TPBG单抗-α-Amanitin偶联物靶向治疗肺癌的研究

抗体-化疗药物偶联物（ADC）充分发挥了抗体和化疗药物（弹头药物）各自的优势，具有高效、毒副作用低等优点，是肿瘤靶向药物的发展方向。TPBG在肺癌等多种肿瘤中高表达，阳性率大于90%，而且还表达于肿瘤干细胞，是较理想的肿瘤治疗靶点。α-Amanitin是一种具有强烈抗肿瘤活性的RNA聚合酶II抑制剂，因肿瘤高表达RNA聚合酶II，其对肿瘤细胞有一定的选择性，是较理想的弹头药物。前期工作中，我们筛选到1株高亲合力、可内化的TPBG抗体，开展了多个ADC药物的研究。在此基础上，本项目拟以TPBG为靶点，α-Amanitin为弹头药物，将TPBG抗体和α-Amanitin通过Linker偶联，构建一种新型的ADC药物，以期利用抗体介导的内化将α-Amanitin靶向运送至肿瘤细胞而杀伤之，在体外细胞和动物实验验证其有效性，探讨其作用机理，为肺癌靶向药物的研发奠定基础。

Antibody-drug conjugates (ADC) combines the unique targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, and is the new direction of targeted therapy for tumor. TPBG （Trophoblast glycoprotein）or 5T4, a cell surface antigen that internalized rapidly, over-express in more than 90% of lung cancer cases and other tumor. Also, TPBG is expressed in tumor stem cells. Thus, it has a potential to efficiently dliver ADC into tumor cells. α-amanitin, an potent RNA polymerase II inhibitor in mammalian cells, can lead to apoptosis in extremly lower dose. In previous study, we identified an anti-TPBG monoclonal antibody (mAb) with high affinity and internalized capacity. In this project, we plan to construct a new ADC by coupling of TPBG antibody with α-amanitin, so as to achieve the targeted killing of tumor cells. What`s more, cell experiment and animal experiment will be performed to assess the anti-tumor activity and its anti-tumor mechanism. This helps to make better foundation for the development of targeted therapy for lung cancer.