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A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells.

Abstract
A recombinant immunotoxin was constructed by fusing a single chain fragment variable antibody fragment, specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), to a truncated variant of Pseudomonas exotoxin A (ETA'), carrying a C-terminal KDEL-peptide for improved retrograde intracellular transport. The resulting immunotoxin MCSP-ETA' was periplasmatically expressed in Escherichia coli and purified under native conditions by affinity chromatography resulting in a yield of approximately 30 mug/l bacterial culture. This immunotoxin induced antigen-specific apoptosis in the cultured human melanoma-derived cell lines A2058 and A375M, and treatment with a single dose of the agent eliminated up to 80% of these cells within 72 h. The dose needed for half-maximum killing (EC50) was approximately 1 nmol/l for both cell lines. MCSP-ETA' also displayed cytotoxic activity against cultured primary melanoma cells from patients with advanced disease (pathologic stages IIIC and IV), with net cell death reaching up to 70% within 96 h after treatment with a single dose of 14 nmol/l. MCSP-ETA' induced cell death synergistically with cyclosporin A, both in established human melanoma cell lines and cultured primary melanoma cells. The distinctive antigen-restricted induction of apoptosis and the synergy with cyclosporin A justify further evaluation of this novel agent with regard to its potential application for the treatment of malignant melanoma.
AuthorsMichael Schwenkert, Katrin Birkholz, Michael Schwemmlein, Christian Kellner, Markus Kügler, Matthias Peipp, Dirk M Nettelbeck, Beatrice Schuler-Thurner, Niels Schaft, Jan Dörrie, Soldano Ferrone, Eckhart Kämpgen, Georg H Fey
JournalMelanoma research (Melanoma Res) Vol. 18 Issue 2 Pg. 73-84 (Apr 2008) ISSN: 0960-8931 [Print] England
PMID18337643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bacterial Toxins
  • Chondroitin Sulfate Proteoglycans
  • Exotoxins
  • Immunosuppressive Agents
  • Immunotoxins
  • Recombinant Fusion Proteins
  • Virulence Factors
  • Cyclosporine
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
Topics
  • ADP Ribose Transferases (immunology, metabolism)
  • Apoptosis
  • Bacterial Toxins (immunology, metabolism)
  • Cell Line, Tumor
  • Chondroitin Sulfate Proteoglycans (immunology, metabolism)
  • Cyclosporine (pharmacology)
  • Cytotoxicity, Immunologic
  • Exotoxins (immunology, metabolism)
  • Humans
  • Immunosuppressive Agents (pharmacology)
  • Immunotherapy
  • Immunotoxins (immunology, isolation & purification, metabolism, pharmacology)
  • Melanoma (immunology, metabolism, pathology, therapy)
  • Recombinant Fusion Proteins (immunology)
  • Tumor Cells, Cultured
  • Virulence Factors (immunology, metabolism)

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