title: Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus.
abstract: This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.
authors.affiliation: Drug Safety Research and Development, Pfizer, Andover, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Masek-Hammerman
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Cambridge, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Peeva
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Menon
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Afsharvand
authors.affiliation: Pfizer China Research and Development Center, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Peng Qu
authors.affiliation: PDM-NCE Regulated Bioanalytical Group, Pfizer, Groton, CT, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Cheng
authors.affiliation: Drug Safety Research and Development, Pfizer, Andover, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Syed
authors.affiliation: Drug Safety Research and Development, Pfizer, Andover, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Drug Safety Research and Development, Pfizer, Andover, MA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: O'Neil
authors.affiliation: PDM-NCE Regulated Bioanalytical Group, Pfizer, Groton, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pleasic-Williams
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Collegeville, PA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Cox
authors.affiliation: PharmaTherapeutics Clinical Research and Development, Pfizer, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Beidler
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000652:urine; D003094:Collagen / Q000652:urine; D003402:Creatine Kinase / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D006644:Histiocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008178:Lupus Erythematosus, Cutaneous / Q000188:drug therapy* / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects / Q000473:pathology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; C461299:urinary N-telopeptide of type I collagen, human; D016173:Macrophage Colony-Stimulating Factor; D003094:Collagen; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase
keywords: CD14/CD16 monocytes; cutaneous lupus erythematosus; immunohistochemistry; macrophage colony-stimulating factor; osteoclasts