Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment
Seckinger A (1), Delgado JA (2), Moser S (3), Moreno L (2), Neuber B 4, Grab A (1), Lipp S (1), Merino J (2), Prosper F (2), Emde M (1), Delon C (3), Latzko M (3), Gianotti R (3), Lüoend R (3), Murr R (3), Hosse RJ (3), Harnisch LJ (3), Bacac M (3), Fauti T (3), Klein C (3), Zabaleta A (2), Hillengass J (4), Cavalcanti-Adam EA (5), Ho AD (4), Hundemer M (4), San Miguel JF (2), Strein K (6), Umaña P (3), Hose D (7), Paiva B (8), Vu MD (9).
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.
CITATION Cancer Cell. 2017 Mar 13;31(3):396-410. doi: 10.1016/j.ccell.2017.02.002