An EGF receptor-targeting amphinase recombinant protein mediates anti-tumor activity in vitro and in vivo
An EGF receptor-targeting amphinase recombinant protein mediates anti-tumor activity in vitro and in vivo
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DOI：
10.1093/abbs/gmy016
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发表时间：
2018-04-01
影响因子：
3.7
通讯作者：
Fei，Jian
中科院分区：
文献类型：
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作者：
Shen，Ruling;Ye，Danrong;Fei，Jian
利用与肿瘤靶向分子连接的细胞毒性蛋白作为抗肿瘤药物是一种很有前途的方法。然而，大多数来自细菌或植物的细胞毒素具有固有的问题，例如大分子量，并且它们引发强烈的免疫系统反应，这导致药物失效和严重的副作用。两栖酶（Amph）是一种低分子量的核糖核酸酶，存在于北方豹蛙卵母细胞中。它在体外对肿瘤细胞有较强的杀伤作用，在体内具有较弱的免疫原性，是一种很有希望的靶向药物。与表皮生长因子受体（EGFR）结合的转化生长因子-α（TGF-α）被用作治疗EGFR高表达肿瘤的靶向分子。本研究分别从大肠杆菌中表达并纯化了重组两栖酶及其TGF-α融合蛋白（AGT）。AGT对EGFR高表达肿瘤细胞株的体外细胞毒作用更强，体内抗肿瘤作用更强。该融合蛋白还表现出不寻常的热稳定性，低体内免疫原性，和副作用。我们的研究结果为开发新型、高效、低免疫原性的抗肿瘤靶向生物制剂提供了一个新的切入点。
Utilizing cytotoxic proteins linked to tumor targeting molecules as anti-tumor drugs is a promising approach. However, most cytotoxins derived from bacteria or plants have inherent problems such as large molecular weights and they trigger a strong immune system reaction, which leads to drug failure and serious side effects. Amphinase (Amph) is a ribonuclease with a low molecular weight that is found in northern leopard frog oocytes. It has strong cytotoxicity against tumor cell linesin vitroand weak immunogenicityin vivo, and is a promising candidate in the development of targeted drugs. Transforming growth factor-α (TGF-α) that binds to the epidermal growth factor receptor (EGFR) is being used as a targeting molecule for the treatment of EGFR high-expressing tumors. In this study, we expressed and purified a recombinant amphinase and its TGF-α fusion protein (AGT) separately fromEscherichia coli. AGT exhibited more significant cytotoxicityin vitroon EGFR high-expressing tumor cell lines, and stronger anti-tumor effectsin vivo. This fusion protein also exhibited unusual thermostability, lowin vivoimmunogenicity, and side effects. Our results provide a new entry point for the development of novel, highly efficient anti-tumor targeting biological agents with low immunogenicity.