Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7
Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7
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DOI：
10.1158/0008-5472.can-04-2756
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Helfrich, W
中科院分区：
文献类型：
--
作者：
Bremer, E;Samplonius, DF;Helfrich, W
目前人类T细胞白血病和淋巴瘤的治疗主要限于传统的细胞毒疗法，且治疗反应有限且发病率显着。因此，迫切需要更有效且具有良好毒性的白血病特异性疗法。在这里，我们报告了一种新型治疗性融合蛋白 scFvCD7:sTRAIL 的构建，该蛋白旨在诱导人类 T 细胞肿瘤中靶抗原限制性细胞凋亡。 ScFvCD7:sTRAIL 由诱导死亡的肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 组成，该配体与 T 细胞表面抗原 CD7 特异性的 scFv 抗体片段基因连接。 scFvCD7:sTRAIL 处理可在一系列恶性 T 细胞系中诱导有效的 CD7 限制性细胞凋亡，而正常静息白细胞、活化 T 细胞和血管内皮细胞（人脐静脉内皮细胞）未显示出可检测到的细胞凋亡。 scFvCD7:sTRAIL的凋亡诱导活性强于免疫毒素scFvCD7:ETA。在 CD7 阳性和 CD7 阴性肿瘤细胞的混合培养实验中，scFvCD7:sTRAIL 诱导 CD7 阴性肿瘤细胞的非常有效的旁观者凋亡。对来自急性 T 急性淋巴细胞白血病患者的新鲜血细胞进行体外处理，导致恶性 T 细胞显着凋亡，而长春新碱可显着增强这种凋亡。总之，scFvCD7:sTRAIL是一种新型重组蛋白，可限制人白血病T细胞凋亡，对正常人血液和内皮细胞毒性低。
Current treatment of human T-cell leukemia and lymphoma is predominantly limited to conventional cytotoxic therapy and is associated with limited therapeutic response and significant morbidity. Therefore, more potent and leukemia-specific therapies with favorable toxicity profiles are urgently needed. Here, we report on the construction of a novel therapeutic fusion protein, scFvCD7:sTRAIL, designed to induce target antigen-restricted apoptosis in human T-cell tumors. ScFvCD7:sTRAIL consists of the death-inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genetically linked to an scFv antibody fragment specific for the T-cell surface antigen CD7. Treatment with scFvCD7:sTRAIL induced potent CD7-restricted apoptosis in a series of malignant T-cell lines, whereas normal resting leukocytes, activated T cells, and vascular endothelial cells (human umbilical vein endothelial cells) showed no detectable apoptosis. The apoptosis-inducing activity of scFvCD7: sTRAIL was stronger than that of the immunotoxin scFvCD7:ETA. In mixed culture experiments with CD7-positive and CD7-negative tumor cells, scFvCD7:sTRAIL induced very potent bystander apoptosis of CD7-negative tumor cells. In vitro treatment of blood cells freshly derived from T-acute lymphoblastic leukemia patients resulted in marked apoptosis of the malignant T cells that was strongly augmented by vincristin. In conclusion, scFvCD7:sTRAIL is a novel recombinant protein causing restricted apoptosis in human leukemic T cells with low toxicity for normal human blood and endothelial cells.