Development of novel DNA topoisomerase I inhibitor based ADC technology

Abstract

Antibody-drug conjugate (ADC) represents a promising class of drugs with a wider therapeutic index than conventional chemotherapy due to their efficient and selective drug delivery. We have developed a novel ADC technology with a potent DNA topoisomerase I inhibitor exatecan derivative. The major advantages of the technology are high and homogeneous drug to antibody ratio, potent anti-tumor activity with bystander effect, less safety concerns due to the stable linker limiting the release of free drug in the circulation and short systemic half-life of the payload. Using this technology, we generated a new anti-HER2 ADC called DS-8201a. DS-8201a was effective against T-DM1-insensitive patient-derived xenograft (PDX) models with high HER2 expression and also demonstrated anti-tumor efficacy against breast cancer PDX models with low HER2 expression. The results of Phase 1 study suggest that DS-8201a was well tolerated and clearly active in breast cancer patients including T-DM1 refractory patients, trastuzumab treated gastric cancer patients and other HER2 expressing and/or mutated cancer patients. Currently, Phase 2 and Phase 3 trials are on-going across multiple tumor types. We also confirmed the versatility of the technology to different combinations of targets and antibodies and showed importance of this new class of novel topoisomerase I inhibitor-based ADC technology.