Research Progress of Antibody–Drug Conjugate Therapy for Advanced Gastric Cancer

Abstract

Gastric cancer is an intractable malignant tumor that has the fifth highest morbidity and the third highest mortality in the world. Even though various treatment options did much to ameliorate the prognosis of advanced gastric cancer, the survival time remained unsatisfactory. It is significant to develop new therapeutic agents to improve the long-term outcome. Antibody–drug conjugate is an innovative and potent antineoplastic drug composed of a specifically targeted monoclonal antibody, a chemical linker, and a small molecule cytotoxic payload. Powerful therapeutic efficacy and moderate toxicity are its preponderant advantages, which imply the inevitable pharmaceutical developments to meet the demand for individualized precision therapy. Nevertheless, it is unavoidable that there is a phenomenon of drug resistance in this agent. This article systematically reviewed the recent progress of antibody–drug conjugates in advanced gastric cancer therapy.

Synthetic Approaches to the New Drugs Approved During 2022

“…MMAE and cleavable linker mc-Val-Cit-PABC have been used in combination in a number of other approved ADCs beginning with Adcetris, which was covered in the 2011 installment of this review . Further, two previously approved ADCs, trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (DS-8201a), also target HER2 via conjugation to the known trastuzumab antibody, although with mixed results for the treatment of HER2+ gastric cancer. − Disitamab vedotin employs a novel HER2-targeting antibody, hertuzumab (disitamab), which is known to have a higher binding affinity to HER2 compared to trastuzumab − and targets different epitopes of the HER2 receptor . Clinically this translates to improved antitumor activity with reduced systemic side effects along with selective delivery of MMAE to HER2 positive cells and tumor tissue .…”

“…212−214 Disitamab vedotin employs a novel HER2-targeting antibody, hertuzumab (disitamab), which is known to have a higher binding affinity to HER2 compared to trastuzumab 212−214 and targets different epitopes of the HER2 receptor. 215 Clinically this translates to improved antitumor activity with reduced systemic side effects 213 along with selective delivery of MMAE to HER2 positive cells and tumor tissue. 210 The ADC was developed in collaboration by RemeGen and Seagen, who have entered a joint licensing agreement for development and commercialization.…”

Research progress of antibody-drug conjugates therapy for HER2-low expressing gastric cancer

“…RC48 shows a significant bystander effect with a cuttable linker, and the payload spread to adjacent cells [ 38 , 39 ]. MMAE plays a multifunctional role in inhibiting tubulin polymerization, leading to effective tumor regression [40] . Both in vitro and in vivo experiments confirmed that RC48 can selectively deliver MMAE to target tumor tissues.…”

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

“…Along with myelosuppression, interstitial lung disease was a noted issue in 10% of patients [ 76 ]; this has been previously associated with other anti-HER2 and topoisomerase inhibitor therapies [ 77 ]. After further clinical trials showed favorable responses in HER2+ GC and GEJC patients, Enhertu ® was approved by the US FDA in January of 2021 [ 78 ]. Another ADC named RC48 consists of hertuzumab and monomethyl auristatin E (MMAE), which inhibits tubulin polymerization.…”

“…Another ADC named RC48 consists of hertuzumab and monomethyl auristatin E (MMAE), which inhibits tubulin polymerization. RC48 has shown tolerable safety and antitumor activity in phase I/II trials of HER2+ solid tumor patients, with more clinical trials underway [ 78 ].…”