Unexpected Potency Differences between B-Cell-Activating Factor (BAFF) Antagonist Antibodies against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound
| Autor: | David Presky, Qi Pan, Amy Marie Nicoletti, Ashraf Khalil, Scott M DeWire, Kerry L. M. Ralph, Sathyadevi Venkataramani, Julie Ritchie, Brodeur Scott, Cynthia Hess Kenny |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
CHO Cells Antibodies Monoclonal Humanized Mice 03 medical and health sciences Cricetulus stomatognathic system immune system diseases Cricetinae hemic and lymphatic diseases B-Cell Activating Factor medicine Animals Humans Protein Structure Quaternary skin and connective tissue diseases B-cell activating factor Receptor Cell Proliferation Pharmacology B-Lymphocytes Systemic lupus erythematosus biology Chinese hamster ovary cell Cell Membrane NF-kappa B medicine.disease Belimumab Tabalumab stomatognathic diseases 030104 developmental biology Solubility Immunology biology.protein Molecular Medicine Tumor necrosis factor alpha Protein Multimerization Antibody medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 359:37-44 |
| ISSN: | 1521-0103 |
| DOI: | 10.1124/jpet.116.236075 |
| Popis: | Therapeutic agents antagonizing B-cell-activating factor/B-lymphocyte stimulator (BAFF/BLyS) are currently in clinical development for autoimmune diseases; belimumab is the first Food and Drug Administration-approved drug in more than 50 years for the treatment of lupus. As a member of the tumor necrosis factor superfamily, BAFF promotes B-cell survival and homeostasis and is overexpressed in patients with systemic lupus erythematosus and other autoimmune diseases. BAFF exists in three recognized forms: membrane-bound and two secreted, soluble forms of either trimeric or 60-mer oligomeric states. To date, most in vitro pharmacology studies of BAFF neglect one or more of these forms. Here, we report a comprehensive in vitro cell-based analysis of BAFF in assay systems that measure all forms of BAFF-mediated activation. We demonstrate the effects of these BAFF forms in both a primary human B-cell proliferation assay and in nuclear factor κB reporter assay systems in Chinese hamster ovary cells expressing BAFF receptors and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). In contrast to the mouse system, we find that BAFF trimer activates the human TACI receptor. Further, we profiled the activities of two clinically advanced BAFF antagonist antibodies, belimumab and tabalumab. Unexpectedly, we revealed differences in inhibitory potencies against the various BAFF forms, in particular that belimumab does not potently inhibit BAFF 60-mer. Through this increased understanding of the activity of BAFF antagonists against different forms of BAFF, we hope to influence the discovery of BAFF antagonist antibodies with distinct therapeutic mechanisms for improvement in the treatment of lupus or other related autoimmune pathologies. |
| Databáze: | OpenAIRE |
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