Treatment of hepatocellular carcinoma in a mouse zenograft model with an immunotozin which is engineered to eliminate vascular leak syndrome
Vascular leak syndrome (VLS) is the major dose-limiting toxicity of immunotoxin and interleukin-2 therapy. It has been evidenced that VLS-inducing mole-cules share a three-amino acid consensus motif, (x)D(y), which may be responsible for initiating VLS. Here we have constructed a recombinant immunotoxin (SMFv-PE38KDEL) by genetically fusing PE38KDEL to a single-chain anti-body derived from SM5-1 monoclonal antibody, which has a high specificity for melanoma, hepatocellular carcinoma and breast cancer. In order to eliminate VLS induced by this PE38KDEL-based immunotoxin, a panel of mutants were generated by changing amino acid residues adjacent to its three (x)D(y) motifs in the three-dimensional struc-ture. One of the SMFv-PE38KDEL mutants, denoted as mutl, displayed a similar protein synthesis inhibitory in a reticulocytc lysate translation assay compared to the wild-type SMFv-PE38KDEL (wt). The in vitro cytotoxic-ity assay indicated that mutl specifically killed SM5-1 binding protein-positive tumor cells, although its cytotoxic-ity was slightly less than wt. In contrast, mutl was shown to be much weaker in inducing VLS in mice than wt. The LD50 values of wt and mutl in mice were investigated with the result that the LD50 of mutl was about tenfold higher than that of wt. The in vivo antitumor activity of wt and mutl were also compared in tumor-bearing nude mice. Both wt and mutl were effective in inhibiting the tumor growth but mutl showed improved therapeutic efficacy. These studies suggest mutl may be a novel PE-based immunotoxin with much less toxicity for clinical use.
PE38KDEL SM5-1 monoclonal antibody Immunotozin Antitumor activity Vascular leak syndrome
Hao Wang Jian Zhao Yajun Guo Shuichuan Song Geng Kou Bohua Li Dapeng Zhang Sheng Hou Weizhu Qian Jianxin Dai Liang Tian
International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shangh International zoint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shangh International Joint Cancer Institute, Second Military Medical University, 800 Xiang Yin Road, Shangh
国际会议
广州
英文
130-138
2008-11-01（万方平台首次上网日期，不代表论文的发表时间）