新型抗体偶联药物607-LDM的制备及抗肿瘤活性研究

Preparation and anti-tumor activity of a novel antibody-drug conjugate 607-LDM

抗体偶联药物(antibody-drug conjugates,ADCs)是目前肿瘤治疗药物中最重要的种类之一。人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)特异性高表达于乳腺癌和卵巢癌等多种实体肿瘤,已被证实是ADC的理想靶点。力达霉素(lidamycin,LDM)是中国医学科学院医药生物技术研究所自主研发的强效烯二炔抗肿瘤抗生素,其分子具有可拆分和重建的特点,适于用作ADC的"弹头"药物。本研究利用LDM的分子特点,采用特殊"定点偶联"技术,制备药物抗体比(drug-to-antibody ratio,DAR)为2的抗HER2抗体607与力达霉素的ADC 607-LDM,并研究其抗肿瘤活性,结果表明:607-LDM在体外对人卵巢癌SKOV3和乳腺癌BT-474细胞有强烈杀伤活性,还可诱导二者发生细胞凋亡和G2/M期阻滞。在SKOV3裸鼠移植模型中(动物实验符合中国实验动物护理和使用准则,并经中国医学科学院医药生物技术研究所实验动物伦理委员会批准),1.0 mg·kg^(-1)607-LDM尾静脉注射1次,抑瘤率为72.4%,显著强于单独抗体组(30.2%)、LDM最大耐受剂量组(50.6%)及二者联用组(50.1%)。本研究构建的新型ADC药物607-LDM有望成为治疗HER2阳性肿瘤的候选药物。

Antibody-drug conjugates(ADCs)are one of the most important classes of anticancer therapeutics.Human epidermal growth factor receptor-2(HER2),which is highly expressed in many types of aggressive cancers including breast and ovarian cancer,has been approved as an ideal target for ADCs.Lidamycin(LDM),developed by Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,is an enediyne-containing antibiotic with potent anti-tumor activity.LDM is a promising payload for ADCs.In the present research,using a special site-directed conjugating technology,we made a novel ADC(607-LDM)with a drug-to-antibody ratio(DAR)of2 and composed of the anti-HER2 antibody 607 and LDM.The new ADC exhibited potent antitumor activity against human ovarian cancer SKOV3 and breast cancer BT-474 cells.It also induced apoptosis and G2/M arrest.In nude mice with SKOV3 xenografts and a tumor volume of 150-200 mm3,a single intravenous injection 607-LDM at 1 mg·kg^(-1)induced tumor growth inhibition of 72.4%,which was significant compared to either LDM(50.6%)or antibody(30.2%)treatment alone,or both in combination(50.1%,P<0.05).All animal experiments were performed in accord with National Regulations and approved by the Animal Experiments Ethical Committee of College of Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences.The novel ADC designed in this study,607-LDM,is a promising candidate for the treatment of HER2-positive cancers.