Improved chemical strategies for the targeted therapy of cancer.

The selective targeting of a compound to tumors, or for that matter to any structure in the body, requires high stability of the compound in blood, biodistribution to the target site, adequate contact time with the target, adequate retention by the target, maintenance of drug potency, and adequate clearance of nontargeted compound. For over two decades, antibodies have been the scaffold of choice for delivering contrast agents and chemotherapeutics to tumor cells since they are stable in blood, typically have nanomolar affinities for their target, and, because binding and nonbinding domains are separated physically, tolerate substitution with contrast agents and chemotherapeutics. Although monoclonal antibodies (mAbs) are typically tolerant to the conjugation of chemotherapeutics, the agents themselves often lose potency in the conjugated form. Therefore, novel chemical strategies are required for releasing the cytotoxic agent, either after binding to the cancer cell surface or after endocytosis into the cell. A compelling example of this comes from the antitumor antibiotic calicheamicin. When conjugated to a tumor-targeting mAb through an amide linkage, the conjugate is accumulated by the tumor, but has no appreciable cytotoxicity. In contrast, when conjugated by using a pH-sensitive bifunctional linker that permits release of calicheamicin intracellularly (Figure 1), the conjugate shows potent antitumor activity. Indeed, gemtuzumab ozogamicin (“gem-ozo”, Mylotarg), a conjugate of a CD33-specific mAb and calicheamicin, which utilizes this bifunctional linker, is already approved for the treatment of certain acute myeloid leukemias. The taxanes are a class of potent chemotherapeutics that possess a complex chemical structure. Recently, two different strategies have been employed to conjugate taxanes to tumor-targeting monoclonal antibodies, while retaining chemotherapeutic potency. In conjugate mAb-1 (Scheme 1), an enzymatically cleavable glutarate ester bond is placed between the amide linkage to