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

• Published in: Gene therapy Vol. 13; no. 4; pp. 313 - 320
• Main Authors: YU, C.-J, JIA, L.-T, JIN, B.-Q, CHEN, S.-Y, YANG, A.-G, MENG, Y.-L, ZHAO, J, ZHANG, Y, QIU, X.-C, XU, Y.-M, WEN, W.-H, YAO, L.-B, FAN, D.-M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-02-2006
• Subjects: ADP Ribose Transferases - genetics; Ageing, cell death; Antibodies - genetics; Apoptosis; Apoptosis - genetics; Apoptosis Inducing Factor - genetics; Apoptosis-inducing factor; Bacterial Toxins - genetics; Biological and medical sciences; Biotechnology; Cancer; Carcinoma; Care and treatment; Caspase; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cytoplasm; ErbB-2 protein; Exotoxins; Exotoxins - genetics; Feasibility studies; Female; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene Expression Regulation, Neoplastic; Gene therapy; Genes, erbB-2; Genetic aspects; Genetic Therapy - methods; Health aspects; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Jurkat Cells; Localization; Lymphocytes; Mitochondria; Molecular and cellular biology; Neoplasms - genetics; Neoplasms - therapy; Proteins; Pseudomonas aeruginosa Exotoxin A; Receptor, ErbB-2 - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Transfection - methods; Tumor cells; Virulence Factors - genetics; Xenografts; China; Pseudomonadales; Carcinoma; lymphocytes; Antibody; Apoptosis-inducing factor; erbB2 Gene; Malignant tumor; Pseudomonas; HER2/ErbB2/neu; Pseudomonas exotoxin; C-Onc gene; Bacteria; Pseudomonadaceae; Fusion protein; Gene therapy; Lymphocyte; Apoptosis
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302672

Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFDelta1-120) 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 AIFDelta1-120. 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.