A Novel CD3/BCMA Bispecific T-cell Redirecting Antibody for the Treatment of Multiple Myeloma. Issue 2 (February 2022)

• Record Type: Journal Article
• Authors: Xiong, Mengshang; Liu, Ruoqi; Lei, Xiaomin; Fan, Dongmei; Lin, Fangzhen; Hao, Wei; Yuan, Xiangfei; Yang, Yuanyuan; Zhang, Xiaolong; Ye, Zhou; Lu, Yang; Zhang, Yanjun; Wang, Jianxiang; Xiong, Dongsheng
• Is Part Of: Journal of immunotherapy. Volume 45:Issue 2(2022)
• Publication Date: 2022-02
• Subjects: multiple myeloma -- B-cell maturation antigen -- cluster of differentiation 3 -- bispecific antibody -- immunotherapy; Immunotherapy -- Periodicals; Immunotherapy -- Periodicals; Neoplasms -- therapy -- Periodicals; Electronic journals; Electronic journals; 615.37
• DOI: 10.1097/CJI.0000000000000401
• Languages: English
• ISSNs: 1524-9557

Abstract

Abstract : Multiple myeloma (MM) is a B-cell malignancy for which new treatments are urgently needed. Redirecting the activity of T cells by bispecific antibodies against tumor cells is a potent approach. The B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein and therefore is an ideal therapeutic target for T-cell redirecting therapies. The main objective of this work is to target the BCMA by generating BCMA-specific murine monoclonal antibody and construct a cluster of differentiation 3 (CD3)/BCMA-directed tandem diabodies (Tandab). In brief, using standard hybridoma technology, we developed a novel BCMA-specific monoclonal antibody (clone 69G8), that specifically bind with BCMA + cell lines and MM patient sample; whereas BCMA − cells were not recognized. For T cells by bispecific antibodies application, we constructed a Tandab (CD3/BCMA) simultaneously targeting both CD3 and BCMA and our studies demonstrated that Tandab (CD3/BCMA) was functional with specific binding capability both for CD3 + cells and BCMA + cells. It induced selective, dose-dependent lysis of BCMA + cell lines, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA − cells were not affected. Furthermore, we demonstrated that Tandab activity correlates with BCMA expression, with higher potency observed in highly BCMA expressing tumor cells. In vivo, the purified Tandab (CD3/BCMA) significantly inhibited the tumor growth in a subcutaneous NCI-H929 xenograft model. Taken together, these results show that the Tandab (CD3/BCMA) displays potent and selective anti-MM activities and represents a promising immunotherapeutic for the treatment of MM. Abstract : Supplemental Digital Content is available in the text.