A Novel CD3/BCMA Bispecific T-cell Redirecting Antibody for the Treatment of Multiple Myeloma
A Novel CD3/BCMA Bispecific T-cell Redirecting Antibody for the Treatment of Multiple Myeloma
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一种用于治疗多发性骨髓瘤的新型 CD3/BCMA 双特异性 T 细胞重定向抗体
DOI：
10.1097/cji.0000000000000401
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发表时间：
2022-02-01
影响因子：
3.9
通讯作者：
Xiong, Dongsheng
中科院分区：
文献类型：
--
作者：
Xiong, Mengshang;Liu, Ruoqi;Xiong, Dongsheng
补充数字内容可在文本中找到。多发性骨髓瘤（MM）是一种b细胞恶性肿瘤，迫切需要新的治疗方法。通过针对肿瘤细胞的双特异性抗体重定向T细胞的活性是一种有效的方法。b细胞成熟抗原（BCMA）是一种高浆细胞选择性蛋白，因此是t细胞重定向治疗的理想治疗靶点。本研究的主要目的是通过生成BCMA特异性小鼠单克隆抗体来靶向BCMA，并构建分化3 (CD3)/BCMA定向串联抗体簇（Tandab）。总之，利用标准杂杂瘤技术，我们开发了一种新的BCMA特异性单克隆抗体（克隆69G8），该抗体特异性结合BCMA+细胞系和MM患者样本；而BCMA -细胞不被识别。通过双特异性抗体应用于T细胞，我们构建了同时靶向CD3和BCMA的Tandab (CD3/BCMA)，我们的研究表明，Tandab （CD3/BCMA）对CD3+细胞和BCMA+细胞都具有特异性结合能力。诱导BCMA+细胞系选择性、剂量依赖性裂解、T细胞活化、细胞因子释放和T细胞增殖；而BCMA -细胞不受影响。此外，我们证实Tandab活性与BCMA表达相关，在高BCMA表达的肿瘤细胞中观察到更高的效力。在体内，纯化的Tandab （CD3/BCMA）在皮下NCI-H929异种移植模型中显著抑制肿瘤生长。综上所述，这些结果表明，Tandab （CD3/BCMA）具有有效的选择性抗MM活性，是治疗MM的一种有前景的免疫疗法。
Supplemental Digital Content is available in the text. 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.