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Antibody-drug conjugates (ADCs) present a unique opportunity to increase the safety of highly toxic drugs by utilizing the specificity of antibodies to deliver (typically amine-containing) payloads to specific tissues. However, there are few technologies for attaching alcohol-containing payloads to an antibody. Theoretically, this would be simplest with the use of an ester linkage. However, little is known about the lysosomal and plasma stability of ester linkages on ADCs. Herein, we describe various experiments evaluating this stability in both human/mouse plasma and in lysosomes, as well as the design of a lysosomally cleavable peptide-linked ester. The stability of ester-linked payloads was demonstrated by observing an ester-linked ADC in the presence of lysosomes. The ester remained intact while the antibody backbone was proteolytically degraded. The lysosomal stability of this linkage was additionally confirmed in a cell-based system using SKBR3 cells. We next undertook the design of a novel linker that is stable in mouse plasma, but upon lysosomal uptake, undergoes immolation, resulting in spontaneous ester cleavage. With this research, we hope to further our knowledge of ester linkages in ADCs as well as to develop a feasible way to release an unmodified alcohol-containing drug into a chosen cell type.



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Esters in ADC linkers: Optimization of stability and lysosomal cleavage