Design and Selection of Toca 511 for Clinical Use: Modified Retroviral Replicating Vector With Improved Stability and Gene Expression
Design and Selection of Toca 511 for Clinical Use: Modified Retroviral Replicating Vector With Improved Stability and Gene Expression
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DOI：
10.1038/mt.2012.83
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发表时间：
2012-09-01
影响因子：
12.4
通讯作者：
Jolly, Douglas J.
中科院分区：
文献类型：
--
作者：
Perez, Omar D.;Logg, Christopher R.;Jolly, Douglas J.
逆转录病毒复制载体（RRV）是作为抗癌剂的溶瘤复制病毒的非裂解性替代物，对分裂细胞和具有先天免疫和干扰素应答性缺陷的细胞都具有选择性。肿瘤细胞符合这两种描述。先前的出版物已经描述了基于嗜酸性鼠白血病病毒（MLV）的原型，其编码酵母胞嘧啶脱氨酶（CD），所述酵母胞嘧啶脱氨酶在感染的肿瘤中将前药5-氟胞嘧啶（5-FC）转化为有效的抗癌药物5-氟尿嘧啶（5-FU）。我们在这里报告的选择一个领先的临床候选人的基础上的一般设计目标，以优化病毒的遗传稳定性和CD活性所产生的转基因。检测载体的滴度、遗传稳定性、CD蛋白和酶活性、赋予对5-FC敏感性的能力以及初步的体内抗肿瘤活性和稳定性。一种编码优化CD的载体Toca 511（又名T5.0002）在感染细胞中的比活性比原型RRV感染增加3倍，并显示出显著更高的遗传稳定性。动物试验表明，Toca 511在人肿瘤异种移植物中稳定复制，并且在5-FC给药后，导致此类异种移植物完全消退。Toca 511（vocimagene amiretrorepvec）已进入临床前和临床试验。
Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic replicating viruses as anticancer agents, being selective both for dividing cells and for cells that have defects in innate immunity and interferon responsiveness. Tumor cells fit both these descriptions. Previous publications have described a prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report here the selection of one lead clinical candidate based on a general design goal to optimize the genetic stability of the virus and the CD activity produced by the delivered transgene. Vectors were tested for titer, genetic stability, CD protein and enzyme activity, ability to confer susceptibility to 5-FC, and preliminary in vivo anti-tumor activity and stability. One vector, Toca 511, (aka T5.0002) encoding an optimized CD, shows a threefold increased specific activity in infected cells over infection with the prototype RRV and shows markedly higher genetic stability. Animal testing demonstrated that Toca 511 replicates stably in human tumor xenografts and, after 5-FC administration, causes complete regression of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward to preclinical and clinical trials.