[Biodistribution of monoclonal antibody and Fab fragment and antitumor effect of their conjugates on hepatoma xenografts].
McAb 3A5, a rat monoclonal antibody directed against human hepatoma cells, and its Fab fragment were compared on their biodistribution and the therapeutic effects of their conjugates linked to C1027, a highly potent antitumor antibiotic, on the growth of human hepatoma xenografts in nude mice. Biodistribution study with 125I-labeled McAb 3A5 and its Fab fragment in hepatoma-bearing nude mice revealed that ID%/g values of McAb 3A5 were higher than those of the Fab fragment in tumor, liver, spleen and kidney; however, the T/NT ratios of Fab were higher than those of McAb 3A5. Imaging study with 131I-3A5 and 131I Fab showed that clear images of the tumor emerged 12h after injection of Fab and 40 h after that of McAb 3A5. IC50 values for McAb-C1027 and Fab-C1027 were 4.2 x 10(-14) mol/L, 8.6 x 10(-16) mol/L, respectively. Fab-C1027 conjugate was 49-fold more potent than McAb-C1027. Therapeutic effect of the conjugates was evaluated with hepatoma xenograft in nude mice. When treatment started 3 days after sc transplantation of the tumor with equivalent dose of C1027, 0.15 mg/kg, i.v., x3, tumor inhibition rates for McAb-C1027 and Fab-C1027 conjugates were 68% and 66%, respectively. When the treatment started on day 10 after transplantation with 0.10 mg/kg, i.v., x6, tumor inhibition rates for McAb-C1027 and Fab-C1027 conjugates were 24% and 54%, respectively. The results showed that compared with the intact McAb, Fab fragment displays higher specificity in biodistribution and exerts stronger inhibitory effect on the growth of established tumor xenografts.
Li
J
J
Institute of Medicinal Biotechnology, CAMS, Beijing.
Zhen
Y
Y
Yang
Z
Z
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000628:therapy*; D053281:Enediynes; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D000922:Immunotoxins / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides; D051381:Rats; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D053281:Enediynes; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D010455:Peptides; C058024:C 1027