药学学报, 2010, 45(5): 571-575
引用本文:
封云 邵荣光 戴垚 李保卫 何红伟 任开环. 力达霉素-单抗Fab'片段不同连接偶联物的抗肿瘤作用比较[J]. 药学学报, 2010, 45(5): 571-575.
BIAN Yun, SHAO Rong-Guang, DAI Yao, LI Bao-Wei, HE Hong-Wei, LIN Kai-Huan. Comparison of the antitumor activities of immunoconjugates composed of lidamycin and monoclonal antibody Fab' fragment with different linkers[J]. Acta Pharmaceutica Sinica, 2010, 45(5): 571-575.

力达霉素-单抗Fab'片段不同连接偶联物的抗肿瘤作用比较
封 云1, 邵荣光2*, 戴 垚2, 李保卫2, 何红伟2, 任开环2
(1. 江苏大学基础医学与医学技术学院, 江苏 镇江 212013; 2. 中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050)
摘要:

研究力达霉素与抗型胶原酶单抗的不同连接键的小型化免疫偶联物的抗肿瘤作用。制备长短链的二硫键以及硫醚键抗肿瘤抗生素力达霉素 (LDM) 与抗型胶原酶单抗3G11Fab' 片段连接的免疫偶联物, ELISA法测定偶联物的免疫活性, 体外细胞克隆形成测定和体内荷瘤裸小鼠模型观察两种偶联物的抗肿瘤作用。体外研究显示, Fab'-LDM偶联物部分保留了抗型胶原酶单抗3G11对抗原的亲和力, 硫醚键偶联物对体外培养的人纤维肉瘤HT-1080细胞的杀伤作用强于LDM和二硫键偶联物。实验结果显示, LDM等剂量条件下硫醚键偶联物Fab'-SSMPB-LDMFab'-SMBS-LDM组的抑瘤率分别为87.7%78.0%, 二硫键偶联物Fab'-SPDP-LDMFab'-LCSPDP-LDM组分别为74.8%72.3%, 游离LDM组为70.9%, 相比较长连接键的硫醚键偶联物抑瘤作用显著增强。Fab'-SSMPB-LDMFab'-SMBS-LDM组动物的平均生存时间延长为165.8%145.2%, Fab'-SPDP- LDMFab'-LCSPDP-LDM组分别为82.2%107.5%, LDM组为71.9%。与二硫键偶联物组比较, 硫醚键偶联物组能显著延长荷瘤鼠的生存期; 长硫醚键偶联物抗肿瘤作用和对荷瘤动物生存期延长作用强于短硫醚键偶联物。长链硫醚键偶联物Fab'-SSMPB-LDM肿瘤生长抑制作用提高, 荷瘤动物生存期显著延长, 有望开发为新的肿瘤治疗药物。

关键词:   
Comparison of the antitumor activities of immunoconjugates composed of lidamycin and monoclonal antibody Fab' fragment with different linkers
Abstract:

To investigate the antitumor activities of the immunoconjugates composed of anti-type IV    collagenase monoclonal antibody Fab' fragment and lidamycin (LDM) prepared with different linkers.  The immunoconjugates were prepared by linking Fab' to lysine-69 of LDM apoprotein by SPDP, LCSPDP, SMBS or SSMPB as the intermediate drug linkers.  Immunoreactivities of the conjugates were determined by ELISA.  The cytotoxicities of the conjugates were examined by clonogenic assay.  In vivo antitumor effects of the   conjugates were evaluated in nude mice bearing subcutaneously implanted HT-1080 tumor.  ELISA assay showed that the conjugates retained part of the immunoreactivity of 3G11 against the antigen.  The cytotoxicities of the Fab'-SMBS-LDM and Fab'-SSMPB-LDM to HT-1080 cells were significantly potent, compared with Fab'-SPDP- LDM, Fab'-LCSPDP-LDM and free LDM.  In animal models at the same condition, free LDM, Fab'-SPDP- LDM and Fab'-LCSPDP-LDM inhibited the growth of HT-1080 tumor by 70.9%, 74.8% and 72.3%, while Fab'-SMBS-LDM and Fab'-SSMPB-LDM reached 78.0% and 87.7%, respectively.  The median survival time  of the mice treated with free LDM, Fab'-SPDP-LDM and Fab'-LCSPDP-LDM were prolonged by 71.9%,  82.2% and 107.5%, respectively, compared with that of untreated group.  Whereas, the median survival time of Fab'-SMBS-LDM and Fab'-SSMPB-LDM were prolonged by 145.2% and 165.8%, respectively, indicating that Fab'-SSMPB-LDM was more effective than Fab'-SMBS-LDM in tumor suppression and life span prolongation.  Fab'-SSMPB-LDM has more marked selective antitumor efficacy and lower toxicity, and might be a novel     candidate for cancer therapy.

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