文章：

新型免疫毒素HM1.24-ETA诱导多发性骨髓瘤细胞凋亡

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

原文发布日期：2014-06-13

DOI: 10.1038/bcj.2014.38

类型: Original Article

开放获取: 是

英文摘要：

Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). HM1.24-ETA′ inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA′ efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA′ was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors.

摘要翻译： 

尽管新的治疗方式不断涌现，多发性骨髓瘤（MM）中大量患者的临床结局仍有待改善。针对骨髓瘤患者的抗体靶向治疗可利用HM1.24抗原（CD317）——一种在恶性浆细胞上过度表达并能高效内化的表面分子。本文报道了一种新型免疫毒素HM1.24-ETA′，该毒素通过CD317特异性单链Fv抗体与铜绿假单胞菌外毒素A（ETA′）截短变体的基因融合构建而成。HM1.24-ETA′能有效抑制白细胞介素6（IL-6）依赖性与非依赖性骨髓瘤细胞系的增殖，半最大抑制浓度低至0.3 nM。靶细胞杀伤通过诱导凋亡实现，且在骨髓基质细胞共培养实验中不受影响。HM1.24-ETA′能有效触发新鲜分离/冻存的浆细胞白血病及多发性骨髓瘤患者细胞的凋亡，并在严重联合免疫缺陷（SCID）小鼠移植瘤模型中显示活性。重要的是，该免疫毒素对健康组织中的CD317阳性细胞（单核细胞、人脐静脉内皮细胞）无细胞毒性。这些结果表明CD317可能成为浆细胞肿瘤患者特异性高效免疫毒素治疗的有前景靶点结构。

原文链接：

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells