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

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

doi:10.1016/j.ccell.2017.02.002

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

Cancer Cell. 2017 Mar 13;31(3):396-410. doi: 10.1016/j.ccell.2017.02.002. Epub 2017 Mar 2.

Authors

Anja Seckinger¹, Jose Antonio Delgado², Samuel Moser³, Laura Moreno², Brigitte Neuber⁴, Anna Grab¹, Susanne Lipp¹, Juana Merino², Felipe Prosper², Martina Emde¹, Camille Delon³, Melanie Latzko³, Reto Gianotti³, Remo Lüoend³, Ramona Murr³, Ralf J Hosse³, Lydia Jasmin Harnisch³, Marina Bacac³, Tanja Fauti³, Christian Klein³, Aintzane Zabaleta², Jens Hillengass⁴, Elisabetta Ada Cavalcanti-Adam⁵, Anthony D Ho⁴, Michael Hundemer⁴, Jesus F San Miguel², Klaus Strein⁶, Pablo Umaña³, Dirk Hose⁷, Bruno Paiva⁸, Minh Diem Vu⁹

Affiliations

¹ Universitätsklinikum Heidelberg, Labor für Myelomforschung and Medizinische Klinik V, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
² Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, IDISNA, Avda. Pío XII, 55, 31008 Pamplona, Spain.
³ Roche Innovation Center Zurich, 8952 Schlieren, Switzerland.
⁴ Universitätsklinikum Heidelberg, Medizinische Klinik V, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
⁵ University of Heidelberg, Institute for Physical Chemistry and Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
⁶ EngMab AG, 8808 Pfäffikon, Switzerland.
⁷ Universitätsklinikum Heidelberg, Labor für Myelomforschung and Medizinische Klinik V, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: [email protected].
⁸ Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, IDISNA, Avda. Pío XII, 55, 31008 Pamplona, Spain. Electronic address: [email protected].
⁹ EngMab AG, 8808 Pfäffikon, Switzerland. Electronic address: [email protected].

PMID: 28262554
DOI: 10.1016/j.ccell.2017.02.002

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.

Keywords: BCMA; T cell bispecific antibody; immunotherapy; multiple myeloma; redirected cell killing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Bispecific / biosynthesis
Antibodies, Bispecific / pharmacokinetics
Antibodies, Bispecific / pharmacology
Antibodies, Bispecific / therapeutic use*
B-Cell Maturation Antigen / immunology*
Humans
Lymphocyte Activation
Macaca fascicularis
Mice
Multiple Myeloma / drug therapy*
T-Lymphocytes / immunology*
Xenograft Model Antitumor Assays

Substances

Antibodies, Bispecific
B-Cell Maturation Antigen