Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma
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De-Xiu Bu1,*, Reshma Singh1,*, Eugene E. Choi1,*, Marco Ruella3, Selene Nunez-Cruz3, Keith G. Mansfield1, Paul Bennett1, Nathanial Barton1, Qilong Wu2, Jiquan Zhang2, Yongqiang Wang2, Lai Wei2, Shawn Cogan1, Tucker Ezell1, Shree Joshi1, Kellie J. Latimer1, Brian Granda1, William R. Tschantz1, Regina M. Young3, Heather A. Huet1, Celeste J. Richardson1 and Michael C. Milone3,4
1Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
2China Novartis Institutes for Biomedical Research, Shanghai 201203, China
3Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
4Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
*These authors contributed equally to this work
Michael C. Milone, email: [email protected]
Keywords: BCMA; T cell; CAR; multiple myeloma
Received: November 30, 2017 Accepted: April 24, 2018 Published: May 25, 2018
Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv). We demonstrate that BCMA is prevalently, but variably expressed by all MM with expression on 25–100% of malignant plasma cells. Extensive Immunohistochemical analysis of normal tissue expression using commercially available polyclonal antibodies demonstrated expression within B-lineage cells across a number of tissues as expected. Based upon the highly restricted expression of BCMA within normal tissues, we generated a set of novel, fully human scFv binding domains to BCMA by screening a naïve B-cell derived phage display library. Using a series of in vitro and pre-clinical in vivo studies, we identified a scFv with high specificity for BCMA and robust anti-myeloma activity when used as the binding domain of a second-generation CAR bearing a CD137 costimulatory domain. This BCMA-specific CAR is currently being evaluated in a Phase 1b clinical study in relapsed and refractory MM patients (NCT02546167).
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