Differential activation of TRAIL-R1 and-2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative
Differential activation of TRAIL-R1 and-2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative
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DOI：
10.1038/sj.onc.1204558
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发表时间：
2001-07-05
期刊：
影响因子：
8
通讯作者：
Pfizenmaier, K
中科院分区：
文献类型：
--
作者：
Wajant, H;Moosmayer, D;Pfizenmaier, K
TNF相关凋亡诱导配体(TRAIL)是肿瘤坏死因子(TNF)配体家族的典型成员，其表达为II型膜蛋白(memTRAIL)并通过含有死亡结构域的受体TRAIL-R1和-2发出凋亡信号。TRAIL的可溶性重组衍生物(sTRAIL)被认为是新型肿瘤治疗剂，因为它们在多种人类肿瘤中而非正常细胞中具有选择性凋亡诱导活性。使用 TRAIL-R1 和 TRAIL-R2 特异性抗体的拮抗性抗原结合片段 (Fab) 制剂，我们在这项研究中证明 TRAIL-R1 可以被可溶性和膜结合形式的配体激活，而 TRAIL-R2 只能被 memTRAIL 或由抗体二次交联的可溶性 TRAIL 激活。此外，我们表明，通过与抗体衍生物进行基因融合，sTRAIL 的受限信号能力可以很容易地转化为完全信号能力的 memTRAIL 样分子，即 TRAIL-R2 刺激配体，从而允许融合蛋白依赖于抗原“固定”到细胞表面。我们得出的结论是，抗体靶向依赖性激活可用于设计源自 TNF 家族配体的选择性治疗剂，这些配体在可溶形式下具有生物活性。
TNF-related apoptosis-inducing ligand (TRAIL) is a typical member of the tumor necrosis factor (TNF) ligand family that is expressed as a type Il membrane protein (memTRAIL) and signals apoptosis via the death domain-containing receptors TRAIL-R1 and -2, Soluble recombinant derivatives of TRAIL (sTRAIL) are considered as novel tumors therapeutics because of their selective apoptosis inducing activity in a variety of human tumors but not in normal cells. Using antagonistic antigen-binding fragment (Fab) preparations of TRAIL-R1- and TRAIL-R2-specific antibodies, we demonstrate in this study that TRAIL-R1 becomes activated by both the soluble and the membrane-bound form of the ligand, whereas TRAIL-R2 becomes only activated by memTRAIL or soluble TRAIL secondarily cross-linked by antibodies. Furthermore, we show that the restricted signal capacity of sTRAIL can be readily converted into a fully signal competent memTRAIL-like molecule, i.e. a TRAIL-R2 stimulating ligand, by genetic fusion to an antibody derivative that allows antigen-dependent 'immobilization' of the fusion protein to cell surfaces. We conclude that antibody targeting-dependent activation can be used to design selective therapeutics derived of those ligands of the TNF family that are biologically inactive in their soluble form.