Daunorubicin conjugated to a monoclonal anti-CA125 antibody selectively kills human ovarian cancer cells.
The present study was designed to test the in vitro efficacy for human ovarian cancer cells of daunorubicin (DNR) conjugated to a monoclonal antibody (OC125). The OC125 antibody specifically binds to the antigenic protein CA125 from human ovarian carcinoma. New analogs of DNR containing various linker groups were conjugated to mouse monoclonal anti-CA125 antibody (DNR-OC125); nonspecific murine IgG1 (DNR-IgG1); or bovine serum albumin (DNR-BSA). The DNR-protein conjugates were all stable for several days in neutral solutions at room temperature. The DNR-OC125 conjugates selectively killed dividing cell populations but not nondividing cell populations of two human ovarian cancer cell lines (SK-OV-3 or OVCAR-3) that express the CA125 antigen. Equivalent concentrations of DNR-IgG1 or DNR-BSA conjugates were neither toxic to the dividing nor the nondividing populations of SK-OV-3 or OVCAR-3 cells. Only those DNR-protein conjugates linked to OC125 were cytotoxic to dividing cell populations of both cell lines. This indicates that cytotoxicity is dependent on OC125 antibody-CA125 antigen binding which concentrates DNR on the ovarian cancer cells. We advance the hypothesis that following antibody-antigen binding, DNR is released from the conjugate and it intercalates in DNA by a mechanism similar to that of the unmodified DNR. The new DNR-OC125 conjugate may be useful for delivering DNR to ovarian tumors that express the CA125 antigen because the drug-antibody conjugates (1) retain the cytotoxic characteristics of the unmodified drug: (2) specifically kill the human ovarian cancer cells that express the CA125 antigen; and (3) are completely stable for days in neutral solutions at room temperature.
Sweet
F
F
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110.
Rosik
L O
LO
Sommers
G M
GM
Collins
J L
JL
D000230:Adenocarcinoma / Q000188:drug therapy*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use / Q000633:toxicity; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D003630:Daunorubicin / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D007928:Lethal Dose 50; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D000922:Immunotoxins; D003630:Daunorubicin