Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates

A great deal of interest has surrounded the activities of monoclonal antibodies (mAbs), and mAb-drug, toxin and radionuclide conjugates for the treatment of human cancers. In the last few years, a number of new mAb-based reagents have been clinically approved (Rituxan, Herceptin, and Panorex), and several others are now in advanced clinical trials. Successful therapeutic treatment of solid tumors with drug conjugates of such macromolecules must overcome the barriers to penetration within tumor masses, antigen heterogeneity, conjugated drug potency, and efficient drug release from the mAbs inside tumor cells. An alternative strategy for drug delivery involves a two-step approach to cancer therapy in which mAbs are used to localize enzymes to tumor cell surface antigens. Once the conjugate binds to the cancer cells and clears from the systemic circulation, antitumor prodrugs are administered that are catalytically converted to active drugs by the targeted enzyme. The drugs thus released are capable of penetrating within the tumor mass and eliminating both cells that have and have not bound the mAb-enzyme conjugate. Significant therapeutic effects have been obtained using a broad range of enzymes along with prodrugs that are derived from both approved anticancer drugs and highly potent experimental agents. This review focuses on the activities of several mAb-enzyme/prodrug combinations, with an emphasis on those that have provided mechanistic insight, clinical activity, novel protein constructs, and the potential for reduced immunogenicity.