Doxorubicin conjugates of monoclonal antibodies to hepatoma-associated antigens.
A panel of six murine monoclonal antibodies against hepatocellular carcinoma-associated antigens, reactive with PLC/PRF/5 human hepatoma cells, was conjugated to Adriamycin (doxorubicin) via a dextran bridge. This library of antibodies includes three monoclonal antibodies against hepatitis B virus surface antigen, one anti-alpha-fetoprotein, and two other IgG2a antibodies against PLC/PRF/5 hepatoma-associated antigens. The use of dextran for conjugation of Adriamycin to antibodies enabled a 5- to 10-fold amplification of the number of drug molecules linked to antibody. Conjugation of Adriamycin to dextran caused an occasional reduction in the pharmacologic activity of dextran-Adriamycin in [3H]thymidine incorporation assays in hepatoma cells as compared to nonconjugated Adriamycin. This loss of anticellular activity was partially compensated for by conjugation of specific antibodies to the dextran-Adriamycin conjugate. Conjugated compounds completely retained their binding activity to purified hepatitis B virus surface antigen and alpha-fetoprotein fixed to a solid matrix as compared to binding of homologous nonconjugated antibodies. However, some reduction of the binding activity to intact hepatoma cells was observed in three of six conjugates. Binding activity to hepatoma cells and, as a consequence, suppression of tumor cell DNA synthesis by the various conjugates was enhanced as compared to the same effect in treated colorectal carcinoma cells that do not express the relevant hepatoma-associated proteins. Furthermore, two conjugates containing nonspecific antibodies did not bind to hepatoma cells and caused minimal suppression of DNA synthesis. These results suggest that this panel of monoclonal antibody-dextran-Adriamycin conjugates was effective in suppression of PLC/PRF/5 cell growth in vitro.
Shouval
D
D
Department of Medicine A, Hadassah University Hospital, Jerusalem, Israel.
Adler
R
R
Wands
J R
JR
Hurwitz
E
E
Isselbacher
K J
KJ
Sela
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D003911:Dextrans; D004317:Doxorubicin / Q000008:administration & dosage*; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D000922:Immunotoxins; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D000509:alpha-Fetoproteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D003911:Dextrans; D006514:Hepatitis B Surface Antigens; D007074:Immunoglobulin G; D000922:Immunotoxins; D000509:alpha-Fetoproteins; D004317:Doxorubicin