibody daratumumab provided the first insight into consequences of CD38-targeting antibodies on the immune system outside malignant conditions [11]. We observed overall stable counts of the major blood leukocyte subsets, except for NK cells and pDC, both robustly expressing CD38, which transiently decreased in circulation after anti-CD38 treatment.…”

Section: Discussionmentioning

confidence: 57%

“…Previous studies analyzing the expression of CD38 on leukocytes in SLE indicated increased CD38 expression on different leukocyte subsets compared to healthy controls, such as CD4 + and CD8 + memory T cells [9][10][11][12] and monocytes [13]. Research in CD38 −/− mice found that CD38 deficiency ameliorated the course of pristane-induced lupus [14].…”

Section: Introductionmentioning

confidence: 99%

“…Because CD38 is expressed constitutively at high levels on human antibody-secreting plasmablasts and plasma cells and is inducible on several immune cell subsets upon activation, CD38 has been considered as a potential therapeutic target in autoantibodydriven diseases such as SLE [15], autoimmune encephalitis [16,17], and autoimmune hemolysis [18]. We recently treated two patients with refractory, life-threatening SLE with the anti-CD38 antibody daratumumab, which resulted in substantial clinical and immunological efficacy [11]. Although the CD38-mediated targeting of plasma cells was presumably the most important factor for the observed clinical responses, it remains unclear if and how daratumumab exerts therapeutically relevant effects on other CD38 expressing immune cell subsets.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

Burns

Ostendorf

Biesen

et al. 2021

IJMS

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Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

Burns

Ostendorf

Biesen

et al. 2021

IJMS

Self Cite

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“…As observed for AIHA, most patients responded in a short time, with a variable number of cycles. Notably, in the two patients with SLE, daratumumab promoted depletion of autoreactive longlived plasma cells and was associated with a reduction in interferon type I activity and with modulation of effector T-cell responses (29). wAIHA, warm autoimmune hemolytic anemia; HSCT, hematopoietic stem cell transplant; ALL, acute lymphoblastic leukemia; AA, aplastic anemia; MF, myelofibrosis; ITP, immune thrombocytopenia; LPL, lymphoplasmocytic lymphoma.…”

Section: Case Descriptionmentioning

confidence: 99%

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

et al. 2021

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Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

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