The “API” is the active pharmaceutical ingredient, or the actual active drug molecule which results in an effect in the body. For ADCs the API is often referred to as the “payload” because it is carried and delivered to a target cell by the mAb.
The ABCs of ADCs
What are ADCs?
Antibody drug conjugates (ADC) are a class of therapeutic agents that combine an active pharmaceutical ingredient (API) with a monoclonal antibody to provide a targeted delivery of the API. AbbVie has several ADCs in our pipeline and one commercial product gained with the acquisition of Immunogen. In this issue we will look at the components and mechanism of ADCs.
Let’s look at the parts:
API (drug)
Linker (conjugation agent)
A linker is a molecule that is reactive at one end which can covalently bond to the mAb and reactive at the other end to bond with the API. The linker chemistry needs to balance bonding strength, so the API is not released before it is delivered to the target cell but is released once it does reach the target.
mAb (monoclonal antibody)
A “mAb” is a monoclonal antibody. mAbs are proteins manufactured by bioprocessing using specialized cells (like CHO cells) to produce a specific protein. These mAbs target sources of inflammation.
ADCs can be used to treat many conditions but most often target cancers. The mAbs used in ADCs can target receptors which are more plentiful on the surface of cancer cells than on normal cells. ADCs are engineered to deliver the API directly to the cancer cell.
How do ADCs work?
ADCs are being investigated in many fields of medicine. The mechanism is similar for all. A mAb is used to bring an active ingredient to a specific type of cell in the body. This allows for more precise dosing and delivery. For cancer drugs this is especially important as the goal of cancer drugs is to kill the cancer cells, but often cannot differentiate healthy vs diseased cells and have adverse side effects. The goal of ADC development is to design a monoclonal antibody that is specific to an antigen/receptor present in the condition targeted for treatment, an effective API and a linker that can bring the two together and deliver the API to its target.
An Example:
One type of receptor found on tumor cells is called c-Met. If we use this as an example, then the mAb will be engineered to target the c-Met receptor on the surface of tumor cells.
First the mAb portion of the ADC will bind with the receptor on the surface of the cell and then the cytotoxin (payload) is delivered to the cell.
Once inside the cell, the cytotoxic payload will destroy the cell or prevent the cell from continuing to replicate. The mechanism depends on the design of the cytotoxin. In this example the payload inhibits topoisomerase 1 which is involved in DNA replication. If the cell cannot replicate its DNA, it cannot form another cancer cell.
This is the theory, but it doesn’t work perfectly. Scientists at AbbVie and other companies are working to improve the technology and molecules to make this exciting class of compounds even better!
