All chapters


Topoisomerase Inhibitors as Antibody–Drug Conjugate (ADC) Payloads

Topoisomerase inhibitors represent a novel class of compounds that have been used as stand-alone anticancer agents, and their incorporation into antibody conjugates adds a targeting element to the development of more selective chemotherapy. Topoisomerases are nuclear enzymes involved in relaxing DNA strands for replication and transcription, and inhibitors of these enzymes act by stabilizing DNA–topoisomerase complexes, leading to double-strand breaks. SN-38, the active drug form of the cancer drug irinotecan is a topoisomerase I (TOP1) inhibitor that has been employed in various formulations to improve bioavailability. However, antibody conjugates of SN-38 represent a new approach for improving cancer chemotherapy. This review focuses on the design of antibody–SN-38 conjugates and on the current clinical results obtained for a number of cancers. A more potent form of a TOP1-inhibiting camptothecin derivative, exatecan mesylate, is currently being examined clinically in the antibody–drug conjugate (ADC) format, and DS-8201a, an ADC targeting human epidermal growth factor receptor 2-positive (HER2+) cancers, has shown promising Phase I clinical results in breast and gastric cancers. These ADCs also lend themselves to combination therapy with poly(ADP-ribose)polymerase (PARP) inhibitors and immune checkpoint inhibitors for potentially improving clinical outcomes.

Publication details

Print publication date
15 Jul 2019
Copyright year
Print ISBN
ePub eISBN

From the book series:
Drug Discovery