Introducing Glycolinkers for the Functionalization of Cytotoxic Drugs and Applications in Antibody-Drug Conjugation Chemistry.

Antibody-drug conjugates (ADCs) are promising alternatives to naked antibodies for selective drug-delivery applications and treatment of diseases such as cancer. Construction of ADCs relies upon site-selective, efficient and mild conjugation technologies. The choice of a chemical linker is especially important, as it affects the overall properties of the ADC. We envisioned that hydrophilic bifunctional chemical linkers based on carbohydrates would be a useful class of derivatization agents for the construction of linker-drug conjugates and ADCs. Herein we describe the synthesis of carbohydrate-based derivatization agents, glycolinker-drug conjugates featuring the tubulin inhibitor monomethyl auristatin E and an ADC based on an anti-EGFR antibody. In addition, an initial in vitro cytotoxicity evaluation of the individual components and the ADC is provided against EGFR-positive cancer cells.