Dxd (Exatecan derivative)

DXd is a derivative of Exatecan (DX-8951) [1,2,3]. DXd is a potent DNA topoisomerase I (TOP1) inhibitor with an IC50 of 0.31 µM ^[1].

DXd was used as the conjugated drug for DS-8201a, which is a new HER2-targeting antibody-drug conjugates (ADC ) composed of a humanized anti-HER2 antibody, enzymatically cleavable peptide-linker, and a novel topoisomerase I inhibitor ^[1]. Remarkable inhibitory activity to the cell growth was observed for DS-8201a against HER2-positive KPL-4, NCI-N87, and SK-BR-3, with the IC50 values of 26.8, 25.4, and 6.7 ng/mL, respectively ^[1]. DS-8201a clearly showed more potent antitumor efficacy, indicating 99% Tumor growth inhibition (TGI) at the dose of 4 mg/kg in HER2-positive NCI-N87 xenograft model ^[1].

DXd is a part structure of DS-1062a which is a trophoblast cell surface protein 2 (TROP2)-targeting antibody-drug conjugate (ADC) comprised of a humanized anti-TROP2 monoclonal antibody, enzymatically cleavable peptide-linker, and DXd ^[2].

DXd is an important part structure of DS-7300a, a novel B7-H3-targeting ADC, using DXd-ADC technology, which is composed of a humanized anti-B7-H3 mAb, an enzymatically cleavable tetra-peptide-based linker, and a potent TOP1 inhibitor, DXd ^[3].

References:
[1]. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1Preclinical Efficacy of DS-8201a, a Novel HER2-Targeting ADC[J]. Clinical Cancer Research, 2016, 22(20): 5097-5108.
[2]. Okajima D, Yasuda S, Yokouchi Y, et al. Preclinical efficacy studies of DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd[J]. 2018.
[3]. Yamato M, Hasegawa J, Maejima T, et al. DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-based Antibody-Drug Conjugate Targeting B7-H3 Exerts Potent Antitumor Activities in Preclinical Models[J]. Molecular Cancer Therapeutics, 2022.