%0 Journal Article
%T Generation and antitumor effects of an engineered and energized fusion protein VL-LDP-AE composed of single-domain antibody and lidamycin
%A MIAO QingFang
%A SHANG BoYang
%A OUYANG ZhiGang
%A LIU XiaoYun &
%A ZHEN YongSu
%A <br>
%J 中国科学C辑(英文版)
%D 2007
%I Springer
%X Type IV collagenase plays a pivotal role in invasion, metastasis and angiogenesis of tumor. Single domain antibodies are attractive as tumor-targeting vehicle because of their much smaller size compared with antibody molecules produced by conventional methods. Lidamycin (LDM) is a potent enediyne-containing antitumor antibiotic. In this study an engineered and energized fusion protein VL-LDP-AE composed of lidamycin and VL domain of mAb 3G11 directed against type IV collagenase was prepared using a novel two-step method. First a VL-LDP fusion protein was constructed by DNA recombination. Secondly VL-LDP-AE was obtained by molecular reconstitution. In MTT assay, VL-LDP-AE showed potent cytotoxicity to HT-1080 cells and KB cells with IC 50 values of 8.55×10 12 and 1.70×10 11 mol/L, respectively. VL-LDP-AE showed antiangiogenic activity in chick chrorioallantoic membrane (CAM) assay and tube formation assay. In in vivo experiments, VL-LDP-AE was proved to be more effective than free LDM against the growth of subcutaneously transplanted hepatoma 22 in mice. Drugs were given intravenously on day 3 and 10 after tumor transplantation. Compared in terms of maximal tolerated doses, VL-LDP-AE at 0.25 mg/kg suppressed the tumor growth by 89.5%, LDM at 0.05 mg/kg by 69.9%, and mitomycin at 1 mg/kg by 35%. Having a molecular weight of 25.2 kDa, VL-LDP-AE was much smaller than other reported antibody-based drugs. The results suggested that VL-LDP-AE would be a promising candidate for tumor targeting therapy. And the 2-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers. Supported by the National High Technology Research and Development Program of China (863 Program)(Grant No. 2006AA02A255)
%K single-domain antibody
%K lidamycin
%K fusion protein
%K antibody-based drugs<br>type
%K Ⅳ
%K collagenase
%U http://www.alljournals.cn/get_abstract_url.aspx?pcid=90BA3D13E7F3BC869AC96FB3DA594E3FE34FBF7B8BC0E591&jid=180CF3A72E750F3261A8A60EDC957784&aid=4B58E2C039A8A6EB96FD54B042F8C496&yid=A732AF04DDA03BB3&vid=771152D1ADC1C0EB&iid=E158A972A605785F&sid=C66DE7562B0326E2&eid=522844664D9E629A&journal_id=1674-7305&journal_name=ScienceChina.Lifesciences&referenced_num=0&reference_num=28