Bian Huijie, Wilden Holger, Fournier Philippe, Peeters Ben, Schirrmacher Volker
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Int J Oncol. 2006 Dec;29(6):1359-69.
The aim of the study was: i) to specifically target tumor tissue by Newcastle disease virus (NDV) with oncolytic properties, ii) to improve the delivery system for systemic application of NDV via a bispecific adapter protein and iii) to investigate anti-tumor activity and side-effects. We selected two oncolytic virus strains, one native and the other recombinant, which showed multicyclic replication patterns in tumor cells. In order to reduce normal cell binding, they were modified by preincubation with a recombinant bispecific protein which blocks the viral native cell binding site and introduces a new binding site for a tumor-associated target (in this study, the interleukin-2-receptor, IL-2R). After intravenous transfer to mice, uptake of modified NDV in liver, spleen, kidney and lung was greatly reduced in comparison to unmodified NDV as determined by RRT-PCR of viral M gene copies. In IL-2R+ tumor bearing mice, the same assay revealed a high replication efficiency of the modified virus in the tumor tissue. Tumor therapy experiments showed that the side-effects induced by systemic application were greatly reduced by the adapter protein and that the anti-tumor effects were mostly undiminished. The demonstration of significant systemic anti-tumor activity of this viral vector suggests potential for augmentation by inclusion of one or more therapeutic genes.
i）利用具有溶瘤特性的新城疫病毒（NDV）特异性靶向肿瘤组织；ii）通过双特异性衔接蛋白改善NDV全身应用的递送系统；iii）研究抗肿瘤活性和副作用。我们选择了两种溶瘤病毒株，一种是天然株，另一种是重组株，它们在肿瘤细胞中呈现多轮复制模式。为了减少与正常细胞的结合，通过与重组双特异性蛋白预孵育对它们进行修饰，该蛋白可阻断病毒天然细胞结合位点，并引入一个针对肿瘤相关靶点（在本研究中为白细胞介素-2受体，IL-2R）的新结合位点。静脉注射到小鼠体内后，通过对病毒M基因拷贝进行RRT-PCR检测发现，与未修饰的NDV相比，修饰后的NDV在肝脏、脾脏、肾脏和肺中的摄取量大大降低。在携带IL-2R+肿瘤的小鼠中，同样的检测显示修饰后的病毒在肿瘤组织中具有高复制效率。肿瘤治疗实验表明，衔接蛋白大大降低了全身应用所诱导的副作用，且抗肿瘤效果大多未减弱。这种病毒载体显著的全身抗肿瘤活性表明，通过纳入一个或多个治疗基因有增强疗效的潜力。
