Trastuzumab deruxtecan
(Synonyms: DS-8201 (solution); DS-8201a (solution)) 目录号 : GC61473
Trastuzumab deruxtecan（曲妥珠单抗）是一种人表皮生长因子受体2（HER2）靶向抗体-药物偶联物（ADC），由人源化抗人HER2（抗hHER2）抗体、酶促裂解肽接头和拓扑异构酶I抑制剂（DX-8951衍生物）组成。
Cas No.:1826843-81-5
Sample solution is provided at 25 µL, 10mM.
Trastuzumab deruxtecan is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) composed of a humanized anti-human HER2 (anti-hHER2) antibody, an enzymatically cleavable peptide linker, and a topoisomerase I inhibitor (DX-8951 derivative)[1]. Trastuzumab deruxtecan has shown sustained antitumor activity in a population of patients with previously treated HER2-positive metastatic breast cancer[2]. The primary mechanism of action of Trastuzumab deruxtecan is antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to FcγRIII on immune effector cells[3].
In vitro, Trastuzumab deruxtecan (10μg/mL) treatment of KPL-4 cells for 72h induced Chk1 and histone H2A.X phosphorylation and PARP cleavage, and induced DNA damage and apoptosis[4]. Trastuzumab deruxtecan (0-100μg/mL) treatment of SK-BR-3 cells for 24h induced downregulation of intracellular pAkt in a dose-dependent manner[4]. Trastuzumab deruxtecan (0.2μg/mL) treatment of N87 parental cells and N87 T-DM1-resistant (TDMR) cells for 15 days, significantly inhibited cell proliferation[5].
In vivo, Trastuzumab deruxtecan (10mg/kg, once a week) was intravenously injected into CT26.WT-hHER2 cell xenograft mice for 2 weeks, significantly inhibiting tumor growth in mice and forming immune memory[6].
References:
[1] Nakada T, Sugihara K, Jikoh T, et al. The latest research and development into the antibody–drug conjugate,[fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy[J]. Chemical and Pharmaceutical Bulletin, 2019, 67(3): 173-185.
[2] Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer[J]. New England Journal of Medicine, 2020, 382(7): 610-621.
[3] Mandó P, Rivero S G, Rizzo M M, et al. Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era[J]. The Breast, 2021, 60: 15-25.
[4] 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-DM1[J]. Clinical Cancer Research, 2016, 22(20): 5097-5108.
[5] Takegawa N, Nonagase Y, Yonesaka K, et al. DS‐8201a, a new HER2‐targeting antibody–drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2‐positive gastric cancer T‐DM1 resistance[J]. International journal of cancer, 2017, 141(8): 1682-1689.
[6] Iwata T N, Ishii C, Ishida S, et al. A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model[J]. Molecular cancer therapeutics, 2018, 17(7): 1494-1503.
Trastuzumab deruxtecan（曲妥珠单抗）是一种人表皮生长因子受体2（HER2）靶向抗体-药物偶联物（ADC），由人源化抗人HER2（抗hHER2）抗体、酶促裂解肽接头和拓扑异构酶I抑制剂（DX-8951衍生物）组成[1]。Trastuzumab deruxtecan在接受过治疗的HER2阳性转移性乳腺癌患者群体中显示出持久的抗肿瘤活性[2]。Trastuzumab deruxtecan的主要作用机制是通过与免疫效应细胞上的FcγRIII结合而发挥抗体依赖性细胞介导的细胞毒作用（ADCC）[3]。
在体外，Trastuzumab deruxtecan（10μg/mL）处理KPL-4细胞72h，诱导了Chk1 和组蛋白H2A.X磷酸化以及PARP裂解，诱导了DNA损伤和细胞凋亡[4]。Trastuzumab deruxtecan（0-100μg/mL）处理SK-BR-3细胞24h，以剂量依赖性方式诱导了细胞内pAkt的下调[4]。Trastuzumab deruxtecan（0.2μg/mL）处理N87亲本细胞和N87 T-DM1抗性（TDMR）细胞15天，均显著抑制了细胞的增殖[5]。
在体内，Trastuzumab deruxtecan（10mg/kg, once a week）通过静脉注射治疗CT26.WT-hHER2细胞异种移植小鼠2周，显著抑制了小鼠体内肿瘤生长，并形成了免疫记忆[6]。
| Cell experiment [1]: | |
Cell lines | KPL-4 cells |
Preparation Method | KPL-4 cells were treated with Trastuzumab deruxtecan (10μg/mL), anti-HER2 Ab (10μg/mL), and DXd (10nM) for 72h. Several proteins were detected by Western blotting. |
Reaction Conditions | 10μg/mL; 72h |
Applications | Trastuzumab deruxtecan induced the phosphorylations of Chk1 and Histone H2A.X, and PARP cleavage in KPL-4 cells. |
| Animal experiment [2]: | |
Animal models | BALB/c mice |
Preparation Method | Mice were inoculated with CT26.WT-hHER2 cells suspended in saline into the right flank by s.c. injection. When the average volume of tumors reached approximately 100 to 200mm3, the mice were divided into control and treatment groups based on tumor volumes by using the randomized block method, and treatment was initiated (day 0). Trastuzumab deruxtecan (10mg/kg), anti-hHER2 antibody (10mg/kg), and anti–PD-1 antibody (5mg/kg) were administered i.v. at a volume of 10mL/kg to mice. As a control, ABS buffer (10mM Acetate Buffer, 5% sorbitol, and pH5.5) was administered at the same volume as the Trastuzumab deruxtecan. Trastuzumab deruxtecan and anti-hHER2 antibody were administered on days 0 and 7. Anti–PD-1 antibody was administered on days 0, 3, 7, and 10. |
Dosage form | 10mg/kg , once a week, twice; i.v. |
Applications | Compared with anti-hHER2 antibody, Trastuzumab deruxtecan showed a significant antitumor effect. |
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-DM1[J]. Clinical Cancer Research, 2016, 22(20): 5097-5108. [2]Iwata T N, Ishii C, Ishida S, et al. A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model[J]. Molecular cancer therapeutics, 2018, 17(7): 1494-1503. | |
| Cas No. | 1826843-81-5 | SDF | |
| 别名 | DS-8201 (solution); DS-8201a (solution) | ||
| Canonical SMILES | [Trastuzumab deruxtecan] | ||
| 分子式 | 分子量 | 146298.97 | |
| 溶解度 | Soluble in acetonitrile | 储存条件 | -80°C, protect from light |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.0068 mL | 0.0342 mL | 0.0684 mL |
| 5 mM | 0.0014 mL | 0.0068 mL | 0.0137 mL |
| 10 mM | 0.0007 mL | 0.0034 mL | 0.0068 mL |
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