CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth.

Robert Berahovich,Jian Guan,Jasper Guan,Shuying Zhu,Vita Golubovskaya,Kaihuai Yang,Shuxiang Fu,Yuehua Wei,Hizkia Harto,Hua Zhou,Le Li,Shirley Xu,Lijun Wu

doi:10.3390/cancers10090323

Abstract

The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro. BCMA-dependent cytotoxicity and IFN-γ secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.

Highlights

Multiple myeloma is a cancer of plasma cells characterized by clonal proliferation in the bone marrow microenvironment [1]
Investigators are turning to immunotherapy approaches targeting B cell maturation agent (BCMA), a cell-surface protein expressed by mature B lymphocytes, plasma cells, and most cases of multiple myeloma [4]
We show that BCMA costimulatory domains receptor (CAR)-T cells based on the novel mAb 4C8A significantly decreased multiple myeloma tumor growth, demonstrating great potential for treating patients with multiple myeloma

Summary

Introduction

Multiple myeloma is a cancer of plasma cells characterized by clonal proliferation in the bone marrow microenvironment [1]. Multiple myeloma is the second-most common hematologic malignancy, accounting for 5–10% of all hematologic malignancies in the USA [2,3]. Despite recent progress in treatment, multiple myeloma remains incurable with high rates of relapsed and refractory disease [3]. Investigators are turning to immunotherapy approaches targeting B cell maturation agent (BCMA), a cell-surface protein expressed by mature B lymphocytes, plasma cells, and most cases of multiple myeloma [4]. BCMA has been targeted by antibodies [5] and, recently, Cancers 2018, 10, 323; doi:10.3390/cancers10090323 www.mdpi.com/journal/cancers

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