溶瘤腺病毒Ad657用于前列腺癌的全身病毒治疗。

IF 6.7
Oncolytic Virotherapy Pub Date : 2018-05-03 eCollection Date: 2018-01-01 DOI:10.2147/OV.S155946
Tien V Nguyen, Catherine M Crosby, Gregory J Heller, Zachary I Mendel, Mary E Barry, Michael A Barry
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引用次数: 11

摘要

背景:人C种腺病毒血清5型(Ad5)是典型的溶瘤腺病毒,已被用于绝大多数临床前和临床试验。虽然Ad5可能是稳健的,但C - Ad6具有较低的血清阳性率和副作用,并且作为一种针对许多肿瘤的全身治疗似乎比Ad5更有效。历史上,只有四种C人类腺病毒:血清型1、2、5和6。最近发现了一种新的C腺病毒,Ad57。Ad57与Ad6最相似,它们的衣壳蛋白几乎所有的变异都发生在它们的六邻体蛋白的高变区(HVRs)。大多数腺病毒中和抗体的目标是腺病毒上的hvr。因此,我们将Ad6中的六邻体HVRs替换为Ad57中的六邻体HVRs,创建了一种名为Ad657的新病毒,并探索了这种新型物种C平台作为溶瘤病毒的效用。方法:合成Ad57的HVR区,在细菌中通过同源重组取代Ad6的HVR区,形成新的病毒平台Ad657。在体外和体内比较单次静脉给药后复制活性Ad5、Ad6和Ad657对小鼠肝损伤和前列腺癌的溶瘤作用。结果:Ad5、Ad6和Ad657对人前列腺癌细胞具有相似的体外溶瘤活性。Ad5对小鼠的肝毒性最大,Ad657对小鼠的肝毒性最小。先前的数据表明,经静脉注射后,Ad6在小鼠模型中杀死远端皮下前列腺癌肿瘤的能力优于Ad5。鉴于此,将Ad657与Ad6基准病毒通过单次静脉注射到患有皮下人DU145前列腺癌的小鼠中进行比较。在这些条件下,Ad657首先感染肝脏,然后到达远处的肿瘤。Ad6和Ad657均能显著延缓肿瘤生长和延长生存期,其中Ad6的疗效更高。结论:这些数据表明Ad657可能作为局部或全身溶瘤病毒治疗前列腺癌的效用。这些数据也为溶瘤性C型ad的血清型转换奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer.

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer.

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer.

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer.

Background: Human species C adenovirus serotype 5 (Ad5) is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6. More recently a new species C adenovirus, Ad57, was identified. Ad57 is most similar to Ad6 with virtually all variation in their capsid proteins occurring in the hypervariable regions (HVRs) of their hexon proteins. Most adenovirus neutralizing antibodies target the HVRs on adenoviruses. This led us to replace the hexon HVRs in Ad6 with those from Ad57 to create a new virus called Ad657 and explore this novel species C platform's utility as an oncolytic virus.

Methods: The HVR region from Ad57 was synthesized and used to replace the Ad6 HVR region by homologous recombination in bacteria generating a new viral platform that we call Ad657. Replication-competent Ad5, Ad6, and Ad657 were compared in vitro and in vivo for liver damage and oncolytic efficacy against prostate cancers after single intravenous treatment in mice.

Results: Ad5, Ad6, and Ad657 had similar in vitro oncolytic activity against human prostate cancer cells. Ad5 provoked the highest level of liver toxicity after intravenous injection and Ad657 caused the least damage in mice. Previous data demonstrated that Ad6 was superior to Ad5 at killing distant subcutaneous prostate cancer tumors in mouse models after a intravenous injection. Given this, Ad657 was compared to the Ad6 benchmark virus by single intravenous injection into mice bearing subcutaneous human DU145 prostate cancers. Under these conditions, Ad657 first infected the liver and then reached distant tumors. Both Ad6 and Ad657 mediated significant delays in tumor growth and extension of survival with Ad6 mediating higher efficacy.

Conclusions: These data suggest that Ad657 may have utility as a local or systemic oncolytic virotherapy for prostate cancers. These data also lay the foundation for serotype-switching with oncolytic species C Ads.

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