1. Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment
- Author
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Ramona Murr, Elisabetta Ada Cavalcanti-Adam, Juana Merino, Reto Gianotti, Aintzane Zabaleta, Marina Bacac, Anthony D. Ho, Martina Emde, Jose Antonio Delgado, Samuel Moser, Felipe Prosper, Lydia Jasmin Harnisch, Anna Luise Grab, Jens Hillengass, Melanie Latzko, Klaus Strein, Ralf Hosse, Tanja Fauti, Jesús F. San Miguel, Remo Lüoend, Brigitte Neuber, Bruno Paiva, Pablo Umana, Minh Diem Vu, Christian Klein, Camille Delon, Anja Seckinger, Susanne Lipp, Michael Hundemer, Laura Moreno, Dirk Hose, Hematology, and Basic (bio-) Medical Sciences
- Subjects
0301 basic medicine ,Cancer Research ,B-Cell Maturation Antigen/immunology ,mice ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Multiple Myeloma/drug therapy ,T cell bispecific antibody ,Lymphocyte Activation ,03 medical and health sciences ,0302 clinical medicine ,Multiple myeloma ,Antibodies, Bispecific ,Medicine ,Animals ,Antibodies, Bispecific/biosynthesis ,Humans ,B-Cell Maturation Antigen ,biology ,business.industry ,hematology ,Immunotherapy ,T-Lymphocytes/immunology ,medicine.disease ,Xenograft Model Antitumor Assays ,BCMA ,Granzyme B ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,Redirected cell killing ,Oncology ,Perforin ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Bone marrow ,Ciencias de la Salud::Hematología [Materias Investigacion] ,Antibody ,Multiple Myeloma ,business ,CD8 - Abstract
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3+ T cell/myeloma cell crosslinking, followed by CD4+/CD8+ T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA+ cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration.
- Published
- 2017