Comparison of the antitumor activities of immunoconjugates composed of lidamycin and monoclonal antibody fab' fragment with different linkers.
- Author:
Yun FENG
1
;
Rong-Guang SHAO
;
Yao DAI
;
Bao-Wei LI
;
Hong-Wei HE
;
Kai-Huan REN
Author Information
1. School of Medical Science and Laboratory Medicine of Jiangsu University, Zhenjiang 212013, China.
- Publication Type:Journal Article
- MeSH:
Aminoglycosides;
pharmacology;
Animals;
Antibiotics, Antineoplastic;
pharmacology;
Antibodies, Monoclonal;
immunology;
Cell Line, Tumor;
drug effects;
Cell Proliferation;
drug effects;
Collagenases;
immunology;
Enediynes;
pharmacology;
Fibrosarcoma;
pathology;
Humans;
Immunoconjugates;
pharmacology;
Immunoglobulin Fab Fragments;
immunology;
Matrix Metalloproteinase Inhibitors;
Mice;
Mice, Inbred BALB C;
Mice, Nude;
Neoplasm Transplantation;
Tumor Burden;
drug effects
- From:
Acta Pharmaceutica Sinica
2010;45(5):571-575
- CountryChina
- Language:Chinese
-
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.
