Targeted and shielded adenovectors for cancer therapy
Targeted and shielded adenovectors for cancer therapy
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DOI：
10.1007/s00262-006-0158-2
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发表时间：
2006-11-01
影响因子：
5.8
通讯作者：
Kovesdi, Imre
中科院分区：
文献类型：
--
作者：
Hedley, Susan J.;Chen, Jian;Kovesdi, Imre
条件复制腺病毒（CRAd）载体是新型载体，可用作替代癌症疗法的病毒治疗剂。这些载体已经在人类中建立了广泛的安全记录，并克服了非复制腺病毒 (Ad) 载体的一些局限性。此外，这些载体的一个潜在问题，即肿瘤或组织选择性的实现，已得到广泛解决。然而，限制这些候选药物功效的两个令人困惑的问题仍然存在。肿瘤组织上天然 Ad 受体的缺乏，以及由于人体中预先存在的针对载体本身的中和抗体的滴度而引起的宿主体液反应，在临床背景下已得到强调。已充分表征的 CRAd Ad Delta 24-RGD 的感染性得到增强，从而克服了柯萨奇病毒和腺病毒受体 (CAR) 的缺乏，并且该药物已迅速向临床转化迈进。然而，感知到的宿主体液反应可能会限制感染性增强所带来的收益，因此需要一种削弱针对载体的免疫力的策略。基于这一警告，开发了一种称为屏蔽的新策略，其中病毒体衣壳蛋白的基因修饰将提供均匀屏蔽的 Ad 载体。将 pIX 衣壳蛋白鉴定为屏蔽配体基因掺入的理想场所，以隐藏 Ad 载体免受预先存在的中和抗体的影响，这是屏蔽 CRAd 开发的重大进展。利用与 pIX 蛋白融合的 HSV-TK 的 Ad 载体的初步数据表明，可以实现针对中和抗体的防护。目前正在解决各种蛋白质作为屏蔽分子的效用。 Ad Delta 24S-RGD 是一种感染性增强且屏蔽的 Ad 载体，它的创建将为临床和商业上可行的 CRAd 的开发提供下一步，这些 CRAd 可以多次给药，以在对抗人类癌症方面发挥最大效力。
Conditionally replicative adenovirus (CRAd) vectors are novel vectors with utility as virotherapy agents for alternative cancer therapies. These vectors have already established a broad safety record in humans and overcome some of the limitations of non-replicative adenovirus (Ad) vectors. In addition, one potential problem with these vectors, attainment of tumor or tissue selectivity has widely been addressed. However, two confounding problems limiting efficacy of these drug candidates remains. The paucity of the native Ad receptor on tumor tissues, and host humoral response due to pre-existing titers of neutralizing antibodies against the vector itself in humans have been highlighted in the clinical context. The well-characterized CRAd, Ad Delta 24-RGD, is infectivity enhanced, thus overcoming the lack of coxsackievirus and adenovirus receptor (CAR), and this agent is already rapidly progressing towards clinical translation. However, the perceived host humoral response potentially will limit gains seen from the infectivity enhancement and therefore a strategy to blunt immunity against the vector is required. On the basis of this caveat a novel strategy, termed shielding, has been developed in which the genetic modification of a virion capsid protein would provide uniformly shielded Ad vectors. The identification of the pIX capsid protein as an ideal locale for genetic incorporation of shielding ligands to conceal the Ad vector from pre-existing neutralizing antibodies is a major progression in the development of shielded CRAds. Preliminary data utilizing an Ad vector with HSV-TK fused to the pIX protein indicates that a shield against neutralizing antibodies can be achieved. The utility of various proteins as shielding molecules is currently being addressed. The creation of Ad Delta 24S-RGD, an infectivity enhanced and shielded Ad vector will provide the next step in the development of clinically and commercially feasible CRAds that can be dosed multiple times for maximum effectiveness in the fight against cancers in humans.