The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates

DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

Automated summary

DNA topoisomerases are crucial enzymes for maintaining DNA stability, with topoisomerase inhibitors being utilized as anti-cancer drugs. Among them, camptothecin and its derivatives have shown promise due to their ability to trap TOP1 cleavage complexes. The development of TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) has led to improved therapeutic efficacy, with potential for further enhancement through combinatorial strategies.