ORGN 68 |
| Most anti-cancer drugs have to be used near their maximum tolerated dose for a clinically meaningful therapeutic response. Their lack of tumor specificity results in high systemic toxicity. Monoclonal antibodies that recognize specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific, and thus less toxic. Although specific, many antibodies have little or no cell killing power to be effective against established cancers. The few monoclonal antibodies that have proven to be therapeutically useful in cancer treatment are often more efficacious when combined with a standard chemotherapeutic agent. We have exploited the tumor specificity of monoclonal antibodies for the targeted delivery of highly cytotoxic drugs that are otherwise too toxic to be used on their own. These monoclonal antibody-drug conjugates are stable in circulation, and are virtually non-toxic until they bind to the tumor cell through the antibody component. They are then activated specifically by the tumor into potent cytotoxic agents. In these conjugates, we have incorporated highly cytotoxic drugs with three distinct mechanisms of action: 1) maytansinoids: inhibitors of tubulin polymerization, 2) CC-1065 analogs: DNA alkylators and 3) Taxoids: inhibitors of tubulin de-polymerization. In vitro, these conjugates display a large therapeutic window, being 1000-fold more cytotoxic for target cells as compared to non-target cells. In vivo, serum concentrations that are curative can be achieved in animals with no evidence of toxicity. These antibody-drug conjugates displayed exceptional activity that was superior to that of the naked antibodies or the standard anti-cancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor-targeted anti-cancer agents are now in clinical evaluation. |
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New Molecular Strategies for Tumor-Targeting Drug Delivery
1:25 PM-5:20 PM, Sunday, August 19, 2007 BCEC -- 253 A/B/C, Oral
Division of Organic Chemistry |