Abstract
BAFF is considered a therapeutic target because dysregulated production of BAFF can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels of BAFF are associated with disease severity in systemic lupus erythematosus and rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for blocking BAFF. While studying their interactions with BAFF, we found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors. We also found that a trimeric BAFF can bind more than one BAFF-R-Fc but only one BCMA-Fc. Moreover, we show that, in contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF. Differences in their interaction with BAFF predict BAFF-R-Fc would be a better inhibitor. Indeed, we show BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation in vitro and for blocking BAFF-mediated survival of mouse splenic B lymphocytes in vivo.
MeSH terms
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Animals
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Arthritis, Rheumatoid / metabolism
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Asparagine / chemistry
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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B-Cell Maturation Antigen
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B-Lymphocytes / metabolism
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CHO Cells
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Cell Membrane / metabolism
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Cell Separation
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Cell Survival
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Cricetinae
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Dimerization
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Immunoglobulin G / chemistry*
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Leucine / chemistry
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Lupus Erythematosus, Systemic / metabolism
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Membrane Proteins / chemistry*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Phenotype
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Proline / chemistry
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Protein Binding
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Receptors, Tumor Necrosis Factor / chemistry*
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Recombinant Fusion Proteins / metabolism*
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Spleen / cytology
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Tumor Necrosis Factor-alpha / chemistry*
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Valine / chemistry
Substances
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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B-Cell Maturation Antigen
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Immunoglobulin G
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Membrane Proteins
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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Tnfrsf13c protein, mouse
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Tnfrsf17 protein, mouse
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Tnfsf13b protein, mouse
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Tumor Necrosis Factor-alpha
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Asparagine
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Proline
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Leucine
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Valine