CC-1065 ANALOGS--IDEAL DRUGS FOR ANTICANCER CONJUGATES

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Currently used anti-cancer agents have limited selectivity for the tumor. Immunoconjugates that have been prepared from these drugs are not potent enough to be therapeutically effective. We therefore propose using 100 to 1000-fold more cytotoxic drugs and endow them with tumor-selectivity by linking them to antibodies. Thus, drugs that are too toxic to be used alone can be rendered therapeutically useful. Effective immunoconjugates will be generated by: a) substituting the moderately cytotoxic anti-neoplastic agents in current use in antibody- drug conjugates with CC-1065 analogs which are 100 to 1000-fold more potent and b) linking these CC-1065 analogs to antibodies via disulfide bonds that should be stable in circulation, but efficiently cleaved inside the cell to release fully active drug. In order to realize this goal, new disulfide-containing CC-1065 analogs will be synthesized without affecting the high cytotoxicity of the parent drug. Preliminary experiments indicate that the presence of a disulfide functionality preserves the potency of the drug. The most cytotoxic of these drugs will be linked to antibodies via disulfide bonds and the in vitro cytotoxicity and specificity of these conjugates will be determined. the antibodies we propose to use in this study are already being used in human clinical trials.