Improvement of therapeutic effect by using Fab' fragment in the treatment of carcinoembryonic antigen-positive human solid tumors with adriamycin-entrapped immunoliposomes.
To improve the therapeutic efficiency adriamycin entrapped in antibody-conjugated liposomes, Fab' fragment was used instead of the whole antibody molecule. The murine monoclonal antibody, 21B2, against human carcinoembryonic antigen (CEA) was digested with pepsin, and the thiol residue of intra-heavy chain produced by reduction of F(ab')2 with dithiothreitol was conjugated to liposomes containing adriamycin. The tissue distribution of adriamycin delivered with these liposomes was studied in BALB/c nu/nu female mice bearing CEA-positive human gastric cancer strain MKN-45. An increase in delivery of adriamycin to the tumor was observed in the mice given liposomes with Fab' fragment as compared to those given liposomes with whole antibody. However, the preferential distribution of adriamycin in liposomes to the reticuloendothelial cells remained the same regardless of the use of Fab' fragment. For investigation of in vivo therapeutic effect, three i.v. injections of free adriamycin or adriamycin in liposomes equivalent to 5 mg/kg were given, and adriamycin in Fab' fragment-conjugated liposomes was found most effective in the inhibition of tumor growth. This was confirmed in terms of actual tumor weights excised and CEA concentration in the blood, as well as by pathological observations. The advantages of using Fab' fragment instead of whole antibody are discussed.
Uyama
I
I
Department of Surgery, Keio University School of Medicine, Tokyo.
Kumai
K
K
Yasuda
T
T
Tagawa
T
T
Ishibiki
K
K
Kitajima
M
M
Tadakuma
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011510:Proteolipids; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D011510:Proteolipids; C020485:proteoliposomes; D004317:Doxorubicin