Anti-tumor activity of CC49-doxorubicin immunoconjugates.
The TAG72 reactive monoclonal antibody CC49 was conjugated to doxorubicin with a malonate linker. The immunoconjugate, designated CC49-BAMME-CH-DOX, was approximately a log less potent than unconjugated doxorubicin in an in vitro cytotoxicity assay. Immunoreactivity of the antibody was fully retained. When evaluated in a nude mouse xenograft model with the antigen positive LS174T human colorectal tumor target, CC49-BAMME-CH-DOX and free doxorubicin had similar tumor suppressive activities. The immunoconjugate was clearly less toxic, however, as measured by weight loss and deaths. When evaluated in an NIH:OVCAR-3 human ovarian carcinoma xenograft model, CC49-BAMME-CH-DOX was superior at prolonging survival in comparison to free doxorubicin, unmodified CC49, and a non tumor binding doxorubicin immunoconjugate. These results indicate that targeting of doxorubicin with the CC49 antibody can improve the toxicity and/or the potency of the drug, depending on the tumor target being evaluated. CC49-Doxorubicin immunoconjugates should be considered for clinical evaluation.
Johnson
D A
DA
Cancer Research Division, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285, USA.
Briggs
S L
SL
Gutowski
M C
MC
Barton
R
R
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D004317:Doxorubicin / Q000494:pharmacology*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D014183:Transplantation, Heterologous
D000951:Antigens, Neoplasm; D006023:Glycoproteins; D000922:Immunotoxins; C047052:tumor-associated antigen 72; D004317:Doxorubicin