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首页> 外文期刊>Journal of immunotherapy >Targeted tumor therapy with a fusion protein of an antiangiogenic human recombinant scFv and yeast cytosine deaminase
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Targeted tumor therapy with a fusion protein of an antiangiogenic human recombinant scFv and yeast cytosine deaminase

机译：抗血管生成人重组scFv与酵母胞嘧啶脱氨酶融合蛋白的靶向肿瘤治疗

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In adults, endothelial cell division occurs only in wound healing, during menstruation, or in diseases such as wet age-related macular degeneration or development of benign or malignant tissues. Angiogenesis is one of the major requirements to supply the fast developing tumor tissue with oxygen and nutrients, and enables it to spread into other tissues far from its origin. We selected the extradomain B (ED-B), a splice variant of fibronectin, which is exclusively expressed in ovaries, uterus, during wound healing, and in tumor tissues, as a target for the development of an innovative antiangiogenic, prodrug-based targeted tumor therapy approach. We designed a fusion protein termed L19CDy-His, consisting of the antibody single chain fragment L19 for targeting ED-B and yeast cytosine deaminase for the conversion of 5-fluorocytosine into cytotoxic 5-fluorouracil. We purified high amounts of the fusion protein from Pichia pastoris that is stable, enzymatically active, and retains 75% of its activity after incubation with human plasma for up to 72 hours. The binding of L19CDy-His to ED-B was confirmed by an enzyme-linked immunosorbent assay and quantified by surface plasmon resonance spectroscopy determining a KD value of 81±7 nM. L19CDy-His successfully decreased cell survival of the murine ED-B-expressing teratocarcinoma cell line F9 upon addition of the prodrug 5-fluorocytosine. Our data demonstrate the suitability of targeting ED-B by L19CDy-His for effective prodrug-based tumor therapy.
机译：在成年人中，内皮细胞分裂仅发生在伤口愈合，月经期间或诸如湿性老年性黄斑变性或良性或恶性组织发育之类的疾病中。血管生成是向快速发展的肿瘤组织提供氧气和营养的主要要求之一，并使血管能够扩散到远离其起源的其他组织中。我们选择了额外域B（ED-B），这是纤连蛋白的剪接变体，其在卵巢，子宫，伤口愈合过程中以及在肿瘤组织中专门表达，作为开发创新的抗血管生成，基于前药的靶向药物的靶标肿瘤治疗方法。我们设计了一种融合蛋白，称为L19CDy-His，由用于靶向ED-B的抗体单链片段L19和用于将5-氟胞嘧啶转化为细胞毒性5-氟尿嘧啶的酵母胞嘧啶脱氨酶组成。我们从巴斯德毕赤酵母中纯化了大量稳定，具有酶促活性的融合蛋白，与人血浆孵育长达72小时后仍保留了其活性的75％。 L19CDy-His与ED-B的结合通过酶联免疫吸附测定法确认，并通过表面等离振子共振光谱法定量，确定KD值为81±7 nM。添加前药5-氟胞嘧啶后，L19CDy-His成功降低了表达鼠ED-B的畸胎癌细胞F9的细胞存活率。我们的数据证明了通过L19CDy-His靶向ED-B进行基于前药的有效肿瘤治疗的适用性。

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