Monoclonal antibodies (mAbs) that have the ability to selectively target cancer cells by binding to specific tumor-associated antigens have carved out an important role in anticancer therapy. The idea of combining that specificity with the potency of cytotoxic chemotherapy in the form of an antibody– drug conjugate (ADC) has tempted oncology researchers for decades.
Yet, although the concept was embraced in laboratories, it has been a bumpy road for ADC development—until now. Initial excitement over the FDA’s approval of the first-in-class ADC gemtuzumab ozogamicin (Mylotarg) in 2000 was tempered by its subsequent withdrawal from the market. It took more than a decade for the successful clinical development of 2 more ADCs, ado-trastuzumab emtansine (T-DM1; Kadcyla) and brentuximab vedotin (Adcetris).
Since then, the field has been revitalized as researchers have used past failures to guide the development of newer drugs with improved designs. In recent years, the floodgates have opened; 2 ADCs were approved in 2017 and more than 50 are in various stages of clinical development. Several ADCs are in phase III trials and have the potential to broaden the range of approved indications for this drug class, particularly for the treatment of solid tumors.
Inotuzumab ozogamicin (Besponsa) became the third ADC on the market in August 2017 when it received regulatory approval for the treatment of patients with acute lymphoblastic leukemia (ALL), based on data from the phase III INO-VATE ALL trial.
Revisiting the past also resulted in re-examination of the role of gemtuzumab ozogamicin, leading to the approval of a new dosing regimen in September 2017 for the treatment of pediatric and adult patients with acute myeloid leukemia (AML).
ADCs are often described as targeted payloads, because the idea is to exploit the specificity of a mAb to allow precise tumor-targeted delivery of the cell-killing power of chemotherapy. The goal is to enhance therapeutic efficacy and reduce systemic toxicity (FIGURE 11
Figure 1. Key Steps in Mechanism of Action of ADCs1
ADCs consist of 3 basic components: a tumor-targeted mAb covalently linked to a cytotoxic drug (often dubbed the “warhead”) via a linker. The mAb binds to a specific antigen on the surface of a cancer cell. This allows the ADC to be taken up into the cell in specialized compartments called endosomes that bud off from the cell membrane. The ADC is then trafficked to the lysosome, an organelle that serves as the cell’s digestive system, where the mAb is broken down into individual amino acids, thereby releasing the payload.
Although it is a relatively straightforward concept, designing a clinically effective ADC is incredibly complex and each of the 3 components has different properties and characteristics that can influence efficacy and safety (FIGURE 21
Figure 2. Structure of an ADC
The ideal target antigen should be highly expressed on cancer cells, with limited expression on healthy tissues, should be internalized upon mAb binding, and should undergo minimal shedding, so that it doesn’t mop up all of the ADC in the circulation before it reaches the target cell.
Another important consideration relating to the mAb component is that it can exert its own antitumor activity via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity, which may or may not be beneficial.
Finding an antibody that checks every box can be tricky and is further complicated by the heterogeneity of antigen expression on tumor cells and its evolution over time under the selective pressure of anticancer therapyThe Payload
Numerous studies have shown that only a very small amount of the ADC makes it into the cell. Therefore, the chemotherapy payload must be much more potent than would normally be tolerated.
The majority of payloads used in ADCs that have entered clinical development kill the target cell either by blocking mitosis or inducing DNA damage. These have predominantly involved 2 families of drugs: the auristatins, monomethyl auristatin E and F (MMAE and MMAF), and the maytansinoids, DM1 and DM4. Among the DNA-damaging drugs is calicheamicin, a highly potent antitumor antibiotic that causes doublestrand DNA breaks by binding to the minor groove of the DNA molecule.