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
Many clinically relevant mAbs were initially developed using mouse–human hybridoma technology, which resulted in mAbs that
contained nonhuman proteins. Although therapeutically useful, these nonhuman proteins can cause cytokine-release syndrome
or uncontrolled hypercytokinemia, thus resulting in multiple organ damage. Technologies to reduce the proportion of mouse
protein in the mAb, including chimerization (i.e., partial replacement of mouse mAb sequences with human mAb) and humanization
(i.e., essentially complete replacement with human sequences) reduce this toxicity. Humanized antibodies are approved to treat
in cancer, inflammation, autoimmunity, and infectious diseases and to remediate transplant rejection. The pharmacokinetics
(PK) and pharmacodynamics (PD) of mAbs are complex and depend upon the mAb isotype, subtype, half-life, and target indication
Ideal 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
Figure 1: Structure of trastuzumab emtansine (T-DM1). Reproduced with permission from Discovery Medicine, A. Beck et al.,
Discov. Med. 10 (53), 329–339 (2010). (FIGURE 1 IS COURTESY OF DISCOVERY MEDICINE AS CITED WITH CREDIT IN FIGURE 1.)
Trastuzumab emtansine (T-DM1), an ADC developed by Genentech (now part of Roche), combines the mAb Herceptin (trastuzumab),
which targets human epidermal growth factor receptor 2 (HER2) receptors in breast and stomach cancer, with maytansine, a small-molecule
cytotoxin that binds to tubulin to prevent microtubule formation through a nonreducible bis-maleimido-trixyethylene glycol
linker (see Figure 1). Trastuzumab is approved for use only in HER2-positive cancers, but not all HER2-positive cells have
sufficient apoptotic capacity to be killed by trastuzumab binding alone (3). T-DM1 combines the ability of trastuzumab to
selectively target the HER2 receptor with the potent cytotoxic agent, maytansine, to kill the cell regardless of the HER2-induced
apoptotic response (4). T-DM1 binding to the HER2 receptor causes internalization into the cell where the maytansine is released
from the antibody conjugate to kill the tumor cell (3–7). T-DM1 induces a potent antiproliferative effect in trastuzumab-resistant
tumor cells, but does not affect normal human cells. Also, T-DM1, but not trastuzumab, induces cell lysis in breast tumor
cells in vitro (4). Likewise, T-DM1-inhibited tumor growth caused tumor regression in animal models of HER2-positive breast cancer. T-DM1
showed overall better efficacy and PK than trastuzumabwith diminished toxicity in vivo and in vitro (5). T-DM1 also showed success in recent Phase II clinical trials (4–7).
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).