Related Experiment Video
Updated: Jul 5, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is
Hirokazu Suzuki1, Shotaro Nagase1, Chiemi Saito1
1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Abstract:
Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, and safety profile. In vitro pharmacologic activities and the mechanisms of action of R-DXd were assessed in serous-type ovarian cancer and renal cell carcinoma cell lines. In vivo pharmacologic activities were evaluated with several human cancer cell lines and patient-derived xenograft mouse models. The safety profile in cynomolgus monkeys was also assessed. R-DXd exhibited CDH6 expression-dependent cell growth-inhibitory activity and induced tumor regression in xenograft models. In this process, R-DXd specifically bound to CDH6, was internalized into cancer cells, and then translocated to the lysosome. The DXd released from R-DXd induced the phosphorylation of Chk1, a DNA damage marker, and cleaved caspase-3, an apoptosis marker, in cancer cells. It was also confirmed that the DXd payload had a bystander effect, passing through the cell membrane and impacting surrounding cells. The safety profile of R-DXd was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. R-DXd demonstrated potent antitumor activity against CDH6-expressing tumors in mice and an acceptable safety profile in monkeys. These findings indicate the potential of R-DXd as a new treatment option for patients with CDH6-expressing serous-type ovarian cancer and renal cell carcinoma in a clinical setting.
Insights
A new antibody-drug conjugate, raludotatug deruxtecan (R-DXd), shows potent antitumor activity against CDH6-expressing cancers. This targeted therapy demonstrated tumor regression and an acceptable safety profile in preclinical studies.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Cadherin-6 (CDH6) is a biomarker in several cancers, lacking targeted therapies.
- Antibody-drug conjugates (ADCs) offer targeted cancer treatment strategies.
Purpose of the Study:
- To evaluate the preclinical efficacy and safety of raludotatug deruxtecan (R-DXd), a novel CDH6-targeting ADC.
- To investigate the mechanism of action of R-DXd in CDH6-expressing cancer models.
Main Methods:
- In vitro and in vivo studies using ovarian and renal cancer cell lines and patient-derived xenografts.
- Pharmacologic activity, mechanism of action, and safety assessments in cell lines, xenograft models, and cynomolgus monkeys.
Main Results:
- R-DXd demonstrated CDH6-dependent inhibition of cancer cell growth and significant tumor regression in vivo.
- Internalization, lysosomal translocation, and DNA damage induction (Chk1 phosphorylation, caspase-3 cleavage) by R-DXd were confirmed.
- The DXd payload exhibited a bystander effect, impacting surrounding tumor cells.
- R-DXd showed a favorable safety profile in cynomolgus monkeys, with a highest non-severely toxic dose of 30 mg/kg.
Conclusions:
- R-DXd exhibits potent antitumor activity against CDH6-expressing tumors.
- R-DXd has a promising safety profile, supporting its potential as a novel therapeutic for CDH6-positive ovarian and renal cell carcinomas.
