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.

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

“…B-cell depletion by means of anti-CD20 mAb [12][13][14][15], or inhibition of B-cell activation and proliferation by anti-CD22 mAb Epratuzumab have been applied to lupus patients [16]. The human Lymphostat-B mAb that blocks another important costimulatory receptor, B-cell activating factor (BAFF), has been also successfully introduced [17][18][19].…”

“…B-cell depletion by means of anti-CD20 mAb [12][13][14][15], or inhibition of B-cell activation and proliferation by anti-CD22 mAb Epratuzumab have been applied to lupus patients [16]. The human Lymphostat-B mAb that blocks another important costimulatory receptor, B-cell activating factor (BAFF), has been also successfully introduced [17][18][19].An alternative approach for specific targeting of B-cell response is the delivery of negative signals. The cross-linking of surface immunoglobulin receptors with the inhibitory Fc-gamma IIb (FcgIIb) receptors by IgG-containing immune complexes is a natural negative feedback mechanism of Ab production [20][21][22].…”

B cell modulation in rheumatology

“…In non-human primates, belimumab was shown to be safe and well tolerated at 5-50 mg/kg for up to 26 weeks, with potent biologic activity as demonstrated by significant decreases in peripheral blood and tissue B lymphocytes by 13 weeks of exposure while other leukocyte lineages were unaffected. Moreover, B-cell depletion was generally reversible within a 34-week recovery period [47].…”

Belimumab: targeted therapy for lupus

“…17 In accordance with observations in mice, multiple in vivo studies of belimumab were performed in monkeys. 18 Administration of belimumab for 26 weeks in cynomolgus monkeys, resulted in almost 75% reduction in the number of lymphoid tissue and peripheral blood CD20+ B cells and CD21+ plasmacytoid cells. The effects of belimumab appeared to be dose-dependent after 13 weeks of treatment and maximal in all dose groups by week 26.…”

“…In this 26-week multiple-dose toxicology study, belimumab demonstrated the expected pharmacologic activity of specifically decreasing B lymphocytes both in tissues and in peripheral blood. 18 The phase 1 dose-escalating trial of belimumab was undertaken in 70 patients of SLE with mild to moderate disease activity (Table 1). 19 The patients were randomized to receive either the drug in a dose of 1, 4, 10 or 20 mg/kg or placebo.…”