Significant Growth Inhibition by a Bispecific Affibody Targeting Oncoprotein E7 in both HPV16 and 18 Positive Cervical Cancer in vitro and in vivo.
Significant Growth Inhibition by a Bispecific Affibody Targeting Oncoprotein E7 in both HPV16 and 18 Positive Cervical Cancer in vitro and in vivo.
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DOI：
10.1016/j.ejps.2022.106156
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Xiaochun Tan;Jiani Yang;Jie Jiang;Wenhuan Wang;Jiahuan Ren;Qijia Li;Zixin Xie;Xinan Chen;Lifang Zhang;Wenshu Li
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文献类型：
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作者：
Xiaochun Tan;Jiani Yang;Jie Jiang;Wenhuan Wang;Jiahuan Ren;Qijia Li;Zixin Xie;Xinan Chen;Lifang Zhang;Wenshu Li
HPV 16和18高危型感染占宫颈癌发病率的80%以上，但目前尚无针对HPV的靶向药物用于宫颈癌治疗。我们之前的研究构建了针对HPV16和18早期抗原7（E7，负责受感染细胞恶性转化）的双特异性亲和体Z16-18。在本研究中，我们制备了Z16-18原核表达系统，并通过将细胞周期阻滞在G0/G1期，证实其对SiHa（HPV16阳性）和HeLa（HPV18阳性）宫颈癌细胞具有显着的生长抑制作用。 Z16-18在SiHa和HeLa上的IC50值接近。 Z16-18可以特异性靶向SiHa和HeLa中的E7，并且对SiHa或HeLa来源的肿瘤组织表现出显着的靶向富集，从而抑制体内肿瘤发生和肿瘤生长。此外，Z16-18可以抑制E7和pRb之间的相互作用，从而阻断E7-pRb致癌途径，导致E2F释放减少以及以CDK6和Cyclin D1减少为特征的细胞生长抑制。该研究为基于affibody的靶向治疗提供了新的策略，Z16-18作为针对HPV16和HPV18相关宫颈癌的药物具有巨大的利用和开发潜力。
The infection with HPV 16 and 18 high-risk types account for more than 80 % of cervical cancer incidence, but there is still no targeted agent against HPV for cervical cancer therapy. Our previous study constructed a bispecific affibody Z16-18targeting HPV16 and 18 early antigen 7 (E7, responsible for the infected cell malignant transformation). In the present study, we prepared Z16-18in prokaryotic expression system and confirmed its significant growth inhibition both on SiHa (HPV16 positive) and HeLa (HPV18 positive) cervical cancer cells by arresting cell cycle at G0/G1phase. The IC50of Z16-18on SiHa and HeLa were close in value. Z16-18could specifically target E7 in both SiHa and HeLa, and exhibited prominent targeted enrichment on tumor tissues derived from SiHa or HeLa, resulting in the inhibition of tumourigenesis and tumour growthin vivo. Furthermore, Z16-18could inhibit the interaction between E7 and pRb to block the E7-pRb carcinogenic pathway, resulting in the decreased release of E2F and the cell growth inhibition characterized by the decrease of CDK6 and Cyclin D1. This study provides a new strategy for targeted therapy based on affibody, and Z16-18has great potential for utilisation and development as an agent targeting HPV16 and HPV18 related cervical cancer.