title: Antibody targeting of B-cell maturation antigen on malignant plasma cells.
abstract: B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. BCMA binds to two ligands that promote tumor cell survival, a proliferation inducing ligand (APRIL) and B-cell activating factor. To selectively target BCMA for plasma cell malignancies, we developed antibodies with ligand blocking activity that could promote cytotoxicity of multiple myeloma (MM) cell lines as naked antibodies or as antibody-drug conjugates. We show that SG1, an inhibitory BCMA antibody, blocks APRIL-dependent activation of nuclear factor-kappaB in a dose-dependent manner in vitro. Cytotoxicity of SG1 was assessed as a naked antibody after chimerization with and without Fc mutations that enhance FcgammaRIIIA binding. The Fc mutations increased the antibody-dependent cell-mediated cytotoxicity potency of BCMA antibodies against MM lines by approximately 100-fold with a > or = 2-fold increase in maximal lysis. As an alternative therapeutic strategy, anti-BCMA antibodies were endowed with direct cytotoxic activity by conjugation to the cytotoxic drug, monomethyl auristatin F. The most potent BCMA antibody-drug conjugate displayed IC(50) values of < or = 130 pmol/L for three different MM lines. Hence, BCMA antibodies show cytotoxic activity both as naked IgG and as drug conjugates and warrant further evaluation as therapeutic candidates for plasma cell malignancies.
authors.affiliation: Seattle Genetics, Inc., 21823 30th Drive Southeast, Bothell, WA 98021, USA. mryan@seagen.com
authors.forename: Maureen C
authors.initials: MC
authors.lastname: Ryan
authors.forename: Michelle
authors.initials: M
authors.lastname: Hering
authors.forename: David
authors.initials: D
authors.lastname: Peckham
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: McDonagh
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Kim
authors.forename: Damon L
authors.initials: DL
authors.lastname: Meyer
authors.forename: Roger F
authors.initials: RF
authors.lastname: Zabinski
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Carter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000276:immunology; D053301:B-Cell Maturation Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D053301:B-Cell Maturation Antigen; D047630:Depsipeptides; D016328:NF-kappa B; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13