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，是肿瘤靶向药的发展方向。DOG1主要高表达于胃肠道间质瘤，是其诊断标志之一。前期研究中，我们发现DOG1也在原发性肝癌与肝转移癌高表达，并制备了DOG1抗体，它能有效识别肝癌细胞并诱发抗体介导的内化作用，提示DOG1可作为肝癌治疗的靶点。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。本研究拟以DOG1为靶点α-Amanitin为弹头药物，将DOG1抗体与α-Amanitin通过linker偶联，构建一种新型的肝癌靶向治疗药物，以期利用抗体介导的内化将α-Amanitin靶向运送至肝癌细胞而杀伤之，在体外细胞和动物实验验证其有效性，探讨其作用机理，为肝癌靶向治疗药物的研发奠定基础。

Antibody-drug conjugates（ADC）combine the efficacy of cytotoxic drugs (warhead drugs) and the tumour-specific targeting of antibodies to maximize anti-cancer potency and minimize side effects, high efficiency and low toxicity, indicating the developing direction of tumor-targeted drugs. DOG1 is generally high-expressed in gastrointestinal stromal tumors (GIST) and has already been regarded as a diagnostic marker of GIST. In our previous studies, we found that DOG1 was also high-expressed in hepatocellular carcinomas and liver metastases. We prepared an anti-DOG1 antibody which could effectively identify hepatocellular carcinoma cells and induce antibody-mediated endocytosis, suggesting that DOG1 could function as a therapeutic target for the treatment of hepatocellular carcinoma. α-Amanitin, a RNA polymerase II inhibitor, is an ideal warhead drugs due to its strong anti-tumor activity and tumor cells selectivity. This project is intended to construct a new ADC for hepatocarcinoma targeting treatment by combining the anti-DOG1 antibody and α-Amanitin with designed linker. With the antibody-mediated internalization, α-Amanitin will be transported to hepatocellular carcinoma cells and developed its unique tumor-killing effect. We will verify its validity in vivo and in vitro, explore its mechanisms and provide theoretical foundation for hepatocarcinoma targeting treatment.