Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors
Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors
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DOI：
10.1038/sj.gt.3302103
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发表时间：
2003-11-01
期刊：
影响因子：
5.1
通讯作者：
Gerritsen, WR
中科院分区：
文献类型：
--
作者：
van Beusechem, VW;Mastenbroek, DCJ;Gerritsen, WR
连续复制型腺病毒（CRAd）是用于抗癌病毒治疗方法的潜在有用的药剂。然而，在许多原代肿瘤细胞上缺乏柯萨奇病毒和腺病毒受体（CAR）表达限制了CRAd的溶瘤效力。这使得靶向的概念，即通过CAR非依赖性进入途径重定向感染，与CRAd发展相关。双特异性衔接子分子构成用于腺病毒靶向的高度通用的手段。在这里，我们构建了一个CRAd与Delta 24 E1 A突变，产生针对腺病毒纤维球和表皮生长因子受体（EGFR）的双特异性单链抗体。这种EGFR靶向的CRAd在CAR缺陷型癌细胞上表现出增加的感染效率和溶瘤复制，并在体外CAR缺陷型3-D肿瘤球体中增强了侧向扩散。当与其具有天然向性的亲本对照相比时，新CRAd对CAR阳性癌细胞表现出相似的细胞毒性，但对CAR缺陷型EGFR阳性癌细胞的溶瘤效力增强高达1000倍。此外，EGFR靶向的CRAd杀死了对亲本对照病毒无效的原发性人CAR缺陷型脑肿瘤标本。因此，我们得出结论，表达双特异性靶向衔接子分子的CRAd是有希望的癌症治疗剂。它们的使用可能导致癌组织中增强的溶瘤复制，从而更有效地使肿瘤消退。
Conditionally replicative adenoviruses (CRAds) are potentially useful agents for anticancer virotherapy approaches. However, lack of coxsackievirus and adenovirus receptor ( CAR) expression on many primary tumor cells limits the oncolytic potency of CRAds. This makes the concept of targeting, that is, redirecting infection via CAR-independent entry pathways, relevant for CRAd development. Bispecific adapter molecules constitute highly versatile means for adenovirus targeting. Here, we constructed a CRAd with the Delta24 E1A mutation that produces a bispecific single-chain antibody directed towards the adenovirus fiber knob and the epidermal growth factor receptor ( EGFR). This EGFR-targeted CRAd exhibited increased infection efficiency and oncolytic replication on CAR-deficient cancer cells and augmented lateral spread in CAR-deficient 3-D tumor spheroids in vitro. When compared to its parent control with native tropism, the new CRAd exhibited similar cytotoxicity on CAR-positive cancer cells, but up to 1000-fold enhanced oncolytic potency on CAR-deficient, EGFR-positive cancer cells. In addition, EGFR-targeted CRAd killed primary human CAR-deficient brain tumor specimens that were refractory to the parent control virus. We conclude, therefore, that CRAds expressing bispecific targeting adapter molecules are promising agents for cancer treatment. Their use is likely to result in enhanced oncolytic replication in cancerous tissues and thus in more effective tumor regression.