Single-chain fragment antibody disrupting the EphA4 function as a therapeutic drug for gastric cancer

Chen-Wei Chiang; Yun-Shih Lin; Fu-Ling Chang; Tsai-Yu Lin; Keng-Chang Tsai; Wei-Chun HuangFu; Yu-Ching Lee

doi:10.1016/j.bbrc.2023.09.025

Single-chain fragment antibody disrupting the EphA4 function as a therapeutic drug for gastric cancer

Biochem Biophys Res Commun. 2023 Nov 5:680:161-170. doi: 10.1016/j.bbrc.2023.09.025. Epub 2023 Sep 15.

Authors

Chen-Wei Chiang¹, Yun-Shih Lin², Fu-Ling Chang³, Tsai-Yu Lin³, Keng-Chang Tsai⁴, Wei-Chun HuangFu⁵, Yu-Ching Lee⁶

Affiliations

¹ Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
² Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
³ Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁴ National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan; Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁵ Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
⁶ Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].

PMID: 37741263
DOI: 10.1016/j.bbrc.2023.09.025

Abstract

Studies have shown that the high expression of EphA4 in gastric cancer tissues may correlate with unfavorable clinical pathological characteristics. Therefore, EphA4 may be an effective target for treating gastric cancer in addition to HER-2/neu. In this study, generated scFv S3 can bind endogenous EphA4 of gastric cancer cells and has significant membrane staining. Additionally, scFv S3 binding to EphA4 inhibits the growth and migration of cancer cells and the growth induction that ephrinA1 generates in gastric cancer cells. We found that EphA4 molecules may degrade through antibody treatment of cells, and the increase in LAMP1 and LAMP2 indicates that lysosome is involved in the degradation. The scFv S3 administration leads to the signals pAKT, pERK, and pSTAT3 decrease in cancer cells. The xenograft model of HER-2/neu low expressing gastric cancer cell SNU-16 exhibits better therapeutic effects by scFv S3 than trastuzumab scFv. The scFv S3 administration in vivo can degrade EphA4 molecules in tumor tissues, decreasing Ki67 and increasing cleaved C3 molecule expression. Furthermore, we identified and validated that scFv S3 generates essential ionic bonding with R162 on EphA4. The antibody may provide effective treatment for patients with gastric cancer and abnormal activation or overexpression of EphA4 signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Signal Transduction
Single-Chain Antibodies* / pharmacology
Stomach Neoplasms* / drug therapy

Substances

Single-Chain Antibodies