A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo
A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo
复制标题
DOI：
10.1038/leu.2016.388
复制
发表时间：
2017-08-01
期刊：
影响因子：
11.4
通讯作者：
Friedrich, M.
中科院分区：
文献类型：
--
作者：
Hipp, S.;Tai, Y-T;Friedrich, M.
B细胞成熟抗原（BCMA）是一种高度浆细胞选择性蛋白，在多发性骨髓瘤（MM）患者的恶性浆细胞上表达，因此是T细胞重定向治疗的理想靶点。我们开发了一种靶向BCMA和CD 3 β的双特异性T细胞增殖剂（BiTE）（BI 836909），并研究了其对MM的治疗影响。BI 836909诱导BCMA阳性MM细胞的选择性裂解、T细胞活化、细胞因子释放和T细胞增殖;而BCMA阴性细胞不受影响。BI 836909的活性不受骨髓基质细胞、可溶性BCMA或增殖诱导配体（APRIL）的影响。在离体试验中，BI 836909在新诊断和复发/难治性患者样本中诱导了强效自体MM细胞溶解。在小鼠异种移植研究中，BI 836909在皮下NCI-H929异种移植模型中诱导肿瘤细胞耗竭，并延长原位L-363异种移植模型中的存活期。在食蟹猴研究中，BI 836909给药导致骨髓中BCMA阳性浆细胞耗竭。综上所述，这些结果表明BI 836909是一种选择性耗竭BCMA阳性MM细胞的高效和有效方法，代表了一种治疗MM的新型免疫抑制剂。
B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3 epsilon (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.