Development of novel DNA topoisomerase I inhibitor based ADC technology

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 ad...

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Bibliographic Details
Published inDrug Delivery System Vol. 34; no. 1; pp. 52 - 58
Main Authors Abe, Yuki, Nakada, Takashi, Agatsuma, Toshinori
Format Journal Article
LanguageJapanese
Published Kawasaki THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM 2019
Japan Science and Technology Agency
Subjects
ADC
Antibodies
Anticancer properties
Antitumor agents
Breast cancer
bystander effect
Chemotherapy
Clinical trials
Deoxyribonucleic acid
DNA
DNA topoisomerase
Drug delivery
Drug delivery systems
ErbB-2 protein
exatecan
Gastric cancer
HER2
Inhibitors
Monoclonal antibodies
Targeted cancer therapy
Technology
Trastuzumab
Tumors
Xenografts
Xenotransplantation
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Summary: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.
ISSN:0913-5006
1881-2732
DOI:10.2745/dds.34.52