Antibody Drug conjugates (ADCs) are the connection between the best of the new innovative therapeutic technologies. They are composed of an antibody (mAb) linked to a highly potent cytotoxic anti-cancer molecule (toxin). By combining the unique tumor-targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, ADCs are intended to target and kill only the cancer cells and spare healthy cells.
- stable in the bloodstream in order to prevent systemic toxicity due to the premature release of the toxin,
- able to release the toxin after internalization of the ADC into the cancer cells.
Appropriate attachment to linker
Characterized mechanism of action
Disruption of cytoskeleton
The linker is the spacer that connects the monoclonal antibody and the cytotoxic payload. Its main role is to ensure the stability of the whole molecule while being transported within the bloodstream to the antibody’s target. The choice of the linker will also define the global pharmacokinetics of the ADCs. If it is too weak, the payload might be released off-target which increases ADC’s toxicity. If it is too strong, the payload will not be released within the cancer cell which decreases ADC’s effectiveness. Two categories of linkers have been described so-far:
Even if the linker is too strong to release the payload from the antibody, lysosomal elements are still able to degrade the whole antibody. The payload is then free to exert its role within the cancer cells’ cytoplasm. The main advantage is an increased stability in the plasma and a decreased off-target activity, since the payload will remain bound to the antibody.
On the contrary, selective release of the payload can be achieved using enzyme-sensitive linkers. Lysosomes are full of specific degradation enzymes whose activity can be used to release the payload only once the ADC has undergone endocytose. Such linkers have a very good stability within the bloodstream as well, since such enzymes are absent from plasma.
Most coupling reactions are made through the free amine group of lysines residues or reduced cysteine disulfide bonds. The use of natural amino acids do not require pretreatment and allow efficient reactions. But the variable distribution of these non-specific attachment sites among antibody structure can lead to a great heterogeneity of the conjugates.
Site-specific conjugation methods include hydrazine (using formylglycine-generating enzymes) or isopeptide (using transglutaminase) bonds. Engineered cysteine have also been developed by inserting specific groups into disulfide bonds.