Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma
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...
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| Format: | Article |
| Language: | English |
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Wiley
2015-08-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1016/j.molonc.2015.03.010 |
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| author | Felix Oden Stephen F. Marino Janko Brand Susanne Scheu Cathleen Kriegel Daniel Olal Anna Takvorian Jörg Westermann Buket Yilmaz Michael Hinz Oliver Daumke Uta E. Höpken Gerd Müller Martin Lipp |
| author_facet | Felix Oden Stephen F. Marino Janko Brand Susanne Scheu Cathleen Kriegel Daniel Olal Anna Takvorian Jörg Westermann Buket Yilmaz Michael Hinz Oliver Daumke Uta E. Höpken Gerd Müller Martin Lipp |
| author_sort | Felix Oden |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-92f1eebe156a4ac988b844df2217dbe4 |
| institution | OA Journals |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2015-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-92f1eebe156a4ac988b844df2217dbe42025-08-20T02:07:20ZengWileyMolecular Oncology1574-78911878-02612015-08-01971348135810.1016/j.molonc.2015.03.010Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myelomaFelix Oden0Stephen F. Marino1Janko Brand2Susanne Scheu3Cathleen Kriegel4Daniel Olal5Anna Takvorian6Jörg Westermann7Buket Yilmaz8Michael Hinz9Oliver Daumke10Uta E. Höpken11Gerd Müller12Martin Lipp13Max-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyCharité University Medicine Berlin, Campus Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, Augustenburger Platz 1, 13353 Berlin, GermanyCharité University Medicine Berlin, Campus Virchow-Klinikum, Department of Hematology, Oncology and Tumor Immunology, Augustenburger Platz 1, 13353 Berlin, GermanyMax-Delbrück-Center for Molecular Medicine (MDC), Department of Signal Transduction in Tumor Cells, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center for Molecular Medicine (MDC), Department of Signal Transduction in Tumor Cells, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMax-Delbrück-Center of Molecular Medicine (MDC), Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, GermanyMultiple 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.https://doi.org/10.1016/j.molonc.2015.03.010B cell maturation antigen (BCMA)ImmunotherapyMultiple myelomaMonoclonal antibodyXenograft mouse modelHigh resolution X-ray structure |
| spellingShingle | Felix Oden Stephen F. Marino Janko Brand Susanne Scheu Cathleen Kriegel Daniel Olal Anna Takvorian Jörg Westermann Buket Yilmaz Michael Hinz Oliver Daumke Uta E. Höpken Gerd Müller Martin Lipp Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma Molecular Oncology B cell maturation antigen (BCMA) Immunotherapy Multiple myeloma Monoclonal antibody Xenograft mouse model High resolution X-ray structure |
| title | Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma |
| title_full | Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma |
| title_fullStr | Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma |
| title_full_unstemmed | Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma |
| title_short | Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma |
| title_sort | potent anti tumor response by targeting b cell maturation antigen bcma in a mouse model of multiple myeloma |
| topic | B cell maturation antigen (BCMA) Immunotherapy Multiple myeloma Monoclonal antibody Xenograft mouse model High resolution X-ray structure |
| url | https://doi.org/10.1016/j.molonc.2015.03.010 |
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