Construction and functional characterization of scFv(14E1)-ETA - a novel, highly potent antibody-toxin specific for the EGF receptor.
Construction and functional characterization of scFv(14E1)-ETA - a novel, highly potent antibody-toxin specific for the EGF receptor.
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DOI：
10.1038/bjc.1997.270
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发表时间：
1997
影响因子：
8.8
通讯作者：
Wels, W
中科院分区：
文献类型：
--
作者：
Schmidt, M;Vakalopoulou, E;Schneider, DW;Wels, W
表皮生长因子（EGF）受体过表达是许多上皮来源的人类肿瘤的特征，并与患者预后不良相关。它参与恶性过程，其在肿瘤中的表达升高及其在肿瘤细胞表面的可及性使EGF受体成为定向肿瘤治疗的潜在靶点。我们先前已经表征了重组抗体-假单胞菌外毒素A融合蛋白，scFv（225）-ETA，其对EGF受体过表达的肿瘤细胞显示出抗肿瘤活性，但在肿瘤细胞杀伤方面不如TGF-α-ETA有效，所述重组毒素使用天然EGF受体配体转化生长因子α（TGF-α）作为靶向结构域。在这里，我们描述了一种新的单链抗体毒素，scFv（14 E1）-ETA，独立分离的EGF受体特异性单克隆抗体14 E1的基础上，在体外的建设和功能特性。ScFv（14 E1）-ETA结合与scFv（225）-ETA非常相似或相同的EGF受体表位，亲和力比后者高9倍，并且对EGF受体过表达的肿瘤细胞显示出高10倍以上的细胞毒活性。ScFv（14 E1）-ETA细胞杀伤活性与TGF-α-ETA对受体过表达细胞的杀伤活性非常相似，但与后者相反，scFv（14 E1）-ETA的选择性更高，并且对表达中等EGF受体水平的细胞不显示显著的细胞毒性活性。
Epidermal growth factor (EGF) receptor-overexpression is characteristic of many human tumours of epithelial origin and has been correlated with unfavourable patient prognosis. Its involvement in the malignant process, its elevated expression in tumours and its accessibility on the tumour cell surface make the EGF receptor a potential target for directed tumour therapy. We have previously characterized a recombinant antibody - Pseudomonas exotoxin A fusion protein, scFv(225)-ETA, which displayes antitumoral activity towards EGF receptor-overexpressing tumour cells but is less potent in tumour cell killing than TGF-alpha-ETA, a recombinant toxin using the natural EGF receptor ligand transforming growth factor alpha (TGF-alpha) as a targeting domain. Here, we describe the construction and functional characterization in vitro of a novel single-chain antibody-toxin, scFv(14E1)-ETA, based on the independently isolated EGF receptor-specific monoclonal antibody 14E1. ScFv(14E1)-ETA binds to an EGF receptor epitope that is very similar or identical to that of scFv(225)-ETA with nine times higher affinity than the latter and displays more than tenfold higher cytotoxic activity on EGF receptor-overexpressing tumour cells. ScFv(14E1)-ETA cell killing activity was very similar to that of TGF-alpha-ETA on receptor-overexpressing cells but, in contrast to the latter, scFv(14E1)-ETA was much more selective and did not display significant cytotoxic activity on cells expressing moderate EGF receptor levels.
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影响因子：
6.7
作者：
GULLICK, WJ
通讯作者：
GULLICK, WJ
影响因子：
--
作者：
ENNIS, BW;VALVERIUS, EM;DICKSON, RB
通讯作者：
DICKSON, RB
影响因子：
56.9
作者：
WEBER, W;GILL, GN;SPIESS, J
通讯作者：
SPIESS, J
影响因子：
6.4
作者：
WELS, W;BEERLI, R;HYNES, NE
通讯作者：
HYNES, NE
DOI：
10.1073/pnas.84.13.4538
发表时间：
1987-07-01
影响因子：
11.1
作者：
CHAUDHARY, VK;FITZGERALD, DJ;PASTAN, I
通讯作者：
PASTAN, I