Esophageal cancer (EC) is a gastrointestinal cancer with high morbidity and mortality, along with a low 5-year survival rate, which urgently requires the discovery of new drugs for prevention and treatment. Our previous studies have found a novel EGFR-targeted fusion protein-drug conjugate, Fv-LDP-D3-AE, which exhibits significant inhibitory activity against esophageal cancer. However, the effectiveness of monotherapy still faces major challenges in clinical translation for esophageal cancer treatment. Therefore, there is an urgent need to identify a candidate anti-tumor drug that can be combined with Fv-LDP-D3-AE to enhance therapeutic efficacy. In this study, we report a novel combination treatment regimen of paeonol with Fv-LDP-D3-AE, using human esophageal cancer cells KYSE70 and EC109 for in vitro studies and establishing a BALB/c nude mouse xenograft model for in vivo experiments to investigate the anti-tumor efficacy and potential mechanisms of the combination therapy in esophageal cancer. The results indicated that the combined treatment emerged a synergistic effect, which could effectively inhibit the proliferation, migration, and invasion of esophageal cancer cells, induce more obvious cell apoptosis and DNA damage, and suppress tumor growth in the xenograft mouse model with a tumor inhibition rate of 76%. This may be attributed to the combination therapy simultaneously inhibiting the EGFR/AKT/mTOR signaling pathway and downregulating the expression of nucleolin. Overall, these findings suggest that paeonol could synergize with Fv-LDP-D3-AE to enhance anti-esophageal cancer efficacy, which may be a promising therapeutic strategy for esophageal cancer.

2023-01-01·International journal of biological macromolecules

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation

Article

作者: Wang, Ying ; Zhao, Chun-Yan ; Tao, Hong-Yu ; Sheng, Wei-Jin ; He, Shi-Ming ; Zhen, Yong-Su

OBJECTIVE:

To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy.

METHODS:

We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed.

RESULTS:

As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC₅₀ at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-β in athymic mice.

CONCLUSION:

The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

2022-12-31·Drug delivery2区 · 医学

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

2区 · 医学

ArticleOA

作者: Zhao, Chunyan ; Sheng, Weijin ; Zhen, Yongsu ; Liu, Xiujun ; Tao, Hongyu ; He, Shiming ; Gao, Ruijuan

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.

100 项与 Fv-LDP-D3∼AE 相关的药物交易

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