Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial

Kappos, Ludwig; Hartung, Hans‐Peter; Freedman, Mark S.; Boyko, A. N.; Radü, E. W.; Mikol, Daniel D.; Lamarine, Marc; Hyvert, Yann; Freudensprung, Ulrich; Plitz, Thomas; Beek, Johan van

doi:10.1016/s1474-4422(14)70028-6

Cited by 290 publications

(240 citation statements)

References 31 publications

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“…Recently, TACI-Fc, a receptor blocker for TNFSF13, has been developed and investigated for its effect on autoimmune disease, although both optimistic and negative aspects related to this treatment have coexisted until now. 30,31 Although the results of our work do not provide a definitive reason to use a TNFSF13 blocker in patients with IgAN, these data may be a foundation for future strategies related with a drug intervention for TNFSF13 in progressive IgAN cases. In addition to the hypothesis-driven approach to evaluate the role of TNFSF13 on IgAN, we used RNA sequencing to produce unbiased data showing gene expression after treatment with TNFSF13.…”

Section: Discussionmentioning

confidence: 82%

The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy

Han¹,

Yang

Choi

et al. 2016

JASN

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TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.

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Section: Discussionmentioning

confidence: 82%

The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy

Han¹,

Yang

Choi

et al. 2016

JASN

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“…Treatment with this blocking antibody causes the arrest of splenic B-cell development at the immature transitional T1 stage [Boster et al 2010] and suppresses the production of autoreactive antibodies in mouse models of RA and SLE. However, a phase II trial in patients with MS who received weekly subcutaneous doses of atacicept (25, 75 or 150 mg, ATAMS study) was terminated due to an increase of clinical disease activity [Kappos et al 2014]. ARRs more than doubled in all atacicept groups compared to placebo (ARR placebo: 0.38; ARR atacicept: 0.79-0.98).…”

Section: Atacicept and Vay736mentioning

confidence: 99%

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

Bittner

Ruck

Wiendl

et al. 2016

Ther Adv Neurol Disord

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of specific B-cell subsets and functions to the optimal treatment regimen of B-cell depletion and monitoring thereafter. Here, we will assess our current knowledge of the mechanisms implicating B cells in multiple steps of disease pathology and examine current and future therapeutic approaches for the treatment of MS.

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“…However, in contrast to DCs that are short-lived, B cells can mature into long-lived memory phenotype with the capacity to indefinitely extend autoimmune responses. Additionally, depletion of B cells may unleash potent pro-inflammatory monocyte-derived APCs in the setting of MS (49), and the complexity of B cell targeted therapy in MS has recently been highlighted by the recent findings of the clinical trial using the B cell depleting agent Atacicept that led to exacerbation of MS rather than improvement (50).…”

Section: Discussionmentioning

confidence: 99%

“…Proliferation of CTLL-2 was measured after addition of supernatant by [ 3 H]thymidine incorporation as described (31). EC 50 was calculated by constructing a dose-response curve for each population of APCs, using the concentration of rMOG providing half-maximal IL-2 response by the hybridoma 204.62.…”

Section: Antigen Presentation Assaymentioning

confidence: 99%