Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer

Yinnan KANG; Shun CHEN; Youcheng XIE; Ying ZHENG; Yujing HE; Chuyi LI; Xiaohui YU

doi:10.19401/j.cnki.1007-3639.2023.08.008

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Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer

Review | 更新时间：2025-12-31

- Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer
- China Oncology Vol. 33, Issue 8, Pages: 790-800(2023)
- 作者机构：
  
  1. 甘肃中医药大学第一临床医学院，甘肃兰州 730000
  2. 中国人民解放军联勤保障部队第九四〇医院消化内科二区，甘肃兰州 730000
  3. 兰州大学第二医院，甘肃兰州 730000
  4. 中国人民解放军联勤保障部队第九四〇医院基础医学实验室，甘肃省干细胞与基因药物重点实验室，甘肃兰州 730000
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.08.008
  CLC： R735.2
- Received：26 October 2022，
  
  Revised：2023-07-13，
  
  Published：30 August 2023
- 稿件说明：
移动端阅览
Yinnan KANG, Shun CHEN, Youcheng XIE, et al. Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer[J]. China Oncology, 2023, 33(8): 790-800.
DOI：

Yinnan KANG, Shun CHEN, Youcheng XIE, et al. Application and research progress of antibody drug conjugates in HER2 positive advanced gastric cancer[J]. China Oncology, 2023, 33(8): 790-800. DOI： 10.19401/j.cnki.1007-3639.2023.08.008.

摘要

胃癌是一种异质性和侵袭性极高的恶性肿瘤，在全球范围内其发病率居第5位，死亡率居第3位。多数患者确诊时已处于进展期，预后极差。全身治疗是目前晚期胃癌最主要的治疗方式，人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）是HER2阳性胃癌的重要治疗靶点。随着HER2靶向药物和治疗方式的不断优化，一些胃癌患者已从中获益。但是耐药发生率高、不良反应严重仍是限制HER2靶向药物应用的瓶颈。因此，开发新型抗肿瘤药物对改善HER2阳性胃癌患者的长期生存具有重要意义。抗体药物偶联物（antibody drug conjugate，ADC）是一类新型、高效的抗肿瘤药物，由特异性靶向单克隆抗体、化学接头和小分子细胞毒性有效载荷组成，强大的治疗效果和适度的组织毒性是其主要优势。近年来，ADC在HER2阳性晚期胃癌的靶向治疗领域进展颇丰。首先，经过多年发展，包括DS-8201、RC48等在内的多种ADC已用于胃癌的二线及后线治疗。其次，随着ADC生物工程技术的进步，包括高药物抗体比例、可切割型连接子、能引发旁观者效应的毒性载荷等，使新型ADC能够在针对特定靶点肿瘤的治疗中发挥更为显著的治疗效果，其中一些ADC还具备多靶向性，能针对多个特异性靶点发挥抗癌功效。同时，ADC的研发已到达第三阶段，新一代ADC通过位点特异性偶联技术，其均质单一性更高，细胞毒性载荷更高效，精准度更高，非靶向毒性作用更低。此外，ADC和免疫检查点抑制剂（immune checkpoint inhibitor，ICI）组成的“靶免联合”治疗可能是晚期胃癌一种有前景的治疗策略。本文就靶向治疗时代ADC在HER2阳性晚期胃癌患者中的应用和最新研究进展进行综述，并讨论ADC联合ICI在HER2阳性晚期胃癌中的治疗前景和治疗过程中面临的挑战。

Abstract

Gastric cancer is a malignant tumor with high heterogeneity and invasiveness. Its incidence rate ranks fifth in the world

and its mortality ranks third in the world. Most patients are in a state that cancer cannot be removed by surgery when symptoms appear. At present

systemic treatment is the main treatment for advanced gastric cancer

and human epidermal growth factor receptor 2 (HER2) is one of the important treatment targets for HER2 positive gastric cancer patients. With the continuous optimization of chemotherapy regimen and targeted drugs

the prognosis of some HER2 positive gastric cancer patients has improved significantly. However

the high incidence of drug resistance and high toxicity and side effects are still the bottlenecks limiting the application of HER2 targeted drugs. Therefore

the development of new anti-tumor drugs is of great significance to improve the long-term survival of HER2 positive gastric cancer patients. Antibody drug conjugate (ADC) is a new and efficient anti-tumor drug

which is composed of specific targeted monoclonal antibody

chemical connector and small molecular cytotoxic payload. Its main advantages are strong therapeutic effect and moderate tissue toxicity. In recent years

ADC has set off a huge upsurge in the targeted treatment of HER2 positive advanced gastric cancer. First

after years of development

a variety of ADC including DS-8201 and RC48 have been used in the second- and second-line treatment of gastric cancer. Secondly

with the progress of ADC bioengineering technology

including high proportion of drug antibodies

cleavable linkers

toxic loads that can trigger bystander effect

the new type of ADC can play a more significant therapeutic role in the treatment of specific target tumors

and some of them also have multiple targets and can have anti-tumor effect on multiple specific targets. At the same time

the research and development process of ADC has reached the third stage. The new generation of ADC

through site-specific coupling technology

has higher homogeneity and uniformity

more effective cytotoxic molecules

higher accuracy and lower non-targeted toxicity. In addition

the "targeted immunotherapy" composed of ADC and immune checkpoint inhibitor (ICI) may be a promising treatment strategy for advanced gastric cancer. This article briefly reviewed the application and the latest research progress of ADC in HER2 positive advanced gastric cancer patients in the era of targeted therapy

and discussed the treatment prospects and challenges of ADC combined with ICI in HER2 positive advanced gastric cancer.

关键词

Keywords

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