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Blood, 1 October 2004, Vol. 104, No. 7, pp. 1919-1920. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Murphy, J. R. Search for Related Content PubMed Articles by Murphy, J. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Abi-Habib et al, page 2143 Site-specific conversion of a pro-fusion protein toxin John R. Murphy BOSTON UNIVERSITY SCHOOL OF MEDICINE Substituting the native furin endoprotease activation site with a urokinase plasminogen activator recognition sequence, Abi-Habib and colleagues have constructed a diphtheria toxin–related granulocyte-macrophage colony-stimulating factor fusion protein toxin with increased utility and specificity toward acute myelogeneous leukemic cells. Protein engineering of bacterial protein toxins has been focused largely on substitution of the native receptor-binding domain of the toxin with surrogate ligands in order to selectively redirect toxicity toward those cells that display the appropriate surface target receptor. While there has been extensive work in this field, to date the only fusion protein toxin that has been approved for human clinical use is diptheria fusion protein targeting interleukin-2 receptor (DAB389IL-2 [ONTAK]).1-3 Abi-Habib and colleagues, in their current article, have taken a significant step forward in the field of therapeutic fusion toxins. In this instance, replacement of the native diphtheria toxin receptor-binding domain with granulocyte-macrophage colony-stimulating factor (GM-CSF) targets the fusion protein toxin toward the GM-CSF receptor on acute myeloid leukemia (AML) blasts. While this genetic construct is highly toxic toward AML cells in vitro, the normal distribution of the GM-CSF receptor in vivo is sufficiently broad that a second layer of specificity was engineered into the fusion protein toxin. The diphtheria toxin–related fusion protein toxins follow a highly defined route of entry into the cell.4 The intoxication process begins with receptor binding; the fusion protein toxin is then internalized into the cell by receptor-mediated endocytosis. In the lumen of the early endosome, the endoproteinase furin introduces a "nick" in the -carbon backbone in a protease-sensitive loop that connects the catalytic (C) and transmembrane (T) domains. This nicking event is essential for the subsequent membrane translocation and release of the C-domain into the cytosol of target cells. By replacement of the furin recognition site (RVRRSV) with the urokinase plasminogen activator (uPA) cleavage site (GSGRSA), Abi-Habib and colleagues have constructed a "pro-fusion protein toxin." Their study clearly shows that the targeted action of the modified construct, DTU2GMCSF, strongly correlates with the combined presence of the uPA receptor, uPA, and the GM-CSF receptor. The development of new fusion protein toxins as potential therapeutic agents is still in its infancy. The challenge remains to construct biologics that retain a high level of specificity toward cell surface determinants that are largely restricted to malignant cells in order to minimize damage to normal cells. Since uPA is often up-regulated in particular malignancies, the introduction of the uPA cleavage site into DTU2GMCSF confers a second level of specificity and shifts the balance of action toward the malignant cell population. We await with interest the initiation of and findings from clinical studies with this pro-fusion protein toxin as we anticipate that the coupling of cell-specific drug delivery with site-specific conversion from protoxin to toxin will greatly expand the utility and therapeutic margin of these agents. The DTU2GMCSF described by these authors offers a promising, novel, therapeutic approach for patients with AML resistant to standard treatment. References Williams DP, Snider CE, Strom TB, Murphy JR. Structure function analysis of interleukin-2-toxin (DAB486IL-2): fragment B sequences required for the delivery of fragment A to the cytosol of targeted cells. J Biol Chem. 1990;265: 11885-11889.[Abstract/Free Full Text] Foss FM. DAB389IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. Clin Lymphoma. 2000;1: 110-116.[Medline] [Order article via Infotrieve] Ho VT, Zahrieh D, Hochberg E, et al. Safety and efficacy of denileukin diftitox in patients with steroid refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood. Prepublished on April 27, 2004, as DOI 10.1182/blood-2004-01-0028. Ratts R, Zeng H, Berg EA, etal. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J Cell Biol. 2003;160: 1139-1150.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A urokinase-activated recombinant diphtheria toxin targeting the granulocyte-macrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts Ralph J. Abi-Habib, Shihui Liu, Thomas H. Bugge, Stephen H. Leppla, and Arthur E. Frankel Blood 2004 104: 2143-2148. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Murphy, J. R. Search for Related Content PubMed Articles by Murphy, J. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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