Immunotoxins composed of monoclonal antibody to alpha-fetoprotein and gelonin as a potent hepatoma-targeted drug delivery system.
This study was carried out to evaluate our monoclonal antibody (MoAb) to alpha-fetoprotein (AFP), 80G, as a carrier for targeting AFP-producing hepatoma. Pharmacokinetic analysis showed that the MoAb 80G was actively incorporated into AFP-producing HuH-7N cells (xenograft of human hepatoma cell line, HuH-7) in nude mice. Four conjugates composed of MoAb 80G, and a type 1 ribosome-inactivating protein, gelonin, were prepared. They involve two disulfide-linked and two thioether-linked conjugates. The binding activity of conjugates against AFP remained as high as that of intact 80G according to enzyme-linked immunosorbent assay. The in vitro cytotoxic effects of all the conjugates were specific against AFP-producing HuH-7 cells. Of these conjugates, two containing gelonin modified with 2-iminothiolane were more potent than the others. They showed significant antitumor activity upon AFP-producing HuH-7N cells in nude mice. However, the disulfide conjugate was more toxic to mice than the thioether conjugate judging from the loss in body weight and the liver damage. These results suggest that our MoAb 80G is a suitable carrier for targeting AFP-producing hepatoma cells, and that the noncleavable thioether conjugate is promising as an AFP-producing hepatoma-targeted drug delivery system.
Masuda
K
K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Takahashi
K
K
Nagata
S
S
Hirano
K
K
Takagishi
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000097:blood; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D008099:Liver / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D010940:Plant Proteins / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D054789:Ribosome Inactivating Proteins, Type 1; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D000509:alpha-Fetoproteins; C025674:GEL protein, Gelonium multiflorum; D003404:Creatinine; D001219:Aspartate Aminotransferases