Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins.
Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins.
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DOI：
10.1038/cddis.2010.45
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发表时间：
2010-08-26
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
为了提高肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的肿瘤选择性，设计了一种突变体，将三个TRAIL前体表达为一条单链多肽链(ScTRAIL)。通过与识别ErbB2胞外区的单链抗体片段(ScFv)的基因融合，我们进一步赋予scTRAIL肿瘤靶向性。我们比较了scFv-scTRAIL和非靶向scTRAIL对肿瘤的靶向性和诱导细胞凋亡的作用。重要的是，肿瘤抗原靶向的scTRAIL融合蛋白在体外显示出更高的凋亡活性，其主要作用是通过TRAIL-R2信号转导。药代动力学研究表明，与scTRAIL相比，靶向scTRAIL融合蛋白的血浆半衰期延长。在具有异种移植的Colo205细胞的小鼠肿瘤模型中的体内研究证实，在局部和全身应用方案下，与非靶向scTRAIL相比，ErbB2特异性scTRAIL融合蛋白的反应更好。总之，体外和体内数据证明了肿瘤靶向scFv-scTRAIL分子具有更高的治疗活性的概念。此外，我们预计，通过靶向scTRAIL，潜在的副作用应降至最低。我们认为，单链TRAIL单链抗体介导的肿瘤靶向是一种有希望的策略，可以提高TRAIL的抗肿瘤作用，并将对正常组织的潜在有害作用降至最低。
In an attempt to improve TRAIL's (tumor necrosis factor-related apoptosis-inducing ligand) tumor selective activity a variant was designed, in which the three TRAIL protomers are expressed as a single polypeptide chain (scTRAIL). By genetic fusion with a single-chain antibody fragment (scFv) recognizing the extracellular domain of ErbB2, we further equipped scTRAIL with tumor-targeting properties. We studied tumor targeting and apoptosis induction of scFv–scTRAIL in comparison with non-targeted scTRAIL. Importantly, the tumor antigen-targeted scTRAIL fusion protein showed higher apoptotic activity in vitro, with a predominant action by TRAIL-R2 signaling. Pharmacokinetic studies revealed increased plasma half-life of the targeted scTRAIL fusion protein compared with scTRAIL. In vivo studies in a mouse tumor model with xenotransplanted Colo205 cells confirmed greater response to the ErbB2-specific scTRAIL fusion protein compared with non-targeted scTRAIL both under local and systemic application regimen. Together, in vitro and in vivo data give proof of concept of higher therapeutic activity of tumor-targeted scFv–scTRAIL molecules. Further, we envisage that through targeting of scTRAIL, potential side effects should be minimized. We propose that scFv-mediated tumor targeting of single-chain TRAIL represents a promising strategy to improve TRAIL's antitumoral action and to minimize potential unwanted actions on normal tissues.
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APO2L/TRAIL对SCID小鼠中异种移植物的胰腺腺癌患者胰腺腺癌的抗肿瘤作用。
影响因子：
7.4
作者：
Hylander, BL;Pitoniak, R;Penetrante, RB;Gibbs, JF;Oktay, D;Cheng, JR;Repasky, EA
通讯作者：
Repasky, EA
DOI：
10.1007/400_2008_22
发表时间：
2009-01-01
期刊：
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影响因子：
--
作者：
Gerspach, Jeannette;Wajant, Harald;Pfizenmaier, Klaus
通讯作者：
Pfizenmaier, Klaus
影响因子：
11.2
作者：
Bremer, E;Samplonius, DF;Helfrich, W
通讯作者：
Helfrich, W
影响因子：
6.4
作者：
Bremer, E;Kuulen, J;Helfrich, W
通讯作者：
Helfrich, W
影响因子：
7.5
作者：
Hynes, Nancy E.;MacDonald, Gwen
通讯作者：
MacDonald, Gwen