Trastuzumab (Anti-Human HER2, Humanized Antibody)|180288-69-1|安捷凯

Trastuzumab (Anti-Human HER2, Humanized Antibody)

曲妥珠单抗（Anti-Human HER2, Humanized Antibody）是一种人源化 IgG1 单克隆抗体，适用于过度表达 HER2 的浸润性乳腺癌患者。曲妥珠单抗（抗人 HER2，人源化抗体）具有用于 HER2 阳性转移性乳腺癌和 HER2 阳性胃癌研究的潜力。

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Background

Trastuzumab is a fully humanized monoclonal antibody directed at HER2 which binds the external domain of the receptor and exerts its action via a combination of antibody-dependent cytotoxicity, reduced shedding of the extracellular domain, inhibition of dimerization and possibly receptor downregulation^[1,2]. Trastuzumab is used as a standard treatment for breast and metastatic gastric cancer when the cancer cells overexpress HER2^[3].

Trastuzumab combined with MZ1 significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone^[4]. Trastuzumab treated HER2-overexpressing breast cancer cell lines results in induction of p27KIP1 and the Rb-related protein, p130, which in turn significantly reduces the number of cells undergoing S-phase. A number of other phenotypic changes are observed in vitro as a consequence of trastuzumab binding to HER2-overexpressing cells^[5]. Trastuzumab-dendrimer-fluorine drug delivery system is a new form of trastuzumab to treat breast cancer cells in vitro. The potential of Trastuzumab-dendrimer-fluorine drug delivery system is more efficient than trastuzumab alone^[6]

Trastuzumab causes a significant growth inhibition of the outgrowth of macroscopic JIMT-1 xenograft tumors in both nude and SCID mice^[7]. The administration of MZ1 and trastuzumab induced a reduction in tumor progression, while individual treatments failed to do so^[4]

参考文献:
[1]. Ning G, Zhu Q, et al. A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer. BMC Cancer. 2021;21(1):923. Published 2021 Aug 16. doi:10.1186/s12885-021-08283-9
[2]. Okines AF, Cunningham D. Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer. Therap Adv Gastroenterol. 2012 Sep;5(5):301-18.
[3]. Sarosiek T, Morawski P. Trastuzumab and its biosimilars [Trastuzumab and its biosimilars]. Pol Merkur Lekarski. 2018 May 25;44(263):253-257. Polish.
[4]. Noblejas-López MDM, Nieto-Jiménez C, et al. MZ1 co-operates with trastuzumab in HER2 positive breast cancer. J Exp Clin Cancer Res. 2021 Mar 19;40(1):106.
[5]. Sliwkowski MX, Lofgren JA, et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999 Aug;26(4 Suppl 12):60-70.
[6]. Bartusik-Aebisher D, Chrzanowski G, et al. An analytical study of Trastuzumab-dendrimer-fluorine drug delivery system in breast cancer therapy in vitro. Biomed Pharmacother. 2021 Jan;133:111053.
[7]. Barok M, Isola J, et al. Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol Cancer Ther. 2007 Jul;6(7):2065-72.

曲妥珠单抗是一种针对 HER2 的完全人源化单克隆抗体，它结合受体的外部结构域，并通过抗体依赖性细胞毒性、减少细胞外结构域脱落、抑制二聚化和可能的受体下调来发挥作用^[1,2]。当癌细胞过度表达 HER2^[3] 时，曲妥珠单抗被用作乳腺癌和转移性胃癌的标准治疗方法。

与单独使用任何一种药物相比，曲妥珠单抗联合 MZ1 可显着降低细胞增殖、三维结构的形成和细胞侵袭^[4]。曲妥珠单抗处理的 HER2 过表达乳腺癌细胞系导致 p27KIP1 和 Rb 相关蛋白 p130 的诱导，这反过来显着减少了经历 S 期的细胞数量。由于曲妥珠单抗与 HER2 过表达细胞结合，在体外观察到许多其他表型变化^[5]。曲妥珠单抗-树枝状大分子-氟药物递送系统是一种新形式的曲妥珠单抗，可在体外治疗乳腺癌细胞。曲妥珠单抗-树枝状大分子-氟药物递送系统的潜力比单独使用曲妥珠单抗更有效^[6]

曲妥珠单抗可显着抑制裸鼠和 SCID 小鼠肉眼可见的 JIMT-1 异种移植肿瘤的生长^[7]。 MZ1 和曲妥珠单抗的给药诱导了肿瘤进展的减缓，而单独的治疗则未能做到这一点^[4]

Protocol

Cell experiment [1]:

Cell lines

Breast cancer HER2+ cells BT474 and SKBR3

Preparation Method

Cells were seeded on 48-wells plates and were treated 24h later with indicated doses of each drug (MZ1 and trastuzumab), alone or in combination. Cell medium was replaced at 72h with MTT solution for 45min at 37℃.

Reaction Conditions

25-100nM MZ1, 10nM trastuzumab, 25-100nM MZ1+trastuzumab

Applications

MZ1 showed the highest antiproliferative effect. Trastuzumab combined with MZ1 induced a more profound antiproliferative effect than the administration of single agents in both BT474 and SKBR3 cells. A synergistic interaction between trastuzumab and MZ1 in BT474 cells and an additive interaction in SKBR3 cells was observed.

Animal experiment [2]:

Animal models

Female BALB/c nude mice, 4-6 weeks

Preparation Method

Xenografts were used for the experiments once the tumor volume reached about 150-200mm³. Mice were randomly assigned to different groups as follows: (i) vehicle; (ii) trastuzumab 10mg/kg twice weekly of intraperitoneal injection; (iii) AZD5438 20mg/kg daily by oral gavage; (iv) AZD5438+trastuzumab, for 3 weeks. Experiments were ended once the tumor volume surpassed 1500mm3 or mouse weight loss reached 20%.

Dosage form

10mg/kg trastuzumab, 20mg/kg AZD5438

Applications

Trastuzumab exerted antitumor effects in ERBB2-positive AFPGC PDX models. Statistically significant differences were also present in the tumor volume between the group treated with AZD5438 combined with trastuzumab and those treated with AZD5438 or trastuzumab alone in ERBB2 and CCNE1 co-amplified PDX models, but the results were not observed in CCNE1 non-amplified PDX models.

参考文献:

[1]. Noblejas-López MDM, Nieto-Jiménez C, et al. MZ1 co-operates with trastuzumab in HER2 positive breast cancer. J Exp Clin Cancer Res. 2021 Mar 19;40(1):106.

[2]. Lu J, Ding Y, et al. Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets. Nat Commun. 2021;12(1):3946. Published 2021 Jun 24. doi:10.1038/s41467-021-24170-0