Definitely yes. The ADC linker is of the same, if not more, importance as it determines the final success of an ADC.
A qualified linker should meet a lot of requirements. First, a liker should be stable in circulation which prevents healthy cells from being damaged. However, upon internalization, the linkers should perform its role properly by releasing the cytotoxic drugs in the most ideal microenvironment. The cytotoxic drug will further bind to their targets, thus making cancer cells nowhere to escape. It has been proved that the stability and rupturing capacity of linkers can affect the overall pharmacokinetics (PK) properties, toxicities and therapeutic indexes of ADCs. Whether linkers can effectively balance all these attributes is a determining factor for ADCs to enter the clinic. Some earlier ADCs (BR96-DOX and Mylotarg@, for instance) had been withdrawn from the market due to the poor stability of their linkers.
