Fusion toxins

A close relative of immunotoxins is the growth factor fusion toxin, in which antibody is replaced with a ligand or growth factor to provide selectively of the toxin domain in immunotoxin. One such molecule, containing human interleukin-2 (IL-2) fused to truncated diphtheria toxin (denileukin diftitox or Ontak), was approved by the FDA in 1999. 

Harris JB, Grubb BD, Maltin CA, Dixon R (2000) The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin. Exp Neurol 161 517-26 Haug G, Wilde C, Leemhuis J, Meyer DK, Aktories K et al. (2003) Cellular uptake of Clostridium botulinum C2 toxin membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain. Biochemistry 42 15284-91 Hauschild A (1993) Epidemiology of human foodborne botulism. In Hauschild A, Dodds KL (eds) Clostridium botulinum ecology and control in foods. Marcel Dekker, Inc. New York, pp 69-104... 

Schlick J, Dulieu P, Desvoyes B, et al. Cytotoxicity activity of a recombinant GnRH-PAP fusion toxin on human tumor cell Hues. FEBS Lett 2004 472 21-246. 

Aullo, P., Alcami, J., Popoff, M. R Klatzmann, D. R., Murphy, J. R., and Boquet, P. (1992) A recombinant diphtheria toxin related human CD4 fusion protein specifically kills HIV infected cells which express gpl20 but selects fusion toxin resistant cells which carry HIV. EMBO J. 11, 575-583. 

Making Fusion Toxins to Target Leukemia and Lymphoma... 

Tepler I, Schwartz G, Parker K, et al. Phase I trial of an in-terleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies Complete response in a patient with Hodgkin s disease refractory to chemotherapy. Cancer. 1994 73 1276-1285. 

Shaw JP, Akiyoshi DE, Arrigo DA et al. (1991) Cytotoxic properties of DAB486EGF and DAB389EGF, epidermal growth factor (EGF) receptor-targeted fusion toxins. J Biol Chem 266 21118-21124... 

Rotavirus enterotoxin protein NSP4 fused to CTB Potato Fusion proteins assembled into cholera holo-toxin-like structures that retained enterocyte-binding affinity Orally immunized mice generated levels of serum and mucosal antibodies specific for the native antigen. Induced TH1 immune response. 63,64... 

Replacement of most Virtually all of the murine amino acid sequences with sequences found in human antibodies Fusion protein consisting of the diphtheria toxin linked to interleukin-2 (IL-2)... 

The IL-2 portion of the fusion protein facilitates product interaction with cells displaying cell surface IL-2 receptors, found in high levels on some leukaemia and lymphoma cells, including CTCL cells. Binding appears to trigger internalization of the receptor-fusion protein complex (Figure 9.B1). Sufficient quantities of the latter escape immediate cellular destruction to allow diphtheria toxin-mediated inhibition of cellular protein synthesis. Cell death usually results within hours. 

Proleukin is a recombinant form of IL-2. It is approved for the treatment of malignant melanoma and renal cell cancer. Ontak (denileukin diftitox) is a fusion protein for the treatment of persistent or recurrent T-cell lymphoma. Activated T cells express lL-2 receptors. Ontak has a fragment that binds to the IL-2 receptor while the other part presents a diphtheria toxin to kill the activated T cell. 

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