Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment

Publication date: Available online 2 March 2017
Source:Cancer Cell
Author(s): Anja Seckinger, Jose Antonio Delgado, Samuel Moser, Laura Moreno, Brigitte Neuber, Anna Grab, Susanne Lipp, Juana Merino, Felipe Prosper, Martina Emde, Camille Delon, Melanie Latzko, Reto Gianotti, Remo Lüoend, Ramona Murr, Ralf J. Hosse, Lydia Jasmin Harnisch, Marina Bacac, Tanja Fauti, Christian Klein, Aintzane Zabaleta, Jens Hillengass, Elisabetta Ada Cavalcanti-Adam, Anthony D. Ho, Michael Hundemer, Jesus F. San Miguel, Klaus Strein, Pablo Umaña, Dirk Hose, Bruno Paiva, Minh Diem Vu
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.

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Teaser

Seckinger et al. show that B cell maturation antigen (BCMA) is universally and specifically expressed in normal and malignant plasma cells. They construct a BCMA-CD3 bispecific antibody that efficiently induces myeloma cell death by autologous T cells and depletes BCMA⁺ cells in cynomolgus monkeys.


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