Toxic payload drugs are an essential component of any therapeutic ADC. In reality, not every toxin is suitable to be used as an ADC payload. To serve this very purpose, the toxins must meet some stringent criteria:
- The payload must exert extremely high cytotoxic efficacy (IC50 within the low pM to low nM range). Many factors, including IgG tumor penetration, target antigen expression level, ADC internalization… may lead to limited drug delivery and result in a low intracellular toxin level. Thus, high toxicity is needed to compensate the low drug concentration for efficient tumor cell killing.
- Since current ADC strategies rely on the internalization of the toxin conjugates to achieve drug delivery and the antibody and/or linker lysosomal degradation to achieve drug release, the targets of the payloads must be located inside the cell.
- A suitable payload should be small in size to minimize the risk of immunogenicity. It should also have decent water solubility to facilitate the aqueous conjugation reactions.
- An ADC payload should exert adequate plasma stability to maintain drug efficacy before reaching the target.
