Albumin-binding adenoviruses circumvent pre-existing neutralizing antibodies upon systemic delivery
Albumin-binding adenoviruses circumvent pre-existing neutralizing antibodies upon systemic delivery
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DOI：
10.1016/j.jconrel.2016.07.004
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发表时间：
2016-09-10
影响因子：
10.8
通讯作者：
Alemany, Ramon
中科院分区：
文献类型：
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作者：
Alfonso Rojas, Luis;Condezo, Gabriela N.;Alemany, Ramon
重组腺病毒被用作疫苗、基因治疗载体和溶瘤病毒。然而，这种疗法的疗效受到预先存在的中和抗体(NAB)的限制，特别是当病毒被系统地给予以获得更广泛的生物分布或达到多个转移时。为了保护腺病毒抵抗NABS，我们在主要的腺病毒衣壳蛋白六邻体中插入了白蛋白结合域(ABD)。这个结构域与血清白蛋白结合，在全身给药时保护病毒。Abd修饰的腺病毒结合人和小鼠白蛋白，并在Nab存在的情况下保持感染性和复制能力。在预先免疫的小鼠中，未修饰的病毒被完全中和，而Abd修饰的病毒保留了转导靶器官、诱导肿瘤分解或对表达的蛋白质产生免疫反应的能力。我们的结果表明，白蛋白包裹的病毒衣壳是一种有效的方法来逃避预先存在的NAB。这一策略在用腺病毒进行基因治疗、癌症病毒治疗和疫苗接种方面具有翻译相关性。(C)2016爱思唯尔B.V.保留所有权利。
Recombinant adenoviruses are used as vaccines, gene therapy vectors, and oncolytic viruses. However, the efficacy of such therapies is limited by pre-existing neutralizing antibodies (NAbs), especially when the virus is administered systemically for a wider biodistribution or to reach multiple metastases. To protect adenovirus against NAbs we inserted an albumin-binding domain (ABD) in the main adenovirus capsid protein, the hexon. This domain binds serum albumin to shield the virus upon systemic administration. The ABD-modified adenoviruses bind human and mouse albumin and maintain the infectivity and replication capacity in presence of NAbs. In pre-immunized mice non-modified viruses are completely neutralized, whereas ABD-modified viruses preserve the ability to transduce target organs, induce oncolysis, or generate immune responses to expressed proteins. Our results indicate that albumin coating of the virus capsid represents an effective approach to evade pre-existing NAbs. This strategy has translational relevance in the use of adenovirus for gene therapy, cancer virotherapy, and vaccination. (C) 2016 Elsevier B.V. All rights reserved.