Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers

Abstract

Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation and migration. The overexpression of the HER family has been recognized as one of the most common cellular dysregulation associated with a wide variety of tumor types. Antibody-drug conjugates (ADCs) represent a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with cytotoxicity of chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) and trastuzumab-deruxtecan (DS-8201a), have been approved for HER2-positive metastatic breast cancer by the U.S. Food and Drug Administration (FDA) in 2013 and 2019, respectively. A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. A total of 11 ADCs that target HER family receptors (EGFR, HER2 or HER3) are currently under clinical trials. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

Molecular perspective on targeted therapy in breast cancer: a review of current status

“…Antibody–drug conjugates are a new and promising group of anticancer drugs that combine the cancer specificity of antibodies with the cytotoxic properties of chemotherapeutics [ 37 ].…”

“…Trastuzumab Emtansine, which consists of 1) trastuzumab 2) a non-cleavable thioether linker, N-maleimidomethyl cyclohexane-1-carboxylate (MCC); and 3) a potent microtubule-depolymerizing maytansinoid derivative, DM1, was approved by the FDA in 2013 for the treatment HER2 + metastatic breast cancer (MBC) [ 37 , 38 ]. The mechanism of action of T-DM1 is believed to be mediated by trastuzumab-mediated inhibition of HER2 signaling and metabolites of DM1, which is a cytotoxic antimicrotubule agent and ultimately causes cell apoptosis [ 37 , 39 ]. The most common adverse reactions associated with T-DM1 treatment are anemia, thrombocytopenia, and fatigue [ 40 ].…”

“…Trastuzumab-Deruxtecan, which consists of 1) trastuzumab; 2) an enzymatically cleavable maleimide glycine-glycine-phenylalanine-glycine (GGFG peptide linker that can be cleaved by lysosomal proteases while maintaining stable in serum; and 3) a topoisomerase I inhibitor DXd, which is a novel water-soluble derivative of exatecan, a hexacyclic camptothecin analogue, was approved by the FDA in 2019 for the treatment HER2 + MBC [ 37 , 41 ]. The mechanism of action of DS-8201a is mediated by trastuzumab-mediated inhibition of HER2 signaling and the Dxd component, which binds to the topoisomerase I-DNA complex, inducing double-stranded deoxyribonucleic acid (DNA) damage and cell apoptosis [ 37 ]. Unlike trastuzumab emtansine, trastuzumab deruxtecan has a released charge that readily crosses the cell membrane and enables it to exert a potentially potent cytotoxic effect on neighboring tumor cells regardless of target expression [ 42 ].…”

“…Antibody–drug conjugates are frequently used as second-line therapy in HER2 + patients [ 93 ]. Several clinical trials are underway to evaluate the use of T-DM1 and DS-8201a for other types of HER2-driven cancer types or the use of T-DM1 in combination with other agents such as immune checkpoint inhibitors, CDK4/6 inhibitors, and TKIs [ 37 ]. In HER2- patients, CDK4/6 inhibitor drugs palbociclib, ribociclib, abemaciclib, and PI3K/Akt/mTOR inhibitor drugs alpelisib and everolimus are administered together with endocrine therapy, while the antiangiogenic drug bevacizumab is administered together with paclitaxel or capecitabine.…”

Editorial: The use of chemotherapy in treating gastric cancers

“…In this era of precision and targeted medicine, future researches may need to focus more on forefront aspects including the application of advanced techniques using artificial intelligence for more personalized prediction of net benefits and noteworthy side effects associated with chemotherapy, novel treatment modalities including immune cell therapies (e.g., CAR-T and CAR-NK therapies) and treatment based on innovative antibody drug conjugates (ADCs, like GQ1001 and DS-8201) ( 19 ), utilization of digital mobile medicine interventions (e.g., applets) to improve treatment compliance and case surveillance in patients with GC receiving chemotherapy, etc.…”