1. A Novel CD3/BCMA Bispecific T-cell Redirecting Antibody for the Treatment of Multiple Myeloma
- Author
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Wei Hao, Mengshang Xiong, Yanjun Zhang, Fangzhen Lin, Xiangfei Yuan, Dong-Mei Fan, Yang Lu, Zhou Ye, Dong-sheng Xiong, Xiaomin Lei, Xiaolong Zhang, Yuanyuan Yang, Ruoqi Liu, and Jianxiang Wang
- Subjects
Cancer Research ,medicine.drug_class ,T cell ,CD3 ,T-Lymphocytes ,Immunology ,Monoclonal antibody ,Mice ,Antigen ,Antigens, CD ,Antibodies, Bispecific ,medicine ,Immunology and Allergy ,Animals ,Humans ,B-Cell Maturation Antigen ,Pharmacology ,biology ,Chemistry ,Antibodies, Monoclonal ,medicine.anatomical_structure ,Cell culture ,biology.protein ,Cancer research ,Hybridoma technology ,Antibody ,Clone (B-cell biology) ,Multiple Myeloma - 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.
- Published
- 2021