Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor.
Monoclonal antibodies that recognize the extracellular domain of the epidermal growth factor receptor (mAb108) were conjugated with doxorubicin through a dextran bridge. Several antibody-drug conjugates, containing different amounts of doxorubicin, retained binding capacity to human epidermoid carcinoma (KB) cells overexpressing epidermal growth factor receptors. Slight decrease in drug cytotoxicity was seen in in vitro tests, as determined either by inhibition of thymidine incorporation into cells or by reduction in number and size of KB-cell colonies. Yet, when tested in vivo against KB tumor xenografted into nude mice, the anti-epidermal growth factor-receptor drug conjugates with high drug-substitution levels were significantly more effective than free doxorubicin, antibody alone, mixture of dextran-doxorubicin and antibody, or drug conjugated with irrelevant antibody. When the labile covalent bonds linking antibody to dextran bridge were stabilized by reduction, the therapeutic efficacy of the conjugate was markedly decreased. These results show that antibodies against the extracellular domain of the epidermal growth factor can deliver doxorubicin specifically and efficiently to tumor sites that express high receptor levels exerting a specific antitumor effect.
Aboud-Pirak
E
E
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Hurwitz
E
E
Bellot
F
F
Schlessinger
J
J
Sela
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000628:therapy; D002455:Cell Division; D004317:Doxorubicin / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D004317:Doxorubicin; D066246:ErbB Receptors