By Katie Maass
Antibody-drug conjugates (ADCs) are a promising, emerging class of cancer therapeutics that combine a small molecule drug payload with an antibody that is specific for a cancer-associated antigen. ADCs aim to deliver their drug payload specifically to cancer cells and thus reduce toxicity of the chemotherapeutic drug and increase the amount of drug that gets to the tumor. Currently, there are two FDA-approved ADCs (Trastuzumab-DM1 [Kadcyla] and Brentuximab Vedotin [Adcetris]), with more than 30 other ADCs in clinical trials.
Once an ADC reaches a cancer cell, (1) it binds the target antigen on the cell surface, (2) it gets internalized into the cell (via receptor-mediated endocytosis), (3) it gets degraded in the endosomal/lysosomal compartments, which releases the drug payload from the antibody, and (4) the drug payload binds to its intracellular target, resulting in cell death. In addition, some drug payload may also leave the cell and potentially affect nearby cells, which is known as the bystander effect.
At the upcoming 2015 AAPS National Biotechnology Conference, I will present my work in the Wittrup Lab in collaboration with Chethana Kulkarni and Alison Betts of Pfizer on determining the rates at which each of these processing steps occur for an ADC. We focus on the cellular-level processing since this level is where many of the unanswered questions remain and where ADCs act mechanistically. Previous studies have established that ADCs traffic through the body very similarly to their antibody component, as long as there are not too many drug payloads added per antibody. In our work, we have developed a basic kinetic model for ADC cellular processing as well as generalizable methods for determining the kinetic rate parameters for a given ADC. Although companies developing ADCs have emphasized the importance of internalization rate, we found that for an ADC structurally equivalent to Trastuzumab-DM1, the rate of drug payload efflux is also a key parameter for determining how much drug gets delivered to its intracellular target.
These results also raise many questions yet to be answered:
- How do design parameters (such as linker type, drug payload, and antigen target) affect the rates at which an ADC gets processed by cells?
- How does the drug payload escape the endosomal/lysosomal compartments? How much drug payload actually gets to its intracellular target (i.e., how efficient are ADCs at delivery)?
With our model as a framework, pharmaceutical scientists can now begin to address some of these questions about how ADCs get processed by cells.