An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

Autor: Huang M; Department of Medical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea., Park J; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea., Seo J; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea., Ko S; Department of Biomedical Sciences, Graduate School, Korea University, Seoul, Republic of Korea., Yang YH; Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea., Lee Y; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea., Kim HJ; Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea., Lee BS; Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea., Lee YS; Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea., Ko BJ; School of Biopharmaceutical and Medical Sciences, Sungshin Women's University, Seoul, Republic of Korea., Jung ST; Department of Biomedical Sciences, Graduate School, Korea University, Seoul, Republic of Korea.; Institute of Human Genetics, Korea University College of Medicine, Seoul, Republic of Korea.; BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea., Park D; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.; Advanced College of Bio-convergence Engineering, Ajou University, Suwon, Republic of Korea., Yoo TH; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.; Advanced College of Bio-convergence Engineering, Ajou University, Suwon, Republic of Korea., Kim CH; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.; Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea.; Department of Otolaryngology, Ajou University School of Medicine, Suwon, Republic of Korea.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Jul 15; Vol. 38 (13), pp. e23759.
DOI: 10.1096/fj.202301968R
Abstrakt: The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.
(© 2024 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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