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.
DXd 是 Exatecan (DX-8951) [1,2,3] 的衍生物。 DXd 是一种有效的 DNA 拓扑异构酶 I (TOP1) 抑制剂,IC50 为 0.31 μM [1]。
DXd 用作 DS-8201a 的偶联药物,DS-8201a 是一种新型 HER2 靶向抗体药物偶联物 (ADC),由人源化抗 HER2 抗体、可酶促切割的肽接头和新型拓扑异构酶 I 抑制剂组成[1]。观察到 DS-8201a 对 HER2 阳性 KPL-4、NCI-N87 和 SK-BR-3 具有显着的细胞生长抑制活性,IC50 值分别为 26.8、25.4 和 6.7 ng/mL [1]。 DS-8201a 清楚地显示出更有效的抗肿瘤功效,表明在 HER2 阳性 NCI-N87 异种移植模型中以 4 mg/kg 的剂量达到 99% 的肿瘤生长抑制 (TGI) [1]。
DXd 是 DS-1062a 的部分结构,DS-1062a 是滋养层细胞表面蛋白 2 (TROP2) 靶向抗体-药物偶联物 (ADC),由人源化抗 TROP2 单克隆抗体、酶促可裂解的肽接头和 DXd 组成[2].
DXd 是 DS-7300a 的重要组成部分结构,DS-7300a 是一种新型 B7-H3 靶向 ADC,采用 DXd-ADC 技术,由人源化抗 B7-H3 单克隆抗体、一种可酶促裂解的四肽基抗体组成接头,以及一种有效的 TOP1 抑制剂 DXd [3]。