A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibody chimeric molecule suppresses the growth of HER2-overexpressing tumors

J Immunol. 2004 Jul 1;173(1):61-7. doi: 10.4049/jimmunol.173.1.61.

Abstract

Clinical studies have suggested that human epidermal growth factor receptor-2 (HER2) provide a useful target for antitumor therapy. We previously described the generation of a chimeric HER2-targeted immunocasp-3 protein. In this study, we extend the repertoire of chimeric proapoptotic proteins with immunocasp-6, a construct that comprises a HER2-specific single-chain Ab, a single-chain Pseudomonas exotoxin A, and an active caspase-6, which can directly cleave lamin A leading to nucleus damage and inducing programmed cell death. We demonstrate that the secreted immunocasp-6 molecule selectively recognizes and induces apoptosis in HER2-overexpressing tumor cells in vitro, but not in cells with undetectable HER2. The immunocasp-6 gene was next transferred into BALB/c athymic mice bearing human breast SK-BR-3 tumors by i.m. injection of liposome-encapsulated vectors, by intratumor injection of adenoviral vectors, or by i.v. injection of PBMC modified by retroviral infection. Regardless of the method used, expression of immunocasp-6 suppressed tumor growth and prolonged animal survival significantly. Our data show that the chimeric immunocasp-6 molecule can recognize HER2-positive tumor cells, promptly attack their nucleus, and induce their apoptotic death, suggesting the potential of this strategy for the treatment of human cancers that overexpress HER2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / therapeutic use
  • Adenoviridae / genetics
  • Animals
  • Antibodies / therapeutic use*
  • Apoptosis
  • Bacterial Toxins / therapeutic use
  • Caspase 6
  • Caspases / genetics*
  • Cell Line, Tumor
  • Exotoxins / therapeutic use
  • Genetic Therapy*
  • Humans
  • Jurkat Cells
  • Liposomes
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / chemistry
  • Neoplasms, Experimental / therapy*
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology
  • Recombinant Fusion Proteins / therapeutic use*
  • Retroviridae / genetics
  • Virulence Factors / therapeutic use

Substances

  • Antibodies
  • Bacterial Toxins
  • Exotoxins
  • Liposomes
  • Recombinant Fusion Proteins
  • Virulence Factors
  • immunocasp-6
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • Receptor, ErbB-2
  • CASP6 protein, human
  • Casp6 protein, mouse
  • Caspase 6
  • Caspases