For antibody-drug conjugates (ADCs) with a commonly used cleavable disulfide or peptide linker, immolation is often a necessary step after linker cleavage to exert cell killing activities. The payload delivery to the site of action by an ADC is limited by pharmacokinetic and dispositional characteristics of the antibody and is relatively slow compared to the delivery of a small molecule drug (SM) after oral administration. The ADC linker determines the mechanism and rate of payload release, which affects both payload exposure and cell killing activities, and is thus a critical part of ADC design. A linker will need to release the payload in tumors in a right form and at a proper rate to achieve a threshold concentration to inhibit cell growth. At the same time, it is desirable to prevent premature payload release into circulation and non-targeted organs. Examples will be given to demonstrate that proper immolation is required for both disulfide and peptide linkers for ADC biological activities. <br/>

ADC linker immolation and cell killing activity

254th National Meeting (2017)

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