Bispecific BCMA-CD3 Antibodies Block Multiple Myeloma Tumor Growth

SIMPLE SUMMARY: Multiple myeloma accounts for approximately 10% of hematological cancers in the United States. It is a malignancy of plasma cells which accumulate in the bone marrow and produce a monoclonal protein. Novel treatments are needed to cure multiple myeloma patients. The goal of this report was to develop novel bispecific BCMA-CD3 antibodies targeting a B cell maturation antigen, BCMA, which is overexpressed in multiple myeloma. The data demonstrated high efficacy of BCMA-CD3 antibodies in multiple myeloma cell lines in vitro and in vivo. The data provide a basis for future clinical studies. ABSTRACT: BCMA antigen is overexpressed in multiple myeloma cells and has been shown to be a promising target for novel cellular and antibody therapeutics. The humanized BCMA (clone 4C8A) antibody that effectively targeted multiple myeloma in a CAR (chimeric antigen receptor) format was used for designing several formats of bispecific BCMA-CD3 antibodies. Several different designs of univalent and bivalent humanized BCMA-CD3 CrossMAB and BCMA-FAB-CD3 ScFv-Fc antibodies were tested for binding with BCMA-positive cells and T cells and for killing by real time cytotoxic activity and IFN-gamma secretion with CHO-BCMA target cells and with multiple myeloma MM1S and H929 cell lines. All BCMA-CD3 antibodies demonstrated specific binding by FACS to CHO-BCMA, multiple myeloma cells, and to T cells with affinity Kd in the nM range. All antibodies with T cells specifically killed CHO-BCMA and multiple myeloma cells in a dose-dependent manner. The BCMA-CD3 antibodies with T cells secreted IFN-gamma with EC(50) in the nM range. In addition, three BCMA bispecific antibodies had high in vivo efficacy using an MM1S xenograft NSG mouse model. The data demonstrate the high efficacy of novel hBCMA-CD3 antibodies with multiple myeloma cells and provide a basis for future pre-clinical and clinical development.