title: 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.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.
authors.affiliation: Division of Rheumatology and Allergy-Clinical Immunology, North Shore Long Island Jewish Health System, Marcus Avenue, Lake Success, New York 11042, USA. furie@nshs.edu
authors.forename: Richard
authors.initials: R
authors.lastname: Furie
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Ginzler
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.forename: Nilamadhab
authors.initials: N
authors.lastname: Mishra
authors.forename: Winn
authors.initials: W
authors.lastname: Chatham
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Arthur
authors.initials: A
authors.lastname: Weinstein
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: McCune
authors.forename: John
authors.initials: J
authors.lastname: Zhong
authors.forename: Wendy
authors.initials: W
authors.lastname: Cai
authors.forename: William
authors.initials: W
authors.lastname: Freimuth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; C511911:belimumab
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