title: Unexpected Potency Differences between B-Cell-Activating Factor (BAFF) Antagonist Antibodies against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound.
abstract: 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.
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Nicoletti
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Cynthia Hess
authors.initials: CH
authors.lastname: Kenny
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Ashraf M
authors.initials: AM
authors.lastname: Khalil
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Kerry L M
authors.initials: KL
authors.lastname: Ralph
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Julie
authors.initials: J
authors.lastname: Ritchie
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Sathyadevi
authors.initials: S
authors.lastname: Venkataramani
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: David H
authors.initials: DH
authors.lastname: Presky
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut scott.dewire@boehringer-ingelheim.com.
authors.forename: Scott M
authors.initials: SM
authors.lastname: DeWire
authors.affiliation: Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Brodeur
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology; D053264:B-Cell Activating Factor / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012995:Solubility
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; D016328:NF-kappa B; C511911:belimumab