演題：
Topoisomerase I inhibitors Antibody Drug Conjugates: from molecular pharmacology to predictive biomarkers

演者：
Dr. Yves Pommier
NIH Scientist Emeritus and Chief, 
Laboratory of Molecular Pharmacology & Developmental Therapeutics Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
 
抄録：
Topoisomerase I (TOP1) inhibitors are among the most potent and widely used anticancer agents. Antibody Drug Conjugates (ADCs) are in full development against a variety of solid tumors. They consist of three key components: a humanized antibody, a cytotoxic drug (referred to as the “payload”) and a chemical linker bridging the payload and the antibody. Because the number of drug molecules per antibody (ADR: Antibody Drug Ratio) is limited (currently to up to 16), the payload needs to be potent in the low nanomolar range, which can be achieved with the new TOP1 inhibitor camptothecin derivatives as well as non-camptothecin derivatives. The chemistry of the linker also needs to be tuned to allow the release of the payload inside the targeted cancer cell without release in the blood. Finally, the antibody must be selectively expressed on the surface of tumor cells and not on normal cells. We will discuss the molecular pharmacology differences between payloads (TOP1- vs. tubulin- vs. DNA-targeted drugs) and the importance of choosing the optimum payload based on cellular biomarkers of response such as Schlafen 11 (SLFN11) and drug efflux transporters. We will also propose how to use predictive biomarkers to select appropriate ADCs and how ADCs allow “Gap Scheduling” of TOP1-ADCs with DNA damage response inhibitors, such as PARP and ATR inhibitors.
 
日　時：２０２５年１２月１２日(金)　１５:００〜１６:００
場　所：吉田記念講堂