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Update on the Development of Anti-Viral Agents Against Hepatitis C

Journal of Clinical and Translational Hepatology 2013年第1期1卷 9-21页

作者： Kristin L. MacArthur Robert Smolic Martina V. Smolic Catherine H. Wu George Y. Wu Department of Medicine Beth Israel Deaconess Medical Center Boston MA02215 Faculty of Medicine Osijek Croatia University of Connecticut Health Center Farmington CT USA Department of Medicine Division of Gastroenterology-Hepatology University of Connecticut Health Center Farmington CT USA

Hepatitis C virus (HCV) infects nearly 170 million people worldwide and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The search for a drug.regimen that maximizes efficacy and minimizes side effects is quickly evolving. This review will discuss a wide range of drug.targets currently in all phases of development for the treatment of HCV. Direct data from agents in phase Ⅲ/Ⅳ clinical trials will be presented, along with reported side-effect profiles. The mechanism of action of all treatments and resistance issues are highlighted. Special attention is given to available trial data supporting interferon-free treatment regimens. HCV has become an increasingly important public health concern, and it is important for physicians to stay up to date on the rapidly growing novel therapeutic options.

关键词： HCV Protease Polymerase Triple therapy drug.

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Antitumor effects of the molecule-downsized immunocon-jugate composed of lidamycin and Fab' fragment of monoclonal antibody directed against type IV collagenase

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Science China(Life Sciences) 2004年第1期47卷 66-73页

作者： WANG Fengqiang SHANG Boyang ZHEN Yongsu Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

Type IV collagenase plays an important role in tumor invasion and metastasis through cleaving type IV collagen in the basement membrane and extracellular matrix. In this study a molecule-downsized immunoconjugate (Fab′-LDM) was constructed by linking lidamycin (LDM), a highly potent antitumor antibiotic, to the Fab′ fragment of a monoclonal antibody directed against type IV collagenase and its antitumor effect was investigated. As assayed in 10% SDS-PAGE gel, the molecular weight of Fab′-LDM conjugate was 65 kD with a 1:1 molecular ratio of Fab′ and LDM. The Fab′-LDM conjugate maintained most part of the immunoreactivity of Fab′ fragment to both type IV collagense and mouse hepatoma 22 cells by ELISA. By MTT assay, Fab′-LDM conjugate showed more potent cytotoxicity to hepatoma 22 cells than that of LDM. Administered intravenously, Fab′-LDM conjugate proved to be more effective against the growth of subcutaneously transplanted hepatoma 22 in mice than free LDM in two experiment settings. In Experiment I, the drug. were given intravenously on day 1 and day 8. Fab′-LDM at the doses of 0.025 mg/kg, 0.05 mg/kg and 0.1 mg/kg inhibited tumor growth by 76.7%, 93.3% and 94.8%, while free LDM at 0.05 mg/kg inhibited tumor growth by 76.1%, respectively. In experiment II, the drug. were given intravenously on day 4 and day 11, Fab′-LDM at the doses of 0.025 mg/kg and 0.05 mg/kg inhibited tumor growth by 74.2%, 80.9%, while free LDM at 0.05 mg/kg inhibited tumor growth by 60.5%, respectively. In terms of survival time, Fab′-LDM was more effective than free LDM. The results suggest that the molecule-downsized immunoconjugate directed against type IV collagenase is of high efficacy in experimental cancer therapy.

关键词： anti-type IV collagenase monoclonal antibody, immunoconjugate, lidamycin, antibody-based drug.

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