A recombinant scFv antibody-based fusion protein that targets EGFR associated with IMPDH2 downregulation and its drug conjugate show therapeutic efficacy against esophageal cancer.

Abstract

The present study aimed to evaluate the anti-tumor efficacy of the epidermal growth factor receptor (EGFR)-targeting recombinant fusion protein Fv-LDP-D3 and its antibody-drug conjugate Fv-LDP-D3-AE against esophageal cancer. Fv-LDP-D3, consisting of the fragment variable (Fv) of an anti-EGFR antibody, the apoprotein of lidamycin (LDP), and the third domain of human serum albumin (D3), exhibited a high binding affinity for EGFR-overexpressing esophageal cancer cells, inhibited EGFR phosphorylation and down-regulated inosine monophosphate dehydrogenase type II (IMPDH2) expression. Fv-LDP-D3 was taken up by cancer cells through intensive macropinocytosis; it inhibited the proliferation and induced the apoptosis of esophageal cancer cells. In vivo imaging revealed that Fv-LDP-D3 displayed specific tumor-site accumulation and a long-lasting retention over a 26-day period. Furthermore, Fv-LDP-D3-AE, a pertinent antibody-drug conjugate prepared by integrating the enediyne chromophore of lidamycin into the Fv-LDP-D3 molecule, displayed highly potent cytotoxicity, inhibited migration and invasion, induced apoptosis and DNA damage, arrested cells at G2/M phase, and caused mitochondrial damage in esophageal cancer cells. More importantly, both of Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the growth of esophageal cancer xenografts in athymic mice at well tolerated doses. The present results indicate that Fv-LDP-D3, and Fv-LDP-D3-AE exert prominent antitumor efficacy associated with targeting EGFR, suggesting their potential as promising candidates for targeted therapy against esophageal cancer.

• Authors: Shiming He, Chunyan Zhao, Hongyu Tao, Weijin Sheng, Ruijuan Gao, Xiujun Liu, Yongsu Zhen
• Journal: Drug delivery (Drug Deliv) Vol. 29 Issue 1 Pg. 1243-1256 (Dec 2022) ISSN: 1521-0464 [Electronic] England
• PMID: 35416106 (Publication Type: Journal Article)

Chemical References

• Enediynes
• Immunoconjugates
• Recombinant Fusion Proteins
• IMP Dehydrogenase
• IMPDH2 protein, human
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Cell Line, Tumor
• Down-Regulation
• Enediynes (chemistry, pharmacology)
• ErbB Receptors (metabolism)
• Esophageal Neoplasms (drug therapy, pathology)
• Humans
• IMP Dehydrogenase (genetics, metabolism, therapeutic use)
• Immunoconjugates (metabolism, pharmacology)
• Mice
• Mice, Nude
• Recombinant Fusion Proteins (genetics, pharmacology)
• Xenograft Model Antitumor Assays