1. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator
- Author
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David M. Hilbert, Tristan J. Vaughan, Sarah Helen Main, Bonnie Sturm, Bryan M. Edwards, Vivian R. Albert, Claire Dobson, Les Sekut, Ralph Minter, Wendy Halpern, Carol Poortman, Ruth E. Wager, Todd A. Riccobene, Gil H. Choi, Rodger Smith, Donara Abramian, Kevin P. Baker, Sara Carmen, Patrick B. Lappin, Elizabeth N. Williams, and Viktor Roschke
- Subjects
Male ,medicine.drug_class ,Transmembrane Activator and CAML Interactor Protein ,medicine.medical_treatment ,Immunology ,Biology ,Monoclonal antibody ,Receptors, Tumor Necrosis Factor ,Mice ,Rheumatology ,Neutralization Tests ,medicine ,Animals ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,B-Cell Maturation Antigen ,B-cell activating factor ,Receptor ,B cell ,B-Lymphocytes ,Dose-Response Relationship, Drug ,Antibodies, Monoclonal ,Membrane Proteins ,Belimumab ,Macaca fascicularis ,Cytokine ,medicine.anatomical_structure ,Injections, Intravenous ,Leukocytes, Mononuclear ,Mutagenesis, Site-Directed ,Cancer research ,biology.protein ,Female ,Lymph Nodes ,Antibody ,Cell Division ,Spleen ,B-Cell Activation Factor Receptor ,medicine.drug - Abstract
Objective To identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor–related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases. Methods A human phage display library was screened for antibodies against human BLyS. A human monoclonal antibody, LymphoStat-B, specific for human BLyS was obtained from the library screening and subsequent affinity optimization mutagenesis. The antibody was tested for inhibition of human BLyS in vitro and in an in vivo murine model. Additionally, the consequences of BLyS inhibition were tested in vivo by administration of LymphoStat-B to cynomolgus monkeys. Results LymphoStat-B bound with high affinity to human BLyS and inhibited the binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF-R. LymphoStat-B potently inhibited BLyS-induced proliferation of B cells in vitro, and administration of LymphoStat-B to mice prevented human BLyS-induced increases in splenic B cell numbers and IgA titers. In cynomolgus monkeys, administration of LymphoStat-B resulted in decreased B cell representation in both spleen and mesenteric lymph nodes. Conclusion A fully human monoclonal antibody has been isolated that binds to BLyS with high affinity and neutralizes human BLyS bioactivity in vitro and in vivo. Administration of this antibody to cynomolgus monkeys resulted in B cell depletion in spleen and lymph node. This antibody may prove therapeutically useful in the treatment of autoimmune diseases in humans.
- Published
- 2003
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