title: A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.
abstract: B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.
authors.affiliation: Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim RCV GmbH &Co KG, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Hipp
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Blanset
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Deegen
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Thomas
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Rattel
authors.affiliation: Immune-Modulation and Biotherapeutics Discovery, Boehringer Ingelheim RCV GmbH &Co KG, Vienna, Austria.
authors.forename: P J
authors.initials: PJ
authors.lastname: Adam
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Friedrich
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D017209:Apoptosis; D053301:B-Cell Maturation Antigen / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D053301:B-Cell Maturation Antigen; D017252:CD3 Complex; D016207:Cytokines