Disulfide-Cleavable Linkers in Antibody-Drug Conjugates for Targeted Cancer Therapy

Abstract

This project aims to discover a way to improve the safety of and reduce adverse side effects of disulfide-linked antibody-drug conjugates. Disulfide-cleavable linkers for antibody-drug conjugates function by exploiting the differential concentrations of dominant thiol species in the blood plasma and in the cytosol of malignant cells. This project aimed to identify a relationship between the stability of disulfide cleavable linkers in the blood plasma and disulfide linker structure, to prevent premature release of the cytotoxic drug. Three disulfide linker analogs with varying carbon chain lengths were synthesized through reaction with 2,2’-dipyridyl disulfide. Each analog was conjugated to a fluorescent indicator to allow for visible determination of disulfide bond cleavage. Linker-fluorescein conjugates were assayed in both NaHS and DTT solutions of concentrations ranging from 0.422mM-10mM. The results of this study determined that linker length does influence bond stability and reduction kinetics by influencing the size of the cyclic byproduct, with the 4C linker proving to be the most effective in blood stability and drug release