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

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.

Keywords

• |human epidermal growth factor receptor 2|advanced gastric cancer|antibody drug conjugate|molecular targeted therapy|progress