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

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.
AuthorsYan-Ming Xu, Li-Feng Wang, Lin-Tao Jia, Xiu-Chun Qiu, Jing Zhao, Cui-Juan Yu, Rui Zhang, Feng Zhu, Cheng-Ji Wang, Bo-Quan Jin, Si-Yi Chen, An-Gang Yang
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 173 Issue 1 Pg. 61-7 (Jul 01 2004) ISSN: 0022-1767 [Print] United States
PMID15210759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • Bacterial Toxins
  • Exotoxins
  • Liposomes
  • Recombinant Fusion Proteins
  • Virulence Factors
  • immunocasp-6
  • ADP Ribose Transferases
  • Pseudomonas aeruginosa exotoxin A
  • Receptor, ErbB-2
  • CASP6 protein, human
  • Casp6 protein, mouse
  • Caspase 6
  • Caspases
Topics
  • 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, therapy)
  • Receptor, ErbB-2 (analysis, antagonists & inhibitors, immunology)
  • Recombinant Fusion Proteins (therapeutic use)
  • Retroviridae (genetics)
  • Virulence Factors (therapeutic use)

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