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]。