title: Pre-treatment affinity for LJP 394 influences pharmacodynamic response in lupus patients.
abstract: Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.
authors.affiliation: La Jolla Pharmaceutical Company, San Diego, California 92121, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: McNeeley
authors.forename: G M
authors.initials: GM
authors.lastname: Iverson
authors.forename: R A
authors.initials: RA
authors.lastname: Furie
authors.forename: J M
authors.initials: JM
authors.lastname: Cash
authors.forename: M E
authors.initials: ME
authors.lastname: Cronin
authors.forename: R S
authors.initials: RS
authors.lastname: Katz
authors.forename: M H
authors.initials: MH
authors.lastname: Weisman
authors.forename: C
authors.initials: C
authors.lastname: Aranow
authors.forename: M D
authors.initials: MD
authors.lastname: Linnik
mesh_terms: D000974:Antibodies, Antinuclear / Q000097:blood; D000915:Antibody Affinity; D001667:Binding, Competitive / Q000187:drug effects / Q000276:immunology; D015331:Cohort Studies; D004247:DNA / Q000276:immunology; D004311:Double-Blind Method; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007457:Iodine Radioisotopes; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D009841:Oligonucleotides; D004247:DNA; C094104:abetimus