Abstract
Antibody-drug-conjugates (ADCs) are a class of drugs that deliver potent payloads to specific cells or tissues via cell-specific uptake. ADCs are composed of an antibody that is specific to the intended target which is tethered to a payload by a cleavable linker. They are unique because they have the ability to deliver extremely cytotoxic payloads to only certain areas of the body without harming non-targeted tissues. There are currently ten ADCs that are FDA approved, most of which release amine-containing payloads. There is very limited technology that is effective for releasing alcohol-containing payloads. We have designed a tetrapeptide linker referred to as ”ValCitGlyPro” that has shown success when compared to a simple ester linker (“mc”). We demonstrate that the mc linker is not readily cleaved by lysosomes, while the ValCitGlyPro linker is. Further, we demonstrate that this linker has modest stability in mouse and human serum. Finally, we have evaluated various breast-cancer-targeting ADCs with both the mpValCitGlyPro and the mc linker and have measured the intracellular payload concentration in a breast cancer cell line. Together, this data is being used to evaluate whether the ValCitGlyPro linker system is a suitable technology for the delivery of alcohol-containing payloads.