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腺病毒靶向口腔黏膜表面表达的抗原。

Adenovirus retargeting to surface expressed antigens on oral mucosa.

机构信息

Department of Otolaryngology/Head-Neck Surgery, Section Tumor Biology, VU University Medical Centre, Amsterdam, The Netherlands.

出版信息

J Gene Med. 2010 Apr;12(4):365-76. doi: 10.1002/jgm.1447.

Abstract

BACKGROUND

Head and neck squamous cell carcinomas develop in preneoplastic mucosal fields that can extend over several centimeters in diameter. Most of these fields are microscopically recognized as dysplasias. These fields are often not adequately treated and might cause local relapse. Previous investigations demonstrated that mouthwash therapy with oncolytic adenoviruses appears to be a good option for the treatment of these fields, although, at present, with limited efficacy.

METHODS

Immunohistochemistry on normal and preneoplastic mucosa was applied to determine the expression levels of the coxsackie adenoviral receptor (CAR) and a few surface antigens that might allow retargeting: Ly-6D, CD44v6 and K928. Monoclonal antibodies directed against these surface antigens were used for retargeting of adenoviruses in model experiments with organotypic cultures of mucosal epithelium. A bispecific single chain antibody was constructed against both the adenoviral knob and Ly-6D.

RESULTS

Immunohistochemical staining revealed that CAR is present only at a low level in the basal layers of the oral mucosa of both normal and dysplastic lesions. By contrast, Ly-6D, CD44v6 and K928 were abundantly expressed and Ly-6D even on the most superficial layers. Monoclonal antibodies against Ly-6D and CD44v6 were shown to enhance infection in an organotypic cell culture by one log. Based on these observations, we constructed a bispecific single chain antibody against Ly-6D and adenovirus fiber knob, and showed that this engineered molecule allows efficient CAR-independent infection.

CONCLUSIONS

Retargeting of oncolytic adenovirus to other surface molecules might improve the efficacy of virotherapy of preneoplastic fields in the oral mucosa.

摘要

背景

头颈部鳞状细胞癌发生于癌前黏膜病灶,其直径可超过几厘米。这些病灶大多在显微镜下被识别为发育不良。这些病灶往往不能得到充分治疗,可能导致局部复发。先前的研究表明,使用溶瘤腺病毒漱口水治疗这些病灶似乎是一种很好的选择,尽管目前疗效有限。

方法

对正常和癌前黏膜进行免疫组织化学染色,以确定柯萨奇腺病毒受体(CAR)和一些可能允许重新靶向的表面抗原的表达水平:Ly-6D、CD44v6 和 K928。针对这些表面抗原的单克隆抗体用于在黏膜上皮器官型培养的模型实验中对腺病毒进行重新靶向。针对腺病毒 knob 和 Ly-6D 构建了一种双特异性单链抗体。

结果

免疫组织化学染色显示,CAR 仅在正常和发育不良病变口腔黏膜的基底细胞层低水平表达。相比之下,Ly-6D、CD44v6 和 K928 表达丰富,甚至在最表层也有表达。针对 Ly-6D 和 CD44v6 的单克隆抗体被证明可以在器官型细胞培养中增强感染一个对数级。基于这些观察结果,我们构建了一种针对 Ly-6D 和腺病毒纤维 knob 的双特异性单链抗体,并表明该工程分子允许有效的 CAR 非依赖性感染。

结论

将溶瘤腺病毒重新靶向其他表面分子可能会提高口腔黏膜癌前病灶病毒治疗的疗效。

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