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ToxSci Advance Access published online on March 3, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj148
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 19, 2005
Accepted February 23, 2006

Safety Evaluation

Chronic Administration of Belimumab, a BLyS Antagonist, Decreases Tissue and Peripheral Blood B-Lymphocyte Populations in Cynomolgus Monkeys: Pharmacokinetic, Pharmacodynamic and Toxicologic Effects

Wendy G. Halpern 1 *, Patrick Lappin 2, Thomas Zanardi 2, Wendy Cai 1, Marta Corcoran 1, John Zhong 1, and Kevin P. Baker 1

1 Human Genome Sciences, Inc., Rockville MD 20850; Currently affiliated with Five Prime Therapeutics, Inc., San Francisco CA
2 Charles River Laboratories Preclinical Services, Nevada, Sparks NV 89431; Currently affiliated with Isis Pharmaceuticals, Carlsbad CA

* To whom correspondence should be addressed.
Wendy G. Halpern, E-mail: Wendy_Halpern{at}hgsi.com


  Abstract

The tolerability, pharmacodynamic effects and pharmacokinetics of belimumab (LymphoStat-BTM) were evaluated in cynomolgus monkeys. Belimumab is a fully-human IgG1{lambda} antibody directed against B-lymphocyte stimulator (BLySTM) 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 endpoints, 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 to 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.

Keywords: Agents - pharmaceuticals; Immunotoxicology - autoimmune; Safety Evaluation; Safety Evaluation - toxicity; chronic.
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