Monoclonal antibody designed to target specific attributes of and attach to cancer cells
The 123s of ADCs
How do we make the parts of ADCs?
This week we will look at how Antibody Drug Conjugates (ADC) are made. Not all ADCs are produced in exactly the same way, but here is a high-level overview example. First let’s look at production of the parts of an ADC.
1. mAb
The mAb consists of four polypeptide chains (two identical larger chains referred to as the "heavy" chains and two smaller identical chains referred to as the "light" chains). These chains are connected through chemical bonds. Ab's are produced by fermentation using specialized cell lines. Scientists modify the cells' DNA to produce a specific mAb – one that targets the receptor of interest for a specific disease. The mAb is recovered from the fermentation broth and purified resulting in an aqueous (water based) solution of the mAb.
2. Active drug
Molecule which has the desired effect for cancer, it causes death of the cancer cell
3. Linker
Molecule that joins the mAb and active drug
The active drug and linker are made by chemical synthesis like the active ingredients we make and formulate into tablets or capsules. Because these drugs are delivered directly to target cells and due to their potency, not very much drug is required for each dose.
Due to the smaller amounts of drug which are required for an effective dose, these molecules are usually made in pilot scale manufacturing facilities. Grams vs kilograms are needed for development and launch. The potency and cytotoxicity of these molecules require specific containment equipment and procedures to produce and handle them.
Drug-Linker
The drug and the linker are attached to each other
Drug linkers are produced by chemical synthesis by attaching the drug to one end of the linker molecule and are typically isolated as solid powders.
How do we put the parts together?
So, we have a solution of mAb and we have a container of drug-linker, now what?
The chains of the mAb are attached through disulfide bonds – these are bonds between two sulfur atoms, one attached to each chain. These are represented in the picture below as the black lines.
For the first step in building the ADC, the disulfide bonds are chemically broken. This results in two sulfur atoms freed to react with the drug-linker molecule.
In the next step, the drug-linker is added to the mAb and the other end of the linker is attached to the mAb via chemical bonds with the free sulfur atoms.
The resulting ADC is a combination of a small molecule and a large molecule (biologic). The ADC is treated as a large molecule with respect to purification and formulation. The final product is a solution of the ADC molecules.
The final ADC can be filled into vials as a solution to be added to an IV bag or can be lyophilized to provide a powder in a vial ready to be reconstituted at the hospital.
The parts are not necessarily specific to one ADC product. The drug, the linker and the mAb can be combined in different ways to change the specificity and efficiency of the ADC.
For example, a different drug-linker could be added to the mAb in our example. The resulting ADC would target the same receptor on a cancer cell but deliver a different active drug.
Or the same drug-linker in our example could be added to a different mAb. This resulting would target a different receptor on a cancer cell but deliver the same active drug.
