Bremer Edwin, Samplonius Douwe F, Peipp Matthias, van Genne Linda, Kroesen Bart-Jan, Fey Georg H, Gramatzki Martin, de Leij Lou F M H, Helfrich Wijnand
Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Section Medical Biology, University Hospital Groningen, Groningen University Institute for Drug Exploration, 9713 GZ Groningen, the Netherlands.
Cancer Res. 2005 Apr 15;65(8):3380-8. doi: 10.1158/0008-5472.CAN-04-2756.
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.
目前人类T细胞白血病和淋巴瘤的治疗主要局限于传统的细胞毒性疗法，治疗反应有限且发病率高。因此，迫切需要更有效且具有良好毒性特征的白血病特异性疗法。在此，我们报告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细胞肿瘤中靶抗原受限的细胞凋亡。scFvCD7:sTRAIL由与T细胞表面抗原CD7特异性的单链抗体片段基因连接的死亡诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）组成。用scFvCD7:sTRAIL处理可在一系列恶性T细胞系中诱导有效的CD7受限细胞凋亡，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阴性肿瘤细胞产生非常有效的旁观者细胞凋亡。对T急性淋巴细胞白血病患者新鲜来源的血细胞进行体外处理导致恶性T细胞明显凋亡，长春新碱可显著增强这种凋亡。总之，scFvCD7:sTRAIL是一种新型重组蛋白，可在人类白血病T细胞中诱导受限凋亡，对正常人类血液和内皮细胞毒性低。
