title: Potent anti-tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma.
abstract: Multiple myeloma (MM) is an aggressive incurable plasma cell malignancy with a median life expectancy of less than seven years. Antibody-based therapies have demonstrated substantial clinical benefit for patients with hematological malignancies, particular in B cell Non-Hodgkin's lymphoma. The lack of immunotherapies specifically targeting MM cells led us to develop a human-mouse chimeric antibody directed against the B cell maturation antigen (BCMA), which is almost exclusively expressed on plasma cells and multiple myeloma cells. The high affinity antibody blocks the binding of the native ligands APRIL and BAFF to BCMA. This finding is rationalized by the high resolution crystal structure of the Fab fragment in complex with the extracellular domain of BCMA. Most importantly, the antibody effectively depletes MM cells in vitro and in vivo and substantially prolongs tumor-free survival under therapeutic conditions in a xenograft mouse model. A BCMA-antibody-based therapy is therefore a promising option for the effective treatment of multiple myeloma and autoimmune diseases.
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address: felix.oden@mdc-berlin.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Oden
authors.affiliation: Max-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address: stephen.marino@mdc-berlin.de.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Marino
authors.affiliation: Max-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Janko
authors.initials: J
authors.lastname: Brand
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Scheu
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Kriegel
authors.affiliation: Max-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olal
authors.affiliation: Charité University Medicine Berlin, Campus Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Takvorian
authors.affiliation: Charité University Medicine Berlin, Campus Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Westermann
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Department of Signal Transduction in Tumor Cells, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Buket
authors.initials: B
authors.lastname: Yilmaz
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Department of Signal Transduction in Tumor Cells, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hinz
authors.affiliation: Max-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Daumke
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Uta E
authors.initials: UE
authors.lastname: Höpken
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Müller
authors.affiliation: Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address: mlipp@mdc-berlin.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D053301:B-Cell Maturation Antigen / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D006031:Glycosylation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D053301:B-Cell Maturation Antigen; D000939:Epitopes; D016328:NF-kappa B; C490176:Tnfrsf17 protein, mouse
keywords: B cell maturation antigen (BCMA); High resolution X-ray structure; Immunotherapy; Monoclonal antibody; Multiple myeloma; Xenograft mouse model