Antibody-drug conjugates (ADCs) are an increasingly popular modality for targeted drug delivery in many oncological and immunological applications. Classically, ADC-mediated delivery has been largely restricted to amine-containing payload using the well-studied ValCitPABC linker. There are surprisingly few ADC technologies for releasing alcohols despite its functional prevalence across a myriad of biologically active small molecules. We propose a self-immolative glycine-proline (GlyPro) spacer can be added to the ValCit linker system in order to deliver alcohol-containing payloads via lysosomal cleavage of ValCit, and subsequent cytosolic payload release by GlyPro upon lysosomal egress.<br/>The efficiency of this linker (ValCitGlyPro) was examined using a model system designed to release glucocorticoid dexamethasone. Kinetic studies demonstrated our linker system results in rapid GlyPro-Dexamethasone release in lysosomes, and subsequent cyclization to release dexamethasone in the cytosolic environment. We also report our efforts to expand the utility of this linker system for the release of anilines, amines, and indoles.

GlyPro as a self-immolative spacer for the release of payloads from antibody-drug-conjugates

ACS Spring Meeting 2021

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