Anti-tumor activity of CC49-doxorubicin immunoconjugates

Abstract

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.