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

To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy. 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. 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. 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. Copyright © 2022. Published by Elsevier B.V.

Citation

Hong-Yu Tao, Shi-Ming He, Chun-Yan Zhao, Ying Wang, Wei-Jin Sheng, Yong-Su Zhen. Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation. International journal of biological macromolecules. 2023 Jan 31;226:1088-1099

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PMID: 36435475

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