Treatment of hepatocellular carcinoma in a mouse xenograft model with an immunotoxin which is engineered to eliminate vascular leak syndrome.

摘要: Vascular leak syndrome (VLS) is the major dose-limiting toxicity of immunotoxin and interleukin-2 therapy. It has been evidenced that VLS-inducing molecules share a three-amino acid consensus motif, (x)D(y), which may be responsible for initiating VLS. Here we have constructed recombinant (SMFv-PE38KDEL) by genetically fusing PE38KDEL to single-chain antibody derived from SM5-1 monoclonal antibody, high specificity melanoma, hepatocellular carcinoma breast cancer. In order eliminate VLS induced this PE38KDEL-based immunotoxin, panel mutants were generated changing amino residues adjacent its three (x)D(y) motifs in three-dimensional structure. One SMFv-PE38KDEL mutants, denoted as mut1, displayed similar protein synthesis inhibitory reticulocyte lysate translation assay compared wild-type (wt). The vitro cytotoxicity indicated mut1 specifically killed binding protein-positive tumor cells, although was slightly less than wt. contrast, shown much weaker inducing mice LD50 values wt investigated with result about tenfold higher vivo antitumor activity also tumor-bearing nude mice. Both effective inhibiting growth but showed improved therapeutic efficacy. These studies suggest novel PE-based clinical use.