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Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2

Gene Therapy volume 13, pages 313–320 (2006)Cite this article

Abstract

Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFΔ1–120) can be relocated from the cytoplasm to the nucleus and exhibit a constitutive proapoptotic activity. Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFΔ1–120. Human Jurkat cells transfected with the immuno-AIF gene could express and secrete the chimeric protein, which selectively recognized HER2-overexpressing tumor cells and was endocytosed. Subsequent cleavage of truncated AIF from immuno-AIF and its release from the internalized vesicles resulted in apoptosis of tumor cells. Intramuscular injection of the immuno-AIF gene caused significant suppression of tumors and substantially prolonged mice survival in an HER2-overexpressing xenograft tumor model. Our study demonstrates the feasibility of the immuno-AIF gene as a novel approach to treating cancers that overexpress HER2.

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Acknowledgements

This work was supported by the National High Technology Research and Development Program of China (No. 2001AA217101), the National Basic Research Program of China (No. 2004CB518805) and the Program for Changjiang Scholars and Innovative Research Teams in Universities (PCSIRT) from Ministry of Education of People's Republic of China.

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Authors and Affiliations

  1. Department of Immunology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China

    C-J Yu, Y-L Meng, Y Zhang, W-H Wen, B-Q Jin & A-G Yang

  2. Department of Biochemistry and Molecular Biology, Faculty of Preclinical Medicine, Fourth Military Medical University, Xi'an, China

    L-T Jia, J Zhao, X-C Qiu, Y-M Xu & L-B Yao

  3. Department of Gastroenterology, Xijing Hospital, Fourth Military Medical University, Xi'an, China

    D-M Fan

  4. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    S-Y Chen

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  1. C-J Yu
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Yu, CJ., Jia, LT., Meng, YL. et al. Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2. Gene Ther 13, 313–320 (2006). https://doi.org/10.1038/sj.gt.3302672

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  • DOI: https://doi.org/10.1038/sj.gt.3302672

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