title: Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects.
abstract: The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.
authors.affiliation: Human Genome Sciences, Inc., Rockville, Maryland 20850, USA. wendy_halpern@hgsi.com
authors.forename: Wendy G
authors.initials: WG
authors.lastname: Halpern
authors.forename: Patrick
authors.initials: P
authors.lastname: Lappin
authors.forename: Thomas
authors.initials: T
authors.lastname: Zanardi
authors.forename: Wendy
authors.initials: W
authors.lastname: Cai
authors.forename: Marta
authors.initials: M
authors.lastname: Corcoran
authors.forename: John
authors.initials: J
authors.lastname: Zhong
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Baker
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20 / Q000276:immunology; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000187:drug effects*; D005260:Female; D007136:Immunoglobulins / Q000097:blood; D008198:Lymph Nodes / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D053264:B-Cell Activating Factor; D007136:Immunoglobulins; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; C511911:belimumab