Lin Wen-Wei, Cheng Yi-An, Li Chia-Ching, Ho Kai-Wen, Chen Huei-Jen, Chen I-J U, Huang Bo-Cheng, Liu Hui-Ju, Lu Yun-Chi, Cheng Chiu-Min, Huang Ming-Yii, Lai Hung-Wen, Cheng Tian-Lu
Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Sci Rep. 2021 Apr 7;11(1):7598. doi: 10.1038/s41598-021-87271-2.
Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide. It is important to elevate the drug susceptibility and cytotoxicity of ovarian cancer cells, thereby eliminating resident cancer cells for more effective therapeutic efficacy. Here, we developed a bispecific antibody (BsAb; mPEG × HER2) that can easily provide HER2 tumor tropism to mPEGylated liposomal doxorubicin (PLD) and further increase the drug accumulation in cancer cells via receptor-mediated endocytosis, and improve the cytotoxicity and therapeutic efficacy of HER2 ovarian tumors. The mPEG × HER2 can simultaneously bind to mPEG molecules on the surface of PLD and HER2 antigen on the surface of ovarian cancer cells. Simply mixing the mPEG × HER2 with PLD was able to confer HER2 specificity of PLD to HER2 ovarian cancer cells and efficiently trigger endocytosis and enhance cytotoxicity by 5.4-fold as compared to non-targeted PLD. mPEG × HER2-modified PLD was able to significantly increase the targeting and accumulation of HER2 ovarian tumor by 220% as compared with non-targeted PLD. It could also significantly improve the anti-tumor activity of PLD (P < 0.05) with minimal obvious toxicity in a tumor-bearing mouse model. We believe that the mPEG × HER2 can significantly improve the therapeutic efficacy, potentially reduce the relapse freqency and thereby achieve good prognosis in ovarian cancer patients.
卵巢癌具有高度转移性，复发频率高，是全球女性中最致命的妇科恶性肿瘤。提高卵巢癌细胞的药物敏感性和细胞毒性，从而清除残留癌细胞以获得更有效的治疗效果非常重要。在此，我们开发了一种双特异性抗体（BsAb；mPEG×HER2），它可以轻松地为聚乙二醇化脂质体阿霉素（PLD）提供HER2肿瘤靶向性，并通过受体介导的内吞作用进一步增加癌细胞中的药物积累，提高HER2阳性卵巢肿瘤的细胞毒性和治疗效果。mPEG×HER2可以同时结合PLD表面的mPEG分子和卵巢癌细胞表面的HER2抗原。简单地将mPEG×HER2与PLD混合，就能使PLD对HER2阳性卵巢癌细胞具有特异性，并有效触发内吞作用，与非靶向PLD相比，细胞毒性增强5.4倍。与非靶向PLD相比，mPEG×HER2修饰的PLD能够使HER2阳性卵巢肿瘤的靶向性和积累显著增加220%。在荷瘤小鼠模型中，它还能显著提高PLD的抗肿瘤活性（P<0.05），且毒性极小。我们相信，mPEG×HER2可以显著提高治疗效果，可能降低复发频率，从而使卵巢癌患者获得良好的预后。
