A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

• Published in: Leukemia Vol. 31; no. 8; pp. 1743 - 1751
• Main Authors: Hipp, S, Tai, Y-T, Blanset, D, Deegen, P, Wahl, J, Thomas, O, Rattel, B, Adam, P J, Anderson, K C, Friedrich, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2017; Nature Publishing Group
• Subjects: 13/1; 13/31; 631/67/1059/602; 631/67/1990/804; 64/60; 692/308/153; 692/308/2778; 692/308/575; 692/699/67/1059/2325; 82/1; Animals; Antibodies, Bispecific - therapeutic use; Antigens; Apoptosis; APRIL protein; Autografts; B-Cell Maturation Antigen - immunology; Bone marrow; Cancer Research; Care and treatment; CD3 antigen; CD3 Complex - immunology; Cell activation; Cell proliferation; Cells, Cultured; Critical Care Medicine; Cytokines; Cytokines - secretion; Depletion; Female; Hematology; Humans; Immunotherapy; In vitro methods and tests; Intensive; Internal Medicine; Lymphocyte Activation; Lymphocytes; Lymphocytes B; Lymphocytes T; Lysis; Macaca fascicularis; Maturation; Medicine; Medicine & Public Health; Mice; Multiple myeloma; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Oncology; original-article; Plasma cells; Plasmas (physics); Stromal cells; T cell receptors; T cells; T-Lymphocytes - immunology; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.388

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.