Biologic activity and safety of belimumab a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a Phase I trial in patients with systemic lupus erythematosus

Division of Rheumatology and Allergy-Clinical Immunology, North Shore Long Island Jewish Health System, Marcus Avenue, Lake Success, New York 11042, USA.
Arthritis research & therapy (Impact Factor: 3.75). 10/2008; 10(5):R109. DOI: 10.1186/ar2506
Source: PubMed


This trial evaluated the safety, biologic activity, and pharmacokinetics of belimumab, a fully human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B-cell survival factor B-lymphocyte stimulator (BLyS) in patients with systemic lupus erythematosus (SLE).
Seventy patients with mild-to-moderate SLE were enrolled in a phase I, double-blind, randomized study and treated with placebo (n = 13) or belimumab (n = 57) at four different doses (1.0, 4.0, 10, and 20 mg/kg) as a single infusion or two infusions 21 days apart. Patients were followed for 84 to 105 days to assess adverse events, pharmacokinetics, peripheral blood B-cell counts, serology, and SLE disease activity. Data from the study were summarized using descriptive statistics. chi2 type tests were used to analyze discrete variables. The Kruskal-Wallis test, the Wilcoxon test, and the analysis of covariance were used to analyze the continuous variables, as appropriate. The analysis was performed on all randomized patients who received study agent.
The incidences of adverse events and laboratory abnormalities were similar among the belimumab and placebo groups. Belimumab pharmacokinetics were linear across the 1.0 to 20 mg/kg dose range. Long terminal elimination half-life (8.5 to 14.1 days), slow clearance (7 ml/day per kg), and small volume of distribution (69 to 112 ml/kg) were consistent with a fully human antibody. Significant reductions in median percentages of CD20+ B cells were observed in patients treated with a single dose of belimumab versus placebo (day 42: P = 0.0042; and day 84: P = 0.0036) and in patients treated with two doses of belimumab versus placebo (day 105: P = 0.0305). SLE disease activity did not change after one or two doses of belimumab.
Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.

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    • "The greatest experience to date with BLyS antagonists (Table 1) has accrued with belimumab, a fully human IgG1λ mAb that binds and neutralizes soluble BLyS [115]. Belimumab was shown to be safe in a randomized, double-blind, placebo-controlled phase I trial of SLE, in which the prevalence of adverse events was no different between belimumab-treated and placebo-treated patients [116]. Of note, only modest reductions in peripheral blood B cells were observed among belimumab-treated patients. "
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    ABSTRACT: The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.
    Arthritis research & therapy 07/2011; 13(4):228. DOI:10.1186/ar3349 · 3.75 Impact Factor
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    • "The experience with belimumab in the phase I, II, and III trials indicates the reagent is generally safe and well tolerated with comparable frequency of adverse events (AEs) and serious adverse events (SAEs), including infections and serious infections across placebo and treatment groups. In the phase I study, only one of the patients in the belimumab group experienced infusion interruption due to urticaria and chest pain, requiring histamine blockade [Furie et al. 2008]. Except for an infusion-site reaction in one patient and more infusion-related urticaria events (4% belimumab groups versus 0% in placebo subjects), belimumab was well tolerated in the phase II study [Wallace et al. 2009]. "
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    ABSTRACT: Belimumab is a human genome derived monoclonal antibody with specificity for BLyS (B lymphocyte stimulator, or B-cell activating factor [BAFF]), a cytokine that promotes the survival and maturation of B cells into antibody-secreting plasmablasts. Recent phase III clinical trials with belimumab in patients with active systemic lupus erythematosus (SLE) have been completed and achieved primary efficacy endpoints employing validated disease activity measures (SLEDAI and BILAG) as well as additional secondary endpoints related to disease flares and sparing of corticosteroid use. Significant decreases in numbers of activated B cells as well as levels of autoantibodies are observed during treatment with belimumab. The majority of observed clinical improvements are observed in musculoskeletal, mucocutaneous, and serologic domains of disease activity; the potential effects on more severe neurologic or renal domains of disease are not known. Treatment with belimumab is well tolerated and has not been associated with significant toxicity.
    Therapeutic advances in musculoskeletal disease 06/2011; 3(3):159-64. DOI:10.1177/1759720X11407541
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    ABSTRACT: Summary Lupus nephritis (LN) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The use of aggressive immunosuppressive treatment has improved both patient and renal survival. The objectives of this therapy should be to achieve a prompt renal remission, to avoid renal flares and progression to chronic renal failure with minimal toxicity. Treatment with monthly intravenous cyclophosphamide and glucocorticoids (National Institute of Health regimen) as induction treatment and long-term administration of venous pulses of cyclophosphamide or azathioprine has become standard treatment for severe proliferative LN. Mycophenolate mofetil is an alternative to cyclophosphamide for induction and maintenance therapy of proliferative LN. There are other therapeutic options for resistant LN as more aggressive ciclophosphamide regimens, but at the expense of more toxicity, calcineurin inhibitors, intravenous immunoglobulin, immunoadsorption and therapies that selectively target B cells.
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