Drug-Linker Conjugates for ADC

Antibody Drug Conjugates (ADC) are a rapidly expanding area in the pharmaceutical industry. They comprise of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker. There are over 30 ADCs currently in pre-clinical or clinical development, and further improvements may be required to enhance the therapeutic potential of these ADCs. Monoclonal antibodies (mAbs) are of great use in many applications ranging from basic research to treatment of disease. The Drug-Linker Conjugates can expand the utility of mAbs and improve their potency and effectiveness; the antibodies are thus used as a means to target and delivery a toxic payload to the selected diseased tissue. The site-specific conjugations of Drug-Linker to an antibody may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. The cytotoxic drug, monomethyl auristatin E (MMAE), is conjugated to the three trastuzumab variants using a protease cleavable linker and shows in vivo therapeutic efficacy. The linker-MMAE conjugate is used in the U.S. FDA approved ADC, Brentuximab vedotin. There are also ADCs adopting linker-MMAE conjugate under clinical trials, such as Enfortumab vedotin and Glembatumumab vedotin.