Daratumumab monotherapy for refractory lupus nephritis

Abstract

Refractory lupus nephritis (RLN) is a clinical condition with high risk of a poor outcome and often life-threatening. Six patients (one male and 5 females), aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy, a monoclonal antibody targeting CD38 which is highly expressed on the surface of many immune cells, especially plasma cells. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly (maximum 8 infusions). All patients failed previous treatments with the Standard of Care (SOC) including mycophenolate mofetil (MMF), cyclophosphamide (CYC), azathioprine and rescue therapies including Rituximab (RTX), Ocrelizumab, Belimumab, and iv IgG. One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients showing a clinical response over the same period continued to be treated and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III + V LN in 1 patient and class IV + V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 gr/24 hours to 0.8 g/24 hours (p = 0.001) was achieved at 12 months. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and increase in C4 (p = 0.018) and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated. These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in RLN.

Novel and potential future therapeutic options in systemic autoimmune diseases

“…Ostendorf and colleagues described the cases of two patients with life-threatening refractory lupus who responded well to this anti-CD38 therapy and showed decreased urine protein-creatinine ratio, serum creatinine levels, serum anti-dsDNA titers, and SLEDAI-2K scores upon treatment (17). Moreover, daratumumab was successful in five out of six patients with refractory lupus nephritis in another case series investigation (18). An open-label, phase 2 clinical trial to explore the effectiveness of daratumumab in refractory SLE patients is ongoing (ClinicalTrials.gov Identifier: NCT04810754).…”

Emerging biologic therapies for systemic lupus erythematosus

“…Another monoclonal antibody against CD38, daratumumab, enables direct depletion of plasma cells. Among six patients with refractory LN treated with daratumumab, five patients showed a clinical response based on the improvement of SLEDAI2000, resolution of proteinuria and improvement of renal function [8 ▪ ]. Although monoclonal antibody-mediated depletion of pathogenic cells has realized more target-specific therapy and expanded the scope of treatment, one of the major limitations is its lack of ability to eliminate cells deeply located in the tissues.…”

CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis

“…Single nucleotide polymorphisms (SNPs) in the TLR7 gene result in the overexpression and hyperactivation of TLR7 that amplifies the immune response to self-antigens and are associated with increased risk of SLE and LN [20]. TLR7 detects ssRNA that triggers a signaling cascade that activates transcription factors, such as NF-κB and interferon regulatory factors 3 and 7 (IRF3 and IRF7), and induce production of pro-inflammatory cytokines and IFN I thereby exacerbating kidney injury, tubulointerstitial damage and glomerulosclerosis [1,[21][22][23].…”