Significance of antigen, drug, and tumor cell targets in the preclinical evaluation of doxorubicin, daunorubicin, methotrexate, and mitomycin-C monoclonal antibody immunoconjugates.
We tested drug monoclonal antibody immunoconjugates in vitro in 72 h 3H-thymidine assays and in vivo in athymic mice bearing human tumor xenografts of the same target cells. Experimental arms included control, monoclonal antibody, drug, drug + antibody, the test immunoconjugate, and a negative control immunoconjugate with an equivalent molar amount of drug for in vitro experiments, and the amount of drug conjugated to 500 micrograms of antibody in the animal experiments. Monoclonal antibodies included T101, an IgG2a that reacts with a rapidly modulating antigen, 9.2.27, an IgG2a that reacts with a slowly modulating antigen, and ME7, an IgG1 that reacts with a slowly modulating antigen. Cells used in testing included MOLT-4 (T lymphoma), 8392 (B lymphoma), and M21 (melanoma). Drugs tested were doxorubicin, daunorubicin, methotrexate, and mitomycin-C. M21 cells were resistant to daunorubicin in vitro but were inhibited by the 9.2.27 daunorubicin immunoconjugate. T101, 9.2.27, and ME7 cis-aconitate anthracycline immunoconjugates and mitomycin-C-glutarate immunoconjugates were specifically cytotoxic only for antigen positive cells in vitro and were superior to free drug in vivo. These results confirm that antigen specific-cytotoxic drug immunoconjugates can be produced that are superior to the same dose of free drug. However, each monoclonal antibody drug target system is unique and must be well-characterized for appropriate interpretation of data.
Dillman
R O
RO
Hoag Cancer Center, Newport Beach, CA 92658.
Johnson
D E
DE
Ogden
J
J
Beidler
D
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D003630:Daunorubicin / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use; D004338:Drug Combinations; D004341:Drug Evaluation; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin; D008937:Mitomycins / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D004338:Drug Combinations; D008937:Mitomycins; D016685:Mitomycin; D004317:Doxorubicin; D008727:Methotrexate; D003630:Daunorubicin