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

Gene Ther. 2006 Feb;13(4):313-20. doi: 10.1038/sj.gt.3302672.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / genetics
  • Antibodies / genetics
  • Apoptosis / genetics
  • Apoptosis Inducing Factor / genetics*
  • Bacterial Toxins / genetics
  • Cell Line
  • Cell Line, Tumor
  • Exotoxins / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, erbB-2*
  • Genetic Therapy / methods*
  • Humans
  • Jurkat Cells
  • Neoplasms / genetics
  • Neoplasms / therapy*
  • Receptor, ErbB-2 / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection / methods
  • Virulence Factors / genetics

Substances

  • AIFM1 protein, human
  • Antibodies
  • Apoptosis Inducing Factor
  • Bacterial Toxins
  • Exotoxins
  • Recombinant Fusion Proteins
  • Virulence Factors
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • Receptor, ErbB-2