Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.
Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.
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DOI：
10.1038/ncomms7536
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发表时间：
2015-03-11
影响因子：
16.6
通讯作者：
Ho, Mitchell
中科院分区：
文献类型：
--
作者：
Gao, Wei;Tang, Zhewei;Zhang, Yi-Fan;Feng, Mingqian;Qian, Min;Dimitrov, Dimiter S.;Ho, Mitchell
磷脂酰肌醇蛋白聚糖-3（Glypican-3）是一种与肝癌中Wnt相关的细胞表面糖蛋白。我们开发了两种针对磷脂酰肌醇蛋白聚糖-3的抗体，HN 3和YP 7。第一抗体识别功能性表位并抑制Wnt信号传导，而第二抗体识别C末端表位但不抑制Wnt信号传导。两者都与假单胞菌外毒素A（PE 38）的片段融合以产生免疫毒素。有趣的是，与YP 7（YP 7-PE 38）相比，基于HN 3的免疫毒素（HN 3-PE 38）在体外和体内都具有上级抗肿瘤活性。单独静脉注射HN 3-PE 38或与化疗联合静脉注射可诱导小鼠Hep 3B和HepG 2肝脏肿瘤异种移植物消退。这项研究确立了磷脂酰肌醇蛋白聚糖-3作为一个有前途的候选免疫毒素为基础的肝癌治疗。我们的研究结果表明免疫毒素通过双重机制诱导肿瘤消退：通过抗体灭活癌症信号传导和通过毒素抑制蛋白质合成。
Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first antibody recognizes a functional epitope and inhibits Wnt signaling, whereas the second antibody recognizes a C-terminal epitope but does not inhibit Wnt signaling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has superior anti-tumor activity as compared to YP7 (YP7-PE38) both in vitro and in vivo. Intravenous administration of HN3-PE38 alone, or in combination with chemotherapy, induces regression of Hep3B and HepG2 liver tumor xenografts in mice. This study establishes glypican-3 as a promising candidate for immunotoxin-based liver cancer therapy. Our results demonstrate immunotoxin-induced tumor regression via dual mechanisms: inactivation of cancer signaling via the antibody and inhibition of protein synthesis via the toxin.
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影响因子：
6.4
作者：
Ho, Mitchell;Feng, Mingqian;Fisher, Robert J.;Rader, Christoph;Pastan, Ira
通讯作者：
Pastan, Ira
人类抗体对Wnt信号的失活，该抗体识别肝癌治疗的Glypican-3硫酸盐链。
影响因子：
13.5
作者：
Gao, Wei;Kim, Heungnam;Feng, Mingqian;Phung, Yen;Xavier, Charles P.;Rubin, Jeffrey S.;Ho, Mitchell
通讯作者：
Ho, Mitchell
影响因子：
4
作者：
Capurro, Mariana;Martin, Tonya;Filmus, Jorge
通讯作者：
Filmus, Jorge
DOI：
10.1111/j.1872-034x.2012.01113.x
发表时间：
2013-02
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
--
作者：
Gauthier A;Ho M
通讯作者：
Ho M
影响因子：
8.4
作者：
Ho, Mitchell;Kim, Heungnam
通讯作者：
Kim, Heungnam