Hedley Susan J, Chen Jian, Mountz John D, Li Jing, Curiel David T, Korokhov Nikolay, Kovesdi Imre
VectorLogics, Inc., Birmingham, AL 35294, USA.
Cancer Immunol Immunother. 2006 Nov;55(11):1412-9. doi: 10.1007/s00262-006-0158-2. Epub 2006 Apr 13.
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, AdDelta24-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 AdDelta24S-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.
条件性复制腺病毒（CRAd）载体是一类新型载体，可作为病毒治疗剂用于替代癌症疗法。这些载体已在人体中建立了广泛的安全记录，并克服了非复制性腺病毒（Ad）载体的一些局限性。此外，这些载体的一个潜在问题，即实现肿瘤或组织选择性，已得到广泛关注。然而，限制这些候选药物疗效的两个混杂问题仍然存在。肿瘤组织上天然Ad受体的缺乏，以及由于人体中预先存在针对载体本身的中和抗体滴度而产生的宿主体液反应，在临床背景中已被凸显出来。特征明确的CRAd，即AdDelta24-RGD，其感染性增强，从而克服了柯萨奇病毒和腺病毒受体（CAR）的缺乏，并且这种药物已迅速朝着临床转化发展。然而，预计的宿主体液反应可能会限制感染性增强所带来的益处，因此需要一种策略来减弱针对该载体的免疫反应。基于这一警告，已开发出一种名为屏蔽的新策略，其中病毒粒子衣壳蛋白的基因改造将提供均匀屏蔽的Ad载体。将衣壳蛋白pIX鉴定为用于基因掺入屏蔽配体以保护Ad载体免受预先存在的中和抗体影响的理想位点，是屏蔽型CRAds开发中的一个重大进展。利用与pIX蛋白融合了单纯疱疹病毒胸苷激酶（HSV-TK）的Ad载体的初步数据表明，可以实现对中和抗体的屏蔽。目前正在研究各种蛋白质作为屏蔽分子的效用。创建感染性增强且经过屏蔽的Ad载体AdDelta24S-RGD，将为开发临床上和商业上可行的CRAds迈出下一步，这种CRAds可以多次给药，以在对抗人类癌症中发挥最大效力。
