ADCs at work
Adcetris consists of three parts: the chimeric IgG1 antibody cAC10, specific for human CD30, the microtubule-disrupting agent monomethyl auristatin E (MMAE), and a protease-cleavable linker that covalently attaches MMAE to cAC10 (1). Before the approval of Adcetris this year, the only other ADC approved by FDA was Mylotarg (gemtuzumab ozogamicin), approved more than 10 years ago in 2000. The drug, an anti-CD33 mAb conjugated to the cytotoxin calicheamicin, was developed by Wyeth (now part of Pfizer) and was granted accelerated approval in 2000 but was voluntarily withdrawn by Pfizer in 2010 because a required Phase III trial failed to demonstrate a survival advantage for Mylotarg plus chemotherapy compared with chemotherapy alone. Despite this setback, there are several ADCs currently in development, with more than 15 in Phase I development and several compounds from Roche and Pfizer in late-stage clinical trials. In the decade that has elapsed between the first ADC approval and the second, advances in the understanding of cancer biology, lessons learned from the development of mAbs as therapeutics, and better methods for linking small molecules to mAbs have coalesced to advance ADCs into the forefront of new therapies.The most active area of development for this class of therapeutics has been oncology, where a mAb serves to target the therapy to cancer cells while a potent small-molecule chemotherapeutic provides the cell-killing efficacy. Both mAbs and small-molecule chemotherapeutics are used individually as cancer therapies, but an ADC is designed to overcome the limitations of each. MAbs are highly specific, but as therapeutics have demonstrated only modest efficacy and often are used in combination with a conventional chemotherapy. Chemotherapeutics are highly toxic, but nonspecific, and so suffer from poor side-effect profiles and dose-limiting toxicities. In combination, the ADC serves to keep the chemotherapuetic bound until it reaches the cancer cell, thereby limiting its ability to interact with nontargeted tissues and therefore limiting nonspecific toxicity (2).
The concept of an ADC is not a new one, but creating a clinically successful one has been challenging. For the therapeutic to work well, each of the parts—the antibody, the toxin, and the linker that holds them together—must be carefully considered.
Choosing the right antibody
In general, mAbs as therapeutics are selected to have high affinity for the targeted antigen and high selectivity. Other desirable properties in an antibody include long circulation times, immune-effector functions, and tumor-suppressing activity (2). When choosing the antigen, it is important that it be expressed at high levels in the tissue of interest to maximize the amount of ADC bound by the tumor, but at low levels elsewhere in the body to minimize off-target toxicity. Moreover, it is thought that internalization of the ADC is important for its effectiveness. Many of the chemical-linking strategies used to construct ADCs rely on conditions found inside a cell, either in the cytoplasm or in the lysosome, to release the active agent (3).
In some instances, developers have been able to leverage experience gained through the development of mAb therapies to create their ADC. Trastuzumab emtansine (T-DM1) is an ADC in Phase III, which combines trastuzumab, (Herceptin), which targets human epidermal growth factor receptor 2 (HER2) receptors in breast and stomach cancer, with a maytansine derivative DM1, a small-molecule cytotoxin that binds to tubulin to prevent microtubule formation, through a nonreducible bis-maleimido-trixyethylene glycol linker (4). Trastuzumab was developed by Genentech (now part of Roche) and was approved by FDA in 1998 for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. The maytansine derivative DM1 and linking technology were developed by ImmunoGen. In the case of the ADC trastuzumab emtansine, developers were able to use a target that had already been validated and a well-characterized antibody with a known safety and efficacy profile as the starting point for an ADC.