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Antibody drug-conjugate (ADC) technology is a rapidly evolving modality for targeted drug delivery. Much of the success of ADCs is due to technical advances made in the design of the peptide linkage between the antibody and the therapeutic payload. This linkage has been optimized to be stable in circulation while maintaining a rapid release mechanism that is specific to lysosomal conditions. However, some ADCs have exhibited stability problems due to high solvent exposure of the linker-payload to the surrounding environment which can result in premature cleavage of the linkage by endogenous proteases in circulation, thus leading to off-target toxicity. For example, the prototypical ADC linker ValCitPABC has been shown to undergo premature cleavage by esterases and by neutrophil elastases, thus driving some adverse effects. The goal of this project is to develop a new generation of proteolytically cleavable linkers that offer increased stability to extracellular esterases and proteases.



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Optimization of ADC linkers: Design and Evaluation of a FRET-based ADC Linker-Library