Oncology treatment options have expanded considerably in the past decade, particularly to include biologic-based molecules. Classical small-molecule chemotherapeutic agents are generally nonspecific (i.e., they bind to and affect other physiological targets) and may cause significant side effects. In contrast, targeted monoclonal antibody (mAb) therapy generally is very selective and has a milder side-effect profile, although rare but serious adverse events can occur, including infusion reactions, thrombocytopenia, cardiac arrest, acute renal failure, immune toxicity, pulmonary toxicity, and susceptibility to latent viral infections (1).
Antibody–drug conjugatesIdeal therapeutics would combine the specificity of antibody-targeting with the potency and pharmacokinetics of small-molecule drugs, an idea that has spawned the field of antibody–drug conjugates (ADCs). These constructs combine an antibody against a target of interest with a compound that adds interesting pharmacology, such as cytotoxicity. However, the theory of using mAb targeting to deliver a lethal drug payload to tumor cells gives rise to complex technical challenges when put into practice. The mAb must be conjugated to a potent cytotoxin with a linker that is stable enough not to release large amounts of the drug into systemic circulation, but labile enough to release the cytotoxin upon internalization by the targeted cell. The manufacturing process to couple the cytotoxin onto the mAb must produce an ADC that maintains recognition of the target after conjugation. The number of conjugated cytotoxins per intact mAb, as well as the level of unconjugated mAb, must be controlled to reduce batch-to-batch variability.
In contrast to the current success by T-DM1, the only approved ADC, Mylotarg (gemzutumab ozogamicin), was voluntarily removed from the market by Pfizer on June 21, 2010, after postapproval clinical trials in acute myeloid leukemia, a bone-marrow cancer, revealed safety and efficacy issues (8–12). Mylotarg is an ADC chemotherapy agent composed of a recombinant, humanized IgG4, kappa antibody against the CD33 antigen, conjugated to a cytotoxic antitumor antibiotic, N-acetyl gamma calicheamicin dimethyl hydrazide (DNA-disrupting agent), through the acid labile acetylphenoxy butanoic linker (12). Mylotarg is a heterogenous mixture of approximately 50% mAb with two to three cytotoxin moieties per mAb and 50% unconjugated mAb (10, 12). This ADC was never approved in Europe and did not extend survival rates, but showed a higher fatal toxicity rate than chemotherapy alone (8, 9, 11, 12).