Selective antitumor effect of thioether-linked immunotoxins composed of gelonin and monoclonal antibody to alpha-fetoprotein or its F(ab')2 fragment.
Two thioether-linked conjugates composed of monoclonal antibody (MoAb) to alpha-fetoprotein (AFP), 80G or its F(ab')2 fragment, and a type 1 ribosome-inactivating protein (RIP), gelonin, were prepared as potent immunotoxins [80G-CS-GL(IT) and F(ab')2-CS-GL(IT)]. Each conjugate contained one gelonin per 80G or its F(ab')2 fragment. The binding activity of these conjugates was as high as that of intact 80G or F(ab')2. The in vitro cytotoxic effect of F(ab')2-CS-GL(IT) on AFP-producing HuH-7 cells was approximately 100-fold more potent than that of 80G-CS-GL(IT). Also, F(ab')2-CS-GL(IT) showed slight cytotoxicity against non-AFP-producing HuH-13 cells, while 80G-CS-GL(IT) did not. On the other hand, both conjugates had similar selective antitumor activity against HuH-7N cells in nude mice, possibly due to their similar distribution in the tumor. The results suggest that our MoAb 80G is a suitable carrier for delivering type 1 RIP such as gelonin into AFP-producing hepatoma cells and that its F(ab')2 fragmentation does not enhance targeting efficiency.
Masuda
K
K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Takahashi
K
K
Hirano
K
K
Takagishi
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins / Q000378:metabolism / Q000633:toxicity*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D010940:Plant Proteins / Q000493:pharmacokinetics / Q000633:toxicity*; D011500:Protein Synthesis Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D054789:Ribosome Inactivating Proteins, Type 1; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D000509:alpha-Fetoproteins; C025674:GEL protein, Gelonium multiflorum