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Immunotoxins for targeted cancer therapy

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Abstract

Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that binds specifically to target cells. Nearly all protein toxins work by enzymatically inhibiting protein synthesis. For the immunotoxin to work, it must bind to and be internalized by the target cells, and the enzymatic fragment of the toxin must translocate to the cytosol. Once in the cytosol, 1 molecule is capable of killing a cell, making immunotoxins some of the most potent killing agents. Various plant and bacterial toxins have been genetically fused or chemically conjugated to ligands that bind to cancer cells. Among the most active clinically are those that bind to hematologic tumors. At present, only 1 agent, which contains human interleukin-2 and truncated diphtheria toxin, is approved for use in cutaneous T-cell lymphoma. Another, containing an anti-CD22 Fv and truncatedPseudomonas exotoxin, has induced complete remissions in a high proportion of cases of hairy-cell leukemia. Refinement of existing immunotoxins and development of new immunotoxins are underway to improve the treatment of cancer.

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References

  1. Moolten FL, Cooperband SR. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells.Science. 1970;169:68–70.

    Article  CAS  PubMed  Google Scholar 

  2. Krolick KA, Villemez C, Isakson P, Uhr JW, Vitetta ES. Selective killing of normal or neoplastic B cells by antibodies coupled to the A chain of ricin.Proc Natl Acad Sci USA. 1980;77: 5419–5423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cawley DB, Herschman HR, Gilliland DG, Collier RJ. Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic.Cell. 1980;22:563–570.

    Article  CAS  PubMed  Google Scholar 

  4. Akhtar S, Maghfoor I. Rituximab plus CHOP for diffuse large-B-cell lymphoma.N Engl J Med. 2002;346:1830–1831.

    Article  PubMed  Google Scholar 

  5. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.Blood. 2002;99: 3554–3561.

    Article  CAS  PubMed  Google Scholar 

  6. Cheson B. Bexxar (Corixa/GlaxoSmithKline).Curr Opin Investig Drugs. 2002;3:165–170.

    CAS  PubMed  Google Scholar 

  7. Nabhan C, Tallman MS. Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg(R)) in acute myeloid leukemia.Clin Lymphoma. 2002;2:S19-S23.

    Article  PubMed  Google Scholar 

  8. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity.Blood. 2003;102:1458–1465.

    Article  CAS  PubMed  Google Scholar 

  9. Naito K, Takeshita A, Shigeno K, et al. Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (Gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines.Leukemia. 2000;14:1436–1443.

    Article  CAS  PubMed  Google Scholar 

  10. Hursey M, Newton DL, Hansen HJ, Ruby D, Goldenberg DM, Rybak SM. Specifically targeting the CD22 receptor of human B-cell lymphomas with RNA damaging agents: a new generation of therapeutics.Leuk Lymphoma. 2002;43:953–959.

    Article  CAS  PubMed  Google Scholar 

  11. Yamaizumi M, Mekada E, Uchida T, Okada Y. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell.Cell. 1978;15:245–250.

    Article  CAS  PubMed  Google Scholar 

  12. Eiklid K, Olsnes S, Pihl A. Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells.Exp Cell Res. 1980;126:321–326.

    Article  CAS  PubMed  Google Scholar 

  13. Carroll SF, Collier RJ. Active site of Pseudomonas aeruginosa exotoxin A. Glutamic acid 553 is photolabeled by NAD and shows functional homology with glutamic acid 148 of diphtheria toxin.J Biol Chem. 1987;262:8707–8711.

    CAS  PubMed  Google Scholar 

  14. Bolognesi A, Polito L, Tazzari PL, et al. In vitro anti-tumour activity of anti-CD80 and anti-CD86 immunotoxins containing type 1 ribosome-inactivating proteins.Br J Haematol. 2000;110:351–361.

    Article  CAS  PubMed  Google Scholar 

  15. Endo Y, Mitsui K, Motizuki M, Tsurugi K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes.J Biol Chem. 1987;262:5908–5912.

    CAS  PubMed  Google Scholar 

  16. Bolognesi A, Tazzari PL, Olivieri F, Polito L, Falini B, Stirpe F. Induction of apoptosis by ribosome-inactivating proteins and related immunotoxins.Int J Cancer. 1996;68:349–355.

    Article  CAS  PubMed  Google Scholar 

  17. Hughes JN, Lindsay CD, Griffiths GD. Morphology of ricin and abrin exposed endothelial cells is consistent with apoptotic cell death.Hum Exp Toxicol. 1996;15:443–451.

    Article  CAS  PubMed  Google Scholar 

  18. Bergamaschi G, Perfetti V, Tonon L, et al. Saporin, a ribosome-inactivating protein used to prepare immunotoxins, induces cell death via apoptosis.Br J Haematol. 1996;93:789–794.

    Article  CAS  PubMed  Google Scholar 

  19. Wesche J, Rapak A, Olsnes S. Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol.J Biol Chem. 1999;274:34443–34449.

    Article  CAS  PubMed  Google Scholar 

  20. Tagge E, Harris B, Burbage C, et al. Synthesis of green fluorescent protein-ricin and monitoring of its intracellular trafficking.Bioconjug Chem. 1997;8:743–750.

    Article  CAS  PubMed  Google Scholar 

  21. Fulton RJ, Uhr JW, Vitetta ES. In vivo therapy of the BCL1 tumor: effect of immunotoxin valency and deglycosylation of the ricin A chain.Cancer Res. 1988;48:2626–2631.

    CAS  PubMed  Google Scholar 

  22. Bourrie BJ, Casellas P, Blythman HE, Jansen FK. Study of the plasma clearance of antibody-ricin-A-chain immunotoxins. Evidence for specific recognition sites on the A chain that mediate rapid clearance of the immunotoxin.Eur J Biochem. 1986;155:1–10.

    Article  CAS  PubMed  Google Scholar 

  23. Blakey DC, Watson GJ, Knowles PP, Thorpe PE. Effect of chemical deglycosylation of ricin A chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A chain and anti-Thy 1.1 antibody.Cancer Res. 1987;47:947–952.

    CAS  PubMed  Google Scholar 

  24. Thorpe PE, Wallace PM, Knowles PP, et al. Improved antitumor effects of immunotoxins prepared with deglycosylated ricin A-chain and hindered disulfide linkages.Cancer Res. 1988;48: 6396–6403.

    CAS  PubMed  Google Scholar 

  25. Ramakrishnan S, Bjorn MJ, Houston LL. Recombinant ricin A chain conjugated to monoclonal antibodies: improved tumor cell inhibition in the presence of lysosomotropic compounds.Cancer Res. 1989;49:613–617.

    CAS  PubMed  Google Scholar 

  26. Lambert JM, McIntyre G, Gauthier MN, et al. The galactose-binding sites of the cytotoxic lectin ricin can be chemically blocked in high yield with reactive ligands prepared by chemical modification of glycopeptides containing traintennary N-linked oligosaccharides.Biochemistry. 1991;30:3234–3247.

    Article  CAS  PubMed  Google Scholar 

  27. Mohanraj D, Ramakrishnan S. Cytotoxic effects of ricin without an interchain disulfide bond; genetic modification and chemical crosslinking studies.Biochim Biophys Acta. 1995;1243:399–406.

    Article  PubMed  Google Scholar 

  28. Kreitman RJ, Chaudhary VK, Siegall CB, FitzGerald DJ, Pastan I. Rational design of a chimeric toxin: an intramolecular location for the insertion of transforming growth factor α withinPseudomonas exotoxin as a targeting ligand.Bioconjug Chem. 1992;3:58–62.

    Article  CAS  PubMed  Google Scholar 

  29. Cook JP, Savage PM, Lord JM, Roberts LM. Biblogically active interleukin-2-4icin A chain fusion proteins may require intracellular proteolytic cleavage to exhibit a cytotoxic effect.Bioconjug Chem. 1993;4:440–447.

    Article  CAS  PubMed  Google Scholar 

  30. Dore JM, Gras E, Wijdenes J. Expression and activity of a recombinant chimeric protein composed of pokeweed antiviral protein and of human interleukin-2.FEBS Lett. 1997;402:50–52.

    Article  CAS  PubMed  Google Scholar 

  31. Francisco JA, Gawlak SL, Siegall CB. Construction, expression, and characterization of BD1-G28-5 sFv, a single-chain anti-CD40 immunotoxin containing the ribosome-inactivating protein bryodin 1.J Biol Chem. 1997;272:24165–24169.

    Article  CAS  PubMed  Google Scholar 

  32. Fabbrini MS, Carpani D, Bello-Rivero I, Soria MR. The aminoterminal fragment of human urokinase directs a recombinant chimeric toxin to target cells: internalization is toxin mediated.FASEB J. 1997;11:1169–1176.

    CAS  PubMed  Google Scholar 

  33. Tetzke TA, Caton MC, Maher PA, Parandoosh Z. Effect of fibroblast growth factor saporin mitotoxins on human bladder cell lines.Clin Exp Metastasis. 1997;15:620–629.

    Article  CAS  PubMed  Google Scholar 

  34. Kreitman RJ. Getting plant toxins to fuse.Leuk Res. 1997;21:997–999.

    Article  CAS  PubMed  Google Scholar 

  35. Phan LD, Perentesis JP, Bodley JW. Saccharomyces cerevisiae elongation factor 2. Mutagenesis of the histidine precursor of diphthamide yields a functional protein that is resistant to diphtheria toxin.J Biol Chem. 1993;268:8665–8668.

    CAS  PubMed  Google Scholar 

  36. Hwang J, FitzGerald DJ, Adhya S, Pastan I. Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli.Cell. 1987;48:129–136.

    Article  CAS  PubMed  Google Scholar 

  37. Allured VS, Collier RJ, Carroll SF, McKay DB. Structure of exotoxin A ofPseudomonas aeruginosa at 3.0 Angstrom resolution.Proc Natl Acad Sci USA. 1986;83:1320–1324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ogata M, Fryling CM, Pastan I, FitzGerald DJ. Cell-mediated cleavage ofPseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol.J Biol Chem. 1992;267:25396–25401.

    CAS  PubMed  Google Scholar 

  39. Uchida T, Jr, Pappenheimer AM, Jr, Harper AA. Reconstitution of diphtheria toxin from two nontoxic cross-reacting mutant proteins.Science. 1972;175:901–903.

    Article  CAS  PubMed  Google Scholar 

  40. Rolf JM, Gaudin HM, Eidels L. Localization of the diphtheria toxin receptor-binding domain to the carboxyl-terminal Mr∼6000 region of the toxin.J Biol Chem. 1990;265:7331–7337.

    CAS  PubMed  Google Scholar 

  41. Kaul P, Silverman J, Shen WH, et al. Roles of Glu 349 and Asp 352 in membrane insertion and translocation by diphtheria toxin.Protein Sci. 1996;5:687–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li M, Dyda F, Benhar I, Pastan I, Davies DR. Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation.Proc Natl Acad Sci USA. 1996;93:6902–6906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hessler JL, Kreitman RJ. An early step in Pseudomonas exotoxin action is removal of the terminal lysine residue, which allows binding to the KDEL receptor.Biochemistry. 1997;36:14577–14582.

    Article  CAS  PubMed  Google Scholar 

  44. Kounnas MZ, Morris RE, Thompson MR, FitzGerald DJ, Strickland DK, Saelinger CB. The α2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A.J Biol Chem. 1992;267:12420–12423.

    CAS  PubMed  Google Scholar 

  45. Chiron MF, Fryling CM, FitzGerald DJ. Cleavage of Pseudomonas exotoxin and diphtheria toxin by a furin-like enzyme prepared from beef liver.J Biol Chem. 1994;269: 18167–18176.

    CAS  PubMed  Google Scholar 

  46. McKee ML, FitzGerald DJ. Reduction of furin-nicked Pseudomonas exotoxin A: an unfolding story.Biochemistry. 1999;38:16507–16513.

    Article  CAS  PubMed  Google Scholar 

  47. Chaudhary VK, Jinno Y, FitzGerald D, Pastan I.Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity.Proc Natl Acad Sci USA. 1990;87:308–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kreitman RJ, Pastan I. Importance of the glutamate residue of KDEL in increasing the cytotoxicity ofPseudomonas exotoxin derivatives and for increased binding to the KDEL receptor.Biochem J. 1995;307:29–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Theuer C, Kasturi S, Pastan I. Domain II ofPseudomonas exotoxin A arrests the transfer of translocating nascent chains into mammalian microsomes.Biochemistry. 1994;33:5894–5900.

    Article  CAS  PubMed  Google Scholar 

  50. Theuer CP, Buchner J, FitzGerald D, Pastan I. The N-terminal region of the 37-kDa translocated fragment ofPseudomonas exotoxin A aborts translocation by promoting its own export after microsomal membrane insertion.Proc Natl Acad Sci USA. 1993;90: 7774–7778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Keppler-Hafkemeyer A, Kreitman RJ, Pastan I. Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies.Int J Cancer. 2000;87:86–94.

    Article  CAS  PubMed  Google Scholar 

  52. Brinkmann U, Brinkmann E, Gallo M, Pastan I. Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1.Proc Natl Acad Sci USA. 1995;92:10427–10431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Choe S, Bennett MJ, Fujii G, et al. The crystal structure of diphtheria toxin.Nature. 1992;357:216–222.

    Article  CAS  PubMed  Google Scholar 

  54. Bell CE, Eisenberg D. Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide.Biochemistry. 1996;35: 1137–1149.

    Article  CAS  PubMed  Google Scholar 

  55. Williams DP, Wen Z, Watson RS, Boyd J, Strom TB, Murphy JR. Cellular processing of the interleukin-2 fusion toxin DAB486-IL-2 and efficient delivery of diphtheria fragment A to the cytosol of target cells requires Arg194.J Biol Chem. 1990;265:20673–20677.

    CAS  PubMed  Google Scholar 

  56. D’Silva PR, Lala AK. Unfolding of diphtheria toxin: identification of hydrophobic sites exposed on lowering of pH by photolabeling.J Biol Chem. 1998;273:16216–16222.

    Article  PubMed  Google Scholar 

  57. Lemichez E, Bomsel M, Devilliers G, et al. Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery.Mol Microbiol. 1997;23:445–457.

    Article  CAS  PubMed  Google Scholar 

  58. Wilson BA, Blanke SR, Reich KA, Collier RJ. Active-site mutations of diphtheria toxin. Tryptophan 50 is a major determinant of NAD affinity.J Biol Chem. 1994;269:23296–23301.

    CAS  PubMed  Google Scholar 

  59. Bennett MJ, Eisenberg D. Refined structure of monomeric diphtheria toxin at 2.3 A resolution.Protein Sci. 1994;3:1464–1475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Greenfield L, Johnson VG, Youle RJ. Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity.Science. 1987;238:536–539.

    Article  CAS  PubMed  Google Scholar 

  61. Kondo T, FitzGerald D, Chaudhary VK, Adhya S, Pastan I. Activity of immunotoxins constructed with modifiedPseudomonas exotoxin A lacking the cell recognition domain.J Biol Chem. 1988;263:9470–9475.

    CAS  PubMed  Google Scholar 

  62. Williams DP, Parker K, Bacha P, et al. Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein.Protein Eng. 1987;1:493–498.

    Article  CAS  PubMed  Google Scholar 

  63. Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I. Functional analysis of domains II, Ib, and III ofPseudomonas exotoxin.J Biol Chem. 1989;264:14256–14261.

    CAS  PubMed  Google Scholar 

  64. Kreitman RJ, Batra JK, Seetharam S, Chaudhary VK. FitzGerald DJ, Pastan I. Single-chain immunotoxin fusions between anti-Tac andPseudomonas exotoxin: relative importance of the two toxin disulfide bonds.Bioconjug Chem. 1993;4:112–120.

    Article  CAS  PubMed  Google Scholar 

  65. Williams DP, Snider CE, Strom TB, Murphy JR. Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells.J Biol Chem. 1990;265:11885–11889.

    CAS  PubMed  Google Scholar 

  66. Chaudhary VK, FitzGerald DJ, Pastan I. A proper amino terminus of diphtheria toxin is important for cytotoxicity.Biochem Biophys Res Commun. 1991;180:545–551.

    Article  CAS  PubMed  Google Scholar 

  67. Seetharam S, Chaudhary VK, FitzGerald D, Pastan I. Increased cytotoxic activity ofPseudomonas exotoxin and two chimeric toxins ending in KDEL.J Biol Chem. 1991;266:17376–17381.

    CAS  PubMed  Google Scholar 

  68. Theuer CP, Kreitman RJ, FitzGerald DJ, Pastan I. Immunotoxins made with a recombinant form ofPseudomonas exotoxin A that do not require proteolysis for activity.Cancer Res. 1993;53:340–347.

    CAS  PubMed  Google Scholar 

  69. van Oosterhout YV, van Emst JL, Bakker HH, et al. Production of anti-CD3 and anti-CD7 ricin A-immunotoxins for a clinical pilot study.Int J Pharm. 2001;221:175–186.

    Article  PubMed  Google Scholar 

  70. Pai LH, Wittes R, Setser A, Willingham MC, Pastan I. Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin.Nat Med. 1996;2:350–353.

    Article  CAS  PubMed  Google Scholar 

  71. Kreitman RJ, Pastan I. Purification and characterization of IL6-PE4E, a recombinant fusion of interleukin 6 withPseudomonas exotoxin.Bioconjug Chem. 1993;4:581–585.

    Article  CAS  PubMed  Google Scholar 

  72. Kreitman RJ, Pastan I. Making fusion toxins to target leukemia and lymphoma. In: Francis GE, Delgado C, eds.Drug Targeting: Strategies, Principles, and Applications. Fotowa, NJ: Humana Press Inc; 2000:215–227.Methods in Molecular Medicine; vol 25.

    Chapter  Google Scholar 

  73. Buchner J, Pastan I, Brinkmann U. A method for increasing the yield of propertly folded recombinant fusion proteins: single-chain immunotoxins from renaturation of bacterial inclusion bodies.Anal Biochem. 1992;205:263–270.

    Article  CAS  PubMed  Google Scholar 

  74. Shao Y, Warman BE, Perentesis JP. Recombinant fusion toxins directed against the human granulocyte-macrophage colony stimulating factor (GM-CSF) receptor.Methods Mol Biol. 2001;166:31–53.

    CAS  PubMed  Google Scholar 

  75. Choo AB, Dunn RD, Broady KW, Raison RL. Soluble expression of a functional recombinant cytolytic immunotoxin in insect cells.Protein Expr Purif. 2002;24:338–347.

    Article  CAS  PubMed  Google Scholar 

  76. Woo JH, Liu YY, Stavrou S, Neville DM. Increasing secretion of a bivalent anti-T-cell immunotoxin by Pichia pastoris.Appl Environ Microbiol. 2004;70:3370–3376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Van Horssen PJ, Preijers FW, Van Oosterhout YV, De Witte TD. Highly potent CD22-recombinant ricin A results in complete cure of disseminated malignant B-cell xenografts in SCID mice but fails to cure solid xenografts in nude mice.Int J Cancer. 1996;68:378–383.

    Article  PubMed  Google Scholar 

  78. Engert A, Diehl V, Schnell R, et al. A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin’s lymphoma.Blood. 1997;89:403–410.

    CAS  PubMed  Google Scholar 

  79. Schnell R, Vitetta E, Schindler J, et al. Treatment of refractory Hodgkin’s lymphoma patients with an anti-CD25 ricin A-chain immunotoxin.Leukemia. 2000;14:129–135.

    Article  CAS  PubMed  Google Scholar 

  80. Amlot PL, Stone MJ, Cunningham D, et al. A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy.Blood. 1993;82:2624–2633.

    CAS  PubMed  Google Scholar 

  81. Sausville EA, Headlee D, Stetler-Stevenson M, et al. Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study.Blood. 1995;85:3457–3465.

    CAS  PubMed  Google Scholar 

  82. Vitetta ES, Stone M, Amlot P, et al. Phase I immunotoxin trial in patients with B-cell lymphoma.Cancer Res. 1991;51:4052–4058.

    CAS  PubMed  Google Scholar 

  83. Stone MJ, Sausville EA, Fay JW, et al. A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.Blood. 1996;88:1188–1197.

    CAS  PubMed  Google Scholar 

  84. Frankel AE, Laver JH, Willingham MC, Burns LJ, Kersey JH, Vallera DA. Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-ricin A chain immunotoxin.Leuk Lymphoma. 1997;26:287–298.

    Article  CAS  PubMed  Google Scholar 

  85. Schnell R, Staak O, Borchmann P, et al. A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin’s and non-Hodgkin’s lymphoma.Clin Cancer Res. 2002;8:1779–1786.

    CAS  PubMed  Google Scholar 

  86. Laske DW, Youle RJ, Oldfield EH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors.Nat Med. 1997;3:1362–1368.

    Article  CAS  PubMed  Google Scholar 

  87. Uckun F. Immunotoxins for the treatment of leukaemia.Br J Haematol. 1993;85:435–438.

    Article  CAS  PubMed  Google Scholar 

  88. Multani PS, O’Day S, Nadler LM, Grossbard ML. Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin’s lymphoma.Clin Cancer Res. 1998;4:2599–2604.

    CAS  PubMed  Google Scholar 

  89. Grossbard ML, Niedzwiecki D, Nadler LM, et al. Anti-B4-blocked ricin (Anti-B4bR) adjuvant therapy postautologous bone marrow transplant (ABMT) (CALGB 9254): a phase III intergroup study.Proc Am Soc Clin Oncol. 1998;17:3a.

    Google Scholar 

  90. O’Toole JE, Esseltine D, Lynch TJ, Lambert JM, Grossbard ML. Clinical trials with blocked ricin immunotoxins.Curr Top Microbiol Immunol. 1998;234:35–56.

    PubMed  Google Scholar 

  91. Winkler U, Barth S, Schnell R, Diehl V, Engert A. The energing role of immunotoxins in leukemia and lymphoma.Ann Oncol. 1997;8:139–146.

    Article  PubMed  Google Scholar 

  92. Laske DW, Muraszko KM, Oldfield EH, et al. Intraventricular immunotoxin therapy for leptomeningeal neoplasia.Neurosurgery. 1997;41:1039–1049.

    Article  CAS  PubMed  Google Scholar 

  93. Epstein C, Lynch T, Shefner J, et al. Use of the immunotoxin N901-blocked ricin in patients with small-cell lung cancer.Int J Cancer. 1994;8:57–59.

    Article  CAS  Google Scholar 

  94. Lynch TJ, Lambert JM, Coral F, et al. Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.J Clin Oncol. 1997;15:723–734.

    Article  CAS  PubMed  Google Scholar 

  95. Foss FM, Bacha P, Osann KE, Demierre MF, Bell T, Kuzel T. Biological correlates of acute hypersensitivity events with DAB(389)IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell lymphoma: decreased frequency and severity with steroid premedication.Clin Lymphoma. 2001;1:298–302.

    Article  CAS  PubMed  Google Scholar 

  96. Frankel AE, Fleming DR, Hall PD, et al. A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia.Clin Cancer Res. 2003;9:3555–3561.

    CAS  PubMed  Google Scholar 

  97. Dang NH, Hagemeister FB, Pro B, et al. Phase II study of denileukin diftitox for relapsed/refractory B-cell non-Hodgkin’s lymphoma.J Clin Oncol. 2004;22:4095–4102.

    Article  CAS  PubMed  Google Scholar 

  98. Kreitman RJ, Wilson WH, Bergeron K, et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia.N Engl J Med. 2001;345:241–247.

    Article  CAS  PubMed  Google Scholar 

  99. Kreitman RJ, Wilson WH, Robbins D, et al. Responses in refractory hairy cell leukemia to a recombinant immunotoxin.Blood. 1999;94:3340–3348.

    CAS  PubMed  Google Scholar 

  100. Kreitman RJ, Wilson WH, White JD, et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies.J Clin Oncol. 2000;18:1622–1636.

    Article  CAS  PubMed  Google Scholar 

  101. Frankel AE, Powell BL, Hall PD, Case LD, Kreitman RJ. Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.Clin Cancer Res. 2002;8:1004–1013.

    CAS  PubMed  Google Scholar 

  102. Pai-Scherf LH, Kreitman RJ, Pastan I. Monoclonal antibodies: basic principles. Immunotoxins and recombinant immunotoxins. In: Rosenberg SA, ed.Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:382–395.

    Google Scholar 

  103. Benhar I, Reiter Y, Pai LH, Pastan I. Administration of disulfide-stabilized Fv-immunotoxins B1(dsFv)-PE38 and B3(dsFv)-PE38 by continuous infusion increases their efficacy in curing large tumor xenografts in nude mice.Int J Cancer. 1995;62:351–355.

    Article  CAS  PubMed  Google Scholar 

  104. Goldberg MR, Heimbrook DC, Russo P, et al. Phase I clinical study of recombinant oncotoxin TP40 in superficial bladder cancer.Clin Cancer Res. 1995;1:57–61.

    CAS  PubMed  Google Scholar 

  105. Sampson JH, Akabani G, Archer GE, et al. Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.J Neurooncol. 2003;65:27–35.

    Article  PubMed  Google Scholar 

  106. Posey JA, Khazaeli MB, Bookman MA, et al. Phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.Clin Cancer Res. 2002;8:3092–3099.

    CAS  PubMed  Google Scholar 

  107. Haggerty HG, Warner WA, Comereski CR, et al. BR96 sFv-PE40 immunotoxin: nonclinical safety assessment.Toxicol Pathol. 1999;27:87–94.

    Article  CAS  PubMed  Google Scholar 

  108. Damle B, Tay L, Comereski C, Warner W, Kaul S. Influence of immunogenicity on the pharmacokinetics of BMS-191352, a Pseudomonas exotoxin immunoconjugate, in rats and dogs.J Pharm Pharmacol. 2000;52:671–678.

    Article  CAS  PubMed  Google Scholar 

  109. Pai-Scherf LH, Villa J, Pearson D, et al. Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor.Clin Cancer Res. 1999;5:2311–2315.

    CAS  PubMed  Google Scholar 

  110. Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK. Intratumoral administration of a recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high grade glioma.Clin Cancer Res. 2000;6:2157–2165.

    CAS  PubMed  Google Scholar 

  111. Weber FW, Floeth F, Asher A. Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma. In: Westphal M, Tonn JC, Ram Z, eds.Local Therapies for Glioma: Present Status and Future Developments. Vienna, Austria: Springer-Verlag, Wien; 2003:93–103.

    Chapter  Google Scholar 

  112. Husain SR, Puri RK. Interleukin-13 receptor as a specific molecular target for cytotoxin therapy of human renal cell carcinoma in a xenograft model.Clin Cancer Res. 1999;5:3766s.

    Google Scholar 

  113. Puri RK, Leland P, Obiri NI, et al. Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR).Blood. 1996;87:4333–4339.

    CAS  PubMed  Google Scholar 

  114. Kunwar S. Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. In: Westphal M, Tonn JC, Ram Z, eds.Local Therapies for Glioma: Present Status and Future Developments. Vienna, Austria: Springer-Verlag Wien; 2003:105–111.

    Chapter  Google Scholar 

  115. Chowdhury PS, Viner JL, Beers R, Pastan I. Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anit-tumor activity.Proc Natl Acad Sci USA. 1998;95:669–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Foss FM, Saleh MN, Krueger JG, Nichols JC, Murphy JR. Diphtheria toxin fusion proteins. In: Frankel AE, ed.Clinical Applications of Immunotoxins. Berlin, Germany: Springer-Verlag; 1998:63–81.

    Chapter  Google Scholar 

  117. Taniguchi T, Minami Y. The IL2/IL-2 receptor system: a current overview.Cell. 1993;73:5–8.

    Article  CAS  PubMed  Google Scholar 

  118. Kodaka T, Uchiyama T, Ishikawa T, et al. Interleukin-2 receptor β-chain (p70–75) expressed on leukemic cells from adult T cell leukemia patients.Jpn J Cancer Res. 1990;81:902–908.

    Article  CAS  PubMed  Google Scholar 

  119. Yagura H, Tamaki T, Furitsu T, et al. Demonstration of high-affinity interleukin-2 receptors on B-chronic lymphocytic leukemia cells: functional and structural characterization.Blut. 1990;60:181–186.

    Article  CAS  PubMed  Google Scholar 

  120. Kreitman RJ, Pastan I. Recombinant single-chain immunotoxins against T and B cell leukemias.Leuk Lymphoma. 1994;13:1–10.

    CAS  PubMed  Google Scholar 

  121. Strauchen JA, Breakstone BA. IL-2 receptor expression in human lymphoid lesions.Am J Pathol. 1987;126:506–512.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Robb RJ, Greene WC, Rusk CM. Low and high affinity cellular receptors for interleukin 2.J Exp Med. 1984;160:1126–1146.

    Article  CAS  PubMed  Google Scholar 

  123. Bacha P, Williams DP, Waters C, Williams JM, Murphy JR, Strom TB. Interleukin 2 receptor-targeted cytotoxicity: interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein.J Exp Med. 1988;167:612–622.

    Article  CAS  PubMed  Google Scholar 

  124. LeMaistre CF, Rosenblum MG, Reuben JM, et al. Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia.Lancet. 1991;337:1124–1125.

    Article  CAS  PubMed  Google Scholar 

  125. LeMaistre CF, Meneghetti C, Rosenblum M, et al. Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptors.Blood. 1992;79:2547–2554.

    CAS  PubMed  Google Scholar 

  126. LeMaistre CF, Craig FE, Meneghetti C, et al. Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers.Cancer Res. 1993;53:3930–3934.

    CAS  PubMed  Google Scholar 

  127. LeMaistre CF, Saleh MN, Kuzel TM, et al. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphom as expressing the receptor for interleukin-2.Blood. 1998;91:399–405.

    CAS  PubMed  Google Scholar 

  128. Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.J Clin Oncol. 2001;19:376–388.

    Article  CAS  PubMed  Google Scholar 

  129. Duvic M, Kuzel TM, Olsen E, Martin AG. Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with Denileukin Diftitox (ONTAK).Clin Lymphoma. 2002;2:222–228.

    Article  CAS  PubMed  Google Scholar 

  130. Railan D, Fivenson DP, Wittenberg G. Capillary leak syndrome in a patient treated with inteleukin 2 fusion toxin for cutaneous T-cell lymphoma.J Am Acad Dermatol. 2000;43:323–324.

    Article  CAS  PubMed  Google Scholar 

  131. Duvic M. Bexarotene and DAB{389}IL-2 (Denileukin diftitox, ONTAK) in treatment of cutaneous t-cell lymphomas: algorithms.Clin Lymphoma. 2000;1:S51-S55.

    Article  PubMed  Google Scholar 

  132. Talpur R, Apisarnthanarax N, Ward S, Duvic M. Treatment of refractory peripheral T-cell lymphoma with denileukin diftitox (ONTAK).Leuk Lymphoma. 2002;43:121–126.

    Article  PubMed  Google Scholar 

  133. McGinnis KS, Shapiro M, Junkins-Hopkins JM, et al. Denileukin diftitox for the treatment of panniculitic lymphoma.Arch Dermatol. 2002;138:740–742.

    Article  PubMed  Google Scholar 

  134. Martin A, Gutierrez E, Muglia J, et al. A multicenter doseescalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.J Am Acad Dermatol. 2001;45:871–881.

    Article  CAS  PubMed  Google Scholar 

  135. Shao RH, Tian X, Gorgun G, Urbano AG, Foss FM. Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene.Leuk Res. 2002;26:1077–1083.

    Article  CAS  PubMed  Google Scholar 

  136. Gorgun G, Foss F. Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox.Blood. 2002;100:1399–1403.

    Article  CAS  PubMed  Google Scholar 

  137. Uchiyama T, Broder S, Waldmann TA. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells, I: production of anti-Tac monoclonal antibody and distribution of Tac(+) cells.J Immunol. 1981;126:1393–1397.

    CAS  PubMed  Google Scholar 

  138. Weissman AM, Harford JB, Svetlik PB, et al. Only high-affinity receptors for interleukin 2 mediate internalization of ligand.Proc Natl Acad Sci USA 1986;83:1463–1466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chaudhary VK, Gallo MG, FitzGerald DJ, Pastan I. A recombinant single-chain immunotoxin composed of anti-Tac variable regions and a truncated diphtheria toxin.Proc Natl Acad Sci USA. 1990;87:9491–9494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kreitman RJ, Pastan I. Accumulation of a recombinant immunotoxin in a tumor in vivo: fewer than 1000 molecules per cell are sufficient for complete responses.Cancer Res. 1998;58:968–975.

    CAS  PubMed  Google Scholar 

  141. Bird RE, Hardman KD, Jacobson JW, et al. Single-chain antigen-binding proteins.Science. 1988;242:423–426.

    Article  CAS  PubMed  Google Scholar 

  142. Huston JS, Levinson D, Mudgett-Hunter M, et al. Protein engineering of antibody binding sites: recovery of specific activity in an antidigoxin single-chain Fv analogue produced inEscherichia coli.Proc Natl Acad Sci USA. 1988;85:5879–5883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I. A recombinant immunotoxin consisting of two antibody variable domains fused toPseudomonas exotoxin.Nature. 1989;339:394–397.

    Article  CAS  PubMed  Google Scholar 

  144. Kobayashi H, Kao CK, Kreitman RJ, et al. Pharmacokinetics of In-111-and I-125-labeled antiTac single-chain Fv recombinant immunotoxin.J Nucl Med. 2000;41:755–762.

    CAS  PubMed  Google Scholar 

  145. Kreitman RJ, Bailon P, Chaudhary VK, FitzGerald DJP, Pastan I. Recombinant immunotoxins containing anti-Tac(Fv) and derivatives ofPseudomonas exotoxin produce complete regression in mice of an interleukin-2 receptor-expressing human carcinoma.Blood. 1994;83:426–434.

    CAS  PubMed  Google Scholar 

  146. Kreitman RJ, Pastan I. TargetingPseudomonas exotoxin to hematologic malignancies.Semin Cancer Biol. 1995;6:297–306.

    Article  CAS  PubMed  Google Scholar 

  147. Robbins DH, Margulies I, Stetler-Stevenson M, Kretiman RJ. Hairy cell leukemia, a B-cell neoplasm which is particularly sensitive to the cytotoxic effect of anti-Tac(Fv)-PE38 (LMB-2).Clin Cancer Res. 2000;6:693–700.

    CAS  PubMed  Google Scholar 

  148. Decker T, Hipp S, Kreitman RJ, Pastan I, Peschel C, Licht T. Sensitization of B-CLL cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligonucleotides.Blood. 2002;99:1320–1326.

    CAS  PubMed  Google Scholar 

  149. Ohno N, Kreitman RJ, Saito T, et al. Augmentation of the activity of an immunotoxin, anti-tac(Fv)-PE40KDEL, in T cell lines infected with human T cell leukemia virus type-I.Leuk Lymphoma. 2002;43:885–888.

    Article  CAS  PubMed  Google Scholar 

  150. Onda M, Kreitman RJ, Vasmatzis G, Lee B, Pastan I. Reduction of the nonspecific toxicity of anti-Tac(Fv)-PE38 by mutations in the framework regions of the Fv which lower the isoelectric point.J Immunol. 1999;163:6072–6077.

    CAS  PubMed  Google Scholar 

  151. Onda M, Willingham M, Wang Q, et al. Inhibition of TNF alpha produced by Kupffer cells protects against the non-specific liver toxicity of immunotoxin anti-Tac(Fv)-PE38, LMB-2.J Immunol. 2000;165:7150–7156.

    Article  CAS  PubMed  Google Scholar 

  152. Schnell R, Vitetta E, Schindler J, et al. Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin’s lymphoma.Leuk Lymphoma. 1998;30:525–537.

    Article  CAS  PubMed  Google Scholar 

  153. Schnell R, Borchmann P, Staak JO, et al. Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin’s lymphoma.Ann Oncol. 2003;14:729–736.

    Article  CAS  PubMed  Google Scholar 

  154. Montagna D, Yvon E, Calcaterra V, et al. Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity.Blood. 1999;93:3550–3557.

    CAS  PubMed  Google Scholar 

  155. Martin PJ, Pei J, Gooley T, et al. Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation.Biol Blood Marrow Transplant. 2004;10:552–560.

    Article  CAS  PubMed  Google Scholar 

  156. Reiter Y, Brinkmann U, Kreitman RJ, Jung S-H, Lee B, Pastan I. Stabilization of the Fv fragments in recombinant immunotoxins by disulfide bonds engineered into conserved framework regions.Biochemistry. 1994;33:5451–5459.

    Article  CAS  PubMed  Google Scholar 

  157. Reiter Y, Kreitman RJ, Brinkmann U, Pastan I. Cytotoxic and antitumor activity of a recombinant immunotoxin composed of disulfide-stabilized anti-Tac Fv fragment and truncatedPseudomonas exotoxin.Int J Cancer. 1994;58:142–149.

    Article  CAS  PubMed  Google Scholar 

  158. Kreitman RJ, Schneider WP, Queen C, et al. Mik-β1(Fv)-PE40, a recombinant immunotoxin cytotoxic toward cells bearing the β-chain of the IL-2 receptor.J Immunol. 1992;149:2810–2815.

    CAS  PubMed  Google Scholar 

  159. Barth S, Huhn M, Wels W, Diehl V, Engert A. Construction andin vitro evaluation of RFT5(scFv)-ETA’, a new recombinant single-chain immunotoxin with specific cytotoxicity toward CD25+ Hodgkin-derived cell lines.Int J Mol Med. 1998;1:249–256.

    CAS  PubMed  Google Scholar 

  160. Barth S, Huhn M, Matthey B, et al. Recombinant anti-CD25 immunotoxin RFT5(ScFv)-ETA’ demonstrates succesful elimination of disseminated human Hodgkin lymphoma in SCID mice.Int J Cancer. 2000;86:718–724.

    Article  CAS  PubMed  Google Scholar 

  161. Matthey B, Engert A, Barth S. Recombinant immunotoxins for the treatment of Hodgkin’s disease (Review).Int J Mol Med. 2000;6:509–514.

    CAS  PubMed  Google Scholar 

  162. Ghetie M-A, May RD, Till M, et al. Evaluation of ricin A chain-containing immunotoxins directed against CD19 and CD22 antigens on normal and malignant human B-cells as potential reagents forin vivo therapy.Cancer Res. 1988;48:2610–2617.

    CAS  PubMed  Google Scholar 

  163. Ghetie M-A, Richardson J, Tucker T, Jones D, Uhr JW, Vitetta ES. Antitumor activity of Fab’ and IgG-anti-CD22 immunotoxins in disseminated human B lymphoma grown in mice with severe combined immunodeficiency disease: effect on tumor cells in extranodal sites.Cancer Res. 1991;51:5876–5880.

    CAS  PubMed  Google Scholar 

  164. Bregni M, Siena S, Formosa A, et al. B-cell restricted saporin immunotoxins: activity against B-cell lines and chronic lymphocytic leukemia cells.Blood. 1989;73:753–762.

    CAS  PubMed  Google Scholar 

  165. Senderowicz AM, Vitetta E, Headlee D, et al. Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin.Ann Intern Med. 1997;126:882–885.

    Article  CAS  PubMed  Google Scholar 

  166. Smallshaw JE, Ghetie V, Rizo J, et al. Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice.Nat Biotechnol. 2003;21:387–391.

    Article  CAS  PubMed  Google Scholar 

  167. Kreitman RJ. Taming ricin toxin.Nat Biotechnol. 2003;21:372–374.

    Article  CAS  PubMed  Google Scholar 

  168. Kreitman RJ, Hansen HJ, Jones AL, FitzGerald DJ, Goldenberg DM. Pastan I.Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab’ induce regression of subcutaneous human B-cell lymphoma in mice.Cancer Res. 1993;53:819–825.

    CAS  PubMed  Google Scholar 

  169. Mansfield E, Chiron MF, Amlot P, Pastan I. Fitz Gerald DJ. Recombinant RFB4 single-chain immunotoxin that is cytotoxic towards CD22-positive cells.Biochem Soc Trans. 1997;25:709–714.

    Article  CAS  PubMed  Google Scholar 

  170. Mansfield E, Amlot P, Pastan I, FitzGeral DJ. Recombinant RFB4 immunotoxins exhibit potent cytotoxic activity for CD22-bearing cells and tumors.Blood. 1997;90:2020–2026.

    CAS  PubMed  Google Scholar 

  171. Kreitman RJ, Wang QC, FitzGerald DJ, Pastan I. Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by cynomolgus monkeys.Int J Cancer. 1999;81:148–155.

    Article  CAS  PubMed  Google Scholar 

  172. Kreitman RJ, Margulies I, Stetler-Stevenson M, Wang QC, FitzGerald DJ, Pastan I. Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) towards fresh malignant cells from patients with B-cell leukemias.Clin Cancer Res. 2000;6:1476–1487.

    CAS  PubMed  Google Scholar 

  173. Salvatore G, Beers R, Margulies I, Kreitnan RJ, Pastan I. Improved cytotoxic activity towards cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display.Clin Cancer Res. 2002;8:995–1002.

    CAS  PubMed  Google Scholar 

  174. Kreitman RJ, Squires DR, Stetler-Stevenson M, et al. Phase I trial of recombinant immunotoxin, RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies.J Clin Oncol. 2005;23:6719–6729.

    Article  CAS  PubMed  Google Scholar 

  175. Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D. The natural history and clinico-pathological features of the variant form of hairy cell leukemia.Leukemia. 2001;15:184–186.

    Article  CAS  PubMed  Google Scholar 

  176. Tallman MS, Hakimian D, Kopecky KJ, et al. Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse.Clin Cancer Res. 1999;5:1665–1670.

    CAS  PubMed  Google Scholar 

  177. Kreitman RJ, Pastan I. Recombinant toxins containing human granulocyte-macrophage colony-stimulating factor and either Pseudomonas exotoxin or diphtheria toxin kill gastrointestinal cancer and leukemia cells.Blood. 1997;90:252–259.

    CAS  PubMed  Google Scholar 

  178. Hall PD, Virella G, Willoughby T, Atchley DH, Kreitman RJ. Frankel AE. Antibody response to DT-GM, a novel fusion toxin consisting of a truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM), during a phase I trial of patients with relapsed or refractory acute myeloid leukemia.Clin Immunol. 2001;100:191–197.

    Article  CAS  PubMed  Google Scholar 

  179. Szatrowski TP, Dodge RK, Reynolds C, et al. Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine: Cancer and Leukemia Group B Stydy 9311.Cancer. 2003;97:1471–1480

    Article  CAS  PubMed  Google Scholar 

  180. Grossbard ML, Gribben JG, Freedman AS, et al. Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin’s lymphoma.Blood. 1993;81:2263–2271.

    CAS  PubMed  Google Scholar 

  181. Scadden DT, Schenkein DP, Bernstein Z, et al. Immunotoxin combined with chemotherapy for patients with AIDS-related non-Hodgkin’s lymphoma.Cancer. 1998;83:2580–2587.

    Article  CAS  PubMed  Google Scholar 

  182. Grossbard ML, Multani PS, Freedman AS, et al. Phase II study of adjuvant therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with relapsed B-cell non-Hodgkin’s lymphoma.Clin Cancer Res. 1999;5:2392–2398.

    CAS  PubMed  Google Scholar 

  183. Longo DL, Duffey PL, Gribben JG, et al. Combination chemotherapy followed by an immunotoxin (anti-B4-blocked ricin) in patients with indolent lymphoma: results of a phase II study.Cancer J. 2000;6:146–150.

    CAS  PubMed  Google Scholar 

  184. Herrera L, Yarbrough S, Ghetie V, Aquino DB, Vitetta ES. Treatment of SCID/human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins.Leukemia. 2003;17:334–338.

    Article  CAS  PubMed  Google Scholar 

  185. Messmann RA, Vitetta ES, Headlee D, et al. A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma.Clin Cancer Res. 2000;6:1302–1313.

    CAS  PubMed  Google Scholar 

  186. Schnell R, Staak O, Borchmann P, et al. Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin’s and non-Hodgkin’s lymphoma.Clin Cancer Res. 2002;8:1779–1786.

    CAS  PubMed  Google Scholar 

  187. Hansen HP, Matthey B, Barth S, et al. Inhibition of metalloproteinases enhances the internalization of anti-CD30 antibody Ki-3 and the cytotoxic activity of Ki-3 immunotoxin.Int J Cancer. 2002;98:210–215.

    Article  CAS  PubMed  Google Scholar 

  188. Klimka A, Barth S, Matthey B, et al. An anti-CD30 single-chain Fv selected by phage display and fused to Pseudomonas exotoxin A (Ki-4(scFv)-ETA’) is a potent immunotoxin against a Hodgkin-derived cell line.Br J Cancer. 1999;80:1214–1222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Barth S, Huhn M, Matthey B, et al. Ki-4(scFv)-ETA’, a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice.Blood. 2000;95:3909–3914.

    CAS  PubMed  Google Scholar 

  190. Rozemuller H, Chowdhury PS, Pastan I, Kreitman RJ. Isolation of new anti-CD30 scFvs from DNA-immunized mice by phage display and biologic activity of recombinant immunotoxins produced by fusion with truncated Pseudomonas exotoxin.Int J Cancer. 2001;92:861–870.

    Article  CAS  PubMed  Google Scholar 

  191. Nagata S, Onda M, Numata Y, et al. Novel anti-CD30 recombinant immunotoxins containing disulfide-stabilized Fv fragments.Clin Cancer Res. 2002;8:2345–2355.

    CAS  PubMed  Google Scholar 

  192. Alexander RL, Kucera GL, Klein B, Frankel AE. In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein.Bioconjug Chem. 2000;11:564–568.

    Article  CAS  PubMed  Google Scholar 

  193. Frankel A, McCubrey J, Miller MS, et al. Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with acute phase chronic myeloid leukemia.Leukemia. 2000;14:576–585.

    Article  CAS  PubMed  Google Scholar 

  194. Alexander RL, Ramage J, Kucera GL, Caligiuri MA, Frankel AE. High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein.Leuk Res. 2001; 25:875–881.

    Article  CAS  PubMed  Google Scholar 

  195. Feuring-Buske M, Frankel AE, Alexander RL, Gerhard B, Hogge DE. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors.Cancer Res. 2002;62:1730–1736.

    CAS  PubMed  Google Scholar 

  196. Black JH, McCubrey JA, Willingham MC, Ramage J, Hogge DE, Frankel AE. Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice.Leukemia. 2003;17:155–159.

    Article  CAS  PubMed  Google Scholar 

  197. Urieto JO, Liu T, Black JH, et al. Expression and purification of the recombinant diphtheria fusion toxin DT388IL3 for phase I clinical trials.Protein Expr Purif. 2004;33:123–133.

    Article  CAS  PubMed  Google Scholar 

  198. Flavell DJ, Boehm DA, Noss A, Warnes SL, Flavell SU. Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin.Br J Cancer. 2001;84:571–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Mehta K, Ocanas L, Malavasi F, Marks JW, Rosenblum MG. Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing of leukemia cells.Mol Cancer Ther. 2004;3: 345–352.

    CAS  PubMed  Google Scholar 

  200. Peipp M, Kupers H, Saul D, et al. A recombinant CD7-specific single-chain immunotoxin is a potent inducer of apoptosis in acute leukemic T cells.Cancer Res. 2002;62:2848–2855.

    CAS  PubMed  Google Scholar 

  201. Polito L, Bolognesi A, Tazzari PL, et al. The conjugate Rituximab/saporin-S6 completely inhibits clonogenic growth of CD20-expressing cells and produces a synergistic toxic effect with Fludarabine.Leukemia. 2004;18:1215–1222.

    Article  CAS  PubMed  Google Scholar 

  202. Zhong RK, van De Winkel JG, Thepen T, Schultz LD, Ball ED. Cytotoxicity of anti-cd64-ricin a chain immunotoxin against human acute myeloid leukemia cells in vitro and in SCID mice.J Hematother Stem Cell Res. 2001;10:95–105.

    Article  CAS  PubMed  Google Scholar 

  203. Tur MK, Huhn M, Thepen T, et al. Recombinant CD64-specific single chain immunotoxin exhibits specific cytotoxicity against acute myeloid leukemia cells.Cancer Res. 2003;63:8414–8419.

    CAS  PubMed  Google Scholar 

  204. Otten HG, deGast GC, Vooijs WC. Preclinical evaluation of anti-CD86 immunotoxin in rhesus monkeys: analysis of systemic toxicity, pharmacokinetics, and effect on primary t-cell responses.Cancer Immunol Immunother. 2003;52:569–575.

    Article  CAS  PubMed  Google Scholar 

  205. Shin YK, Choi YL, Choi EY, et al. Targeted cytotoxic effect of anti-JL1 immunotoxin against a human leukemic cell line and its clinical implications.Cancer Immunol Immunother. 2003;52:506–512.

    Article  CAS  PubMed  Google Scholar 

  206. Pistillo MP, Tazzari PL, Palmisano GL, et al. CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells.Blood. 2003;101:202–209.

    Article  CAS  PubMed  Google Scholar 

  207. FitzGerald DJ, Padmanabhan R, Pastan I, Willingham MC. Adenovirus-induced release of epidermal growth factor and pseudomonas toxin into the cytosol of KB cells during receptor-mediated endocytosis.Cell. 1983;32:607–617.

    Article  CAS  PubMed  Google Scholar 

  208. Chaudhary VK, FitzGerald DJ, Adhyn S, Pastan I. Activity of a recombinant fusion protein between transforming growth factor type α andPseudomonas toxin.Proc Natl Acad Sci USA. 1987;84:4538–4542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Siegall CB, Xu Y-h, Chaudhary VK, Adhya S, FitzGerald D, Pastan I. Cytotoxic activities of a fusion protein comprised of TGFα andPseudomonas exotoxin.FASEB J. 1989;3:2647–2652.

    CAS  PubMed  Google Scholar 

  210. Kreitman RJ, Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I. Properties of chimeric toxins with two recognition domains: interleukin 6 and transforming growth factor α at different locations inPseudomonas exotoxin.Bioconjug Chem. 1992;3:63–68.

    Article  CAS  PubMed  Google Scholar 

  211. Pai LH, Gallo MG, FitzGerald DJ, Pastan I. Antitumor activity of a transforming growth factor α-Pseudomonas exotoxin fusion protein (TGF-α-PE40).Cancer Res. 1991;51:2808–2812.

    CAS  PubMed  Google Scholar 

  212. Shaw JP, Degen D, Nichols JC, Bacha P, Von Hoff DD. Cytotoxicity of an epidermal growth factor receptor targeted fusion toxin for primary and cultured human tumor cells.Proc Am Assoc Cancer Res. 1993;34:2043.

    Google Scholar 

  213. Liu TF, Willingham MC, Tatter SB, et al. Diphtheria toxin-epidermal growth factor fusion protein and Pseudomonas exotoxin-interleukin 13 fusion protein exert synergistic toxicity against human glioblastoma multiforme cells.Bioconjug Chem. 2003;14:1107–1114.

    Article  CAS  PubMed  Google Scholar 

  214. Mishra G, Liu TF, Frankel AE. Recombinant toxin DAB389EGF is cytotoxic to human pancreatic cancer cells.Expert Opin Biol Ther. 2003;3:1173–1180.

    Article  CAS  PubMed  Google Scholar 

  215. Bruell D, Stocker M, Huhn M, et al. The recombinant anti-EGF receptor immunotoxin 425(scFv)-ETA’ suppresses growth of a highly metastatic pancreatic carcinoma cell line.Int J Oncol. 2003;23:1179–1186.

    CAS  PubMed  Google Scholar 

  216. Lorimer IAJ, Wikstrand CJ, Batra SK, Bigner DD, Pastan I. Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors.Clin Cancer Res. 1995;1:859–864.

    CAS  PubMed  Google Scholar 

  217. Lorimer IA, Keppler-Hafkemeyer A, Beers RA, Pegram CN, Bigner DD, Pastan I. Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display.Proc Natl Acad Sci USA. 1996;93:14815–14820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Fu YM, Mesri EA, Yu ZX, Kreitman RJ, Pastan I, Epstein SE, Cytotoxic effects of vascular smooth muscle cells of the chimeric toxin, heparin binding TGF α-Pseudomonas exotoxin.Cardiovasc Res. 1993;27:1691–1697.

    Article  CAS  PubMed  Google Scholar 

  219. Mesri EA, Kreitman RJ, Fu YM, Epstein SE, Pastan I. Heparin-binding transforming growth factor α-Pseudomonas exotoxin A.J Biol Chem. 1993;268:4853–4862.

    CAS  PubMed  Google Scholar 

  220. Mesri EA, Ono M, Kreitman RJ, Klagsbrun M, Pastan I. the heparin-binding domain of heparin-binding EGF-like growth factor can targetPseudomonas exotoxin to kill cells exclusively through heparan sulfate proteoglycans.J Cell Sci. 1994;107:2599–2608.

    CAS  PubMed  Google Scholar 

  221. Pastan I, Lovelace ET, Gallo MG, Rutherford AV, Magnani JL, Willingham MC. Characterization of monoclonal antibodies B1 and B3 that react with mucinous adenocarcinomas.Cancer Res. 1991;51:3781–3787.

    CAS  PubMed  Google Scholar 

  222. Pai LH, Kreitman RJ, Pastan I. Immunotoxin therapy. In: Devita VT Jr, Hellman S, Rosenberg SA, eds.Cancer Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:382–395.

    Google Scholar 

  223. Pai LH, Batra JK, FitzGerald DJ, Willingham MC, Pastan I. Antitumor effects of B3-PE and B3-LysPE40 in a nude mouse model of human breast cancer and the evaluation of B3-PE toxicity in monkeys.Cancer Res. 1992;52:3189–3193.

    CAS  PubMed  Google Scholar 

  224. Pai LH, Batra JK, FitzGerald DJ, Willingham MC, Pastan I. Antitumor activities of immunotoxins made of monoclonal antibody B3 and various forms of Pseudomonas exotoxin.Proc Natl Acad Sci USA. 1991;883358–3362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Kuan C, Pai LH, Pastan I. Immunotoxins containingPseudomonas exotoxin targeting LeY damage human endothelial cells in an antibody-specific mode: relevance to vascular leak syndrome.Clin Cancer Res. 1995;1:1589–1594.

    CAS  PubMed  Google Scholar 

  226. Brinkmann U, Pai LH, FitzGerald DJ, Willingham M, Pastan I. B3(Fv)-PE38KDEL, a single-chain immunotoxin that causes complete regression of a human carcinoma in mice.Proc Natl Acad Sci USA. 1991;88:8616–8620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer.Oncogene. 2000;19:6102–6114.

    Article  CAS  PubMed  Google Scholar 

  228. Wels W, Beerli R, Hellmann P, et al. EGF receptor and p185 (erB-2)-specific single-chain antibody toxins differ in their cell-killing activity on tumor cells expressing both receptor proteins.Int J Cancer. 1995;60:137–144.

    Article  CAS  PubMed  Google Scholar 

  229. Schmidt M, Hynes NE, Groner B, Wels W. A bivalent single-chain antibody-toxin specific for ErbB-2 and the EGF receptor.Int J Cancer. 1996;65:538–546.

    Article  CAS  PubMed  Google Scholar 

  230. Batra JK, Kasprzyk PG, Bird RE, Pastan I, King CR. Recombinant anti-erbB2 immunotoxins containingPseudomonas exotoxin.Proc Natl Acad Sci USA. 1992;89:5867–5871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Shinohara H, Morita S, Kawai M, et al. Expression of HER2 in human gastric cancer cells directly correlates with antitumor activity of a recombinant disulfide-stabilized anti-HER2 immunotoxins.J Surg res. 2002;102:169–177.

    Article  CAS  PubMed  Google Scholar 

  232. Azemar M, Schmidt M, Arlt F, et al. Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vitro growth of human head and neck cancer cells and cause rapid tumor regression in vivo.Int J Cancer. 2000;86:269–275.

    Article  CAS  PubMed  Google Scholar 

  233. Azemar M, Djahansonzi S, Jager E, et al. Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2.Breast Cancer Res Treat. 2003;82:155–164.

    Article  CAS  PubMed  Google Scholar 

  234. Husain SR, Gill P, Kreitman RJ, Pastan I, Puri PK. Interleukin-4 receptor expression on AIDS-associated Kaposi’s sarcoma cells and their targeting by a chimeric protein comprised of circularly permuted IL-4 and Pseudomonas exotoxin.Mol Med. 1997;3:327–338.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Debinski W, Puri RK, Kreitman RJ, Pastan I. A wide range of human cancers express interleukin 4 (IL4) receptors that can be targeted with chimeric toxin composed of IL4 andPseudomonas exotoxin.J Biol Chem. 1993;268:14065–14070.

    CAS  PubMed  Google Scholar 

  236. Kreitman RJ, Puri RK, Leland P, Lee B, Pastan I. Site-specific conjugation to interleukin 4 containing mutated cysteine residues produces interleukin 4-toxin conjugates with improved binding and activity.Biochemistry. 1994;33:11637–11644.

    Article  CAS  PubMed  Google Scholar 

  237. Kreitman RJ. Circularly permuted interleukin 4 retains proliferative and binding activity.Cytokine. 1995;7:311–318.

    Article  CAS  PubMed  Google Scholar 

  238. Kreitman RJ, Puri RK, Pastan I. Increased antitumor activity of a circularly permuted interleukin 4-toxin in mice with interleukin 4 receptor-bearing human carcinoma.Cancer Res. 1995;55:3357–3363.

    CAS  PubMed  Google Scholar 

  239. Kreitman RJ, Puri RK, Pastan I. A circularly permuted recombinant interleukin 4 toxin with increased activity.Proc Natl Acad Sci USA. 1994;91:6889–6893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Husain SR, Behari N, Kreitman RJ, Pastan I, Puri RK. Complete regression of established human glioblastoma tumor xenografts by interleukin-4 toxin therapy.Cancer Res. 1998;58:3649–3653.

    CAS  PubMed  Google Scholar 

  241. Puri RK, Hoon DS, Leland P, et al. Preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncatedPseudomonas exotoxin for therapy of malignant astrocytoma.Cancer Res. 1996;56:5631–5637.

    CAS  PubMed  Google Scholar 

  242. Obiri NI, Debinski W, Leonard WJ, Puri RK. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15.J Biol Chem. 1995;270:8797–8804.

    Article  CAS  PubMed  Google Scholar 

  243. Obiri NI, Leland P, Murata T, Debinski W, Puri RK. The IL-13 receptor structure differs on various cell types and may share more than one component with IL-4 receptor.J Immunol. 1997;158:756–764.

    CAS  PubMed  Google Scholar 

  244. Weaver M, Laske DW. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas.J Neurooncol. 2003;65:3–13.

    Article  PubMed  Google Scholar 

  245. Hagihara N, Walbridge S, Olson AW, Oldfield EH, Youle RJ. Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107.Cancer Res. 2000;60:230–234.

    CAS  PubMed  Google Scholar 

  246. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers.Proc Natl Acad Sci USA. 1996;93:136–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Chowdhury PS, Chang K, Pastan I. Isolation of anti-mesothelin antibodies from a phage display library.Mol Immunol. 1997;34:9–20.

    Article  CAS  PubMed  Google Scholar 

  248. Hassan R, Benbrook DM, Lightfoot SA, et al. SS1(dsFv)-PE38, a recombinant anti-mesothelin immunotoxin targets human gynecologic tumors overexpressing mesothelin.Proc Am Soc Clin Oncol. 2000;19:383a.

    Google Scholar 

  249. Hassan R, Lerner MR, Benbrook D, et al. Antitumor activity of SS(dsFv)PE38 and SS1(dsFv)PE38, recombinant antimesothelin immunotoxins against human gynecologic cancers grown in organotypic culture in vitro.Clin Cancer Res. 2002;8:3520–3526.

    CAS  PubMed  Google Scholar 

  250. Li Q, Verschraegen CF, Mendoza J, Hassan R. Cytotoxic activity of the recombinant anti-mesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas.Anticancer Res. 2004;24:1327–1335.

    CAS  PubMed  Google Scholar 

  251. Fan D, Yano S, Shinohara H, et al. Targeted therapy against human lung cancer in nude mice by high-affinity recombinant antimesothelin single-chain Fv immunotoxin.Mol Cancer Ther. 2002;1:595–600.

    Article  CAS  PubMed  Google Scholar 

  252. Bera TK, Williams-Gould J, Beers R, Chowdhury P, Pastan I. Bivalent disulfide-stabilized fragment variable immunotoxin directed against mesotheliomas and ovarian cancer.Mol Cancer Ther. 2001;1:79–84.

    CAS  PubMed  Google Scholar 

  253. Lynch TJ. Immunotoxin therapy of small-cell lung cancer. N901-blocked ricin for relapsed small-cell lung cancer.Chest. 1993;103:436s-439s.

    Article  PubMed  Google Scholar 

  254. Fidias P, Jr, Grossbard M, Jr, Lynch TJ, Jr. A phase II study of the immunotoxin N901-blocked ricin in small-cell lung cancer.Clin Lung Cancer. 2002;3:219–222.

    Article  PubMed  Google Scholar 

  255. Lanza F, Castoldi GL, Castagnari B, et al. Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells.Br J Haematol. 1998; 103:110–123.

    Article  CAS  PubMed  Google Scholar 

  256. Plesner T, Ralfkiaer E, Wittrup M, et al. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue.Am J Clin Pathol. 1994;102:835–841.

    Article  CAS  PubMed  Google Scholar 

  257. Taniguchi T, Kakkar AK, Tuddenham EGD, Williamson RCN, Lemoine NR. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.Cancer Res. 1998;58:4461–4467.

    CAS  PubMed  Google Scholar 

  258. Sier CFM, Stephens R, Bizik J, et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients.Cancer Res. 1998;58:1843–1849.

    CAS  PubMed  Google Scholar 

  259. Rajagopal V, Kreitman RJ. Recombinant toxins which bind to the urokinase receptor are cytotoxic without requiring binding to the α2 macroglobulin receptor.J Biol Chem. 2000;275:7566–7573.

    Article  CAS  PubMed  Google Scholar 

  260. Ramage JG, Vallera DA, Black JH, Aplan PD, Kees UR, Frankel AE. The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells.Leuk Res. 2003;27:79–84.

    Article  CAS  PubMed  Google Scholar 

  261. Frankel AE, Beran M, Hogge DE, et al. Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein.Exp Hematol. 2002;30:1316–1323.

    Article  CAS  PubMed  Google Scholar 

  262. Vallera DA, Li C, Jin N, Panoskaltsis-Mortari A, Hall WA. Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT.J Natl Cancer Inst. 2002;94:597–606.

    Article  CAS  PubMed  Google Scholar 

  263. Rustamzadeh E, Li C, Doumbia S, Hall WA, Vallera DA. Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme.J Neurooncol. 2003;65:63–75.

    Article  PubMed  Google Scholar 

  264. Todhunter DA, Hall WA, Rustamzadeh E, Shu Y, Doumbia SO, Vallera DA. A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model.Protein Eng Des Sel. 2004;17:157–164.

    Article  CAS  PubMed  Google Scholar 

  265. Rosenblum MG, Murray JL, Cheung L, Rifkin R, Salmon S, Bartholomew R. A specific and potent immunotoxin composed of antibody ZME-018 and the plant toxin gelonin.Mol Biother. 1991;3:6–13.

    CAS  PubMed  Google Scholar 

  266. Rosenblum MG, 3rd, Cheung LH, 3rd, Liu Y, 3rd, Marks JW, 3rd. Design, expression, purification, and characterization, in vitro and in vivo, of an antimelanoma single-chain Fv antibody fused to the toxin gelonin.Cancer Res. 2003;63:3995–4002.

    CAS  PubMed  Google Scholar 

  267. Chan MC, Murphy RM. Kinetics of cellular trafficking and cytotoxicity of 9.2.27-gelonin immunotoxins targeted against the high-molecular-weight melanoma-associated antigen.Cancer Immunol Immunother. 1999;47:321–329.

    Article  CAS  PubMed  Google Scholar 

  268. Hjortland GO, Garman-Vik SS, Juell S, et al. Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme.J Neurosurg. 2004;100:320–327.

    Article  CAS  PubMed  Google Scholar 

  269. Fracasso G, Bellisola G, Cingarlini S, et al. Anti-tumor effects of toxins targeted to the prostate specific membrane antigen.Prostate. 2002;53:9–23.

    Article  CAS  PubMed  Google Scholar 

  270. Huang X, Bennett M, Thorpe PE. Anti-tumor effects and lack of side effects in mice of an immunotoxin directed against human and mouse prostate-specific membrane antigen.Prostate. 2004;61:1–11.

    Article  CAS  PubMed  Google Scholar 

  271. Onda M, Wang QC, Guo HF, Cheung NK, Pastan I. In vitro and in vivo cytotoxic activities of recombinant immunotoxin 8H9(Fv)-PE38 against breast cancer, osteosarcoma, and neuroblastoma.Cancer Res. 2004;64:1419–1424.

    Article  CAS  PubMed  Google Scholar 

  272. Thomas PB, Delatte SJ, Sutphin A, Frankel AE, Tagge EP. Effective targeted cytotoxicity of neuroblastoma cells.J Pediatr Surg. 2002;37:539–544.

    Article  PubMed  Google Scholar 

  273. Di Paolo C, Willuda J, Kubetzko S, et al. A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity.Clin Cancer Res. 2003;9:2837–2848.

    PubMed  Google Scholar 

  274. Jin N, Chen W, Blazar BR, Ramakrishnan S, Vallera DA. Gene therapy of murine solid tumors with T cells transduced with a retroviral vascular endothelial growth factor—immunotoxin target gene.Hum Gene Ther. 2002;13:497–508.

    Article  CAS  PubMed  Google Scholar 

  275. Reddy KR. Development and pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a (40 kD).Semin Liver Dis. 2004;24:33–38.

    Article  CAS  PubMed  Google Scholar 

  276. Graham ML. Pegaspargase: a review of clinical studies.Adv Drug Deliv Rev. 2003:55:1293–1302.

    Article  CAS  PubMed  Google Scholar 

  277. Onda M, Vincent JJ, Lee B, Pastan I. Mutants of immunotoxin anti-Tac(dsFv)-PE38 with variable number of lysine residues as candidates for site-specific chemical modification, I: properties of mutant molecules.Bioconjug Chem. 2003;14:480–487.

    Article  CAS  PubMed  Google Scholar 

  278. Tsutsumi Y, Onda M, Nagata S, Lee B, Kreitman RJ, Pastan I. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity.Proc Natl Acad Sci USA. 2000;97:8548–8553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Roscoe DM, Pai LH, Pastan I. Identification of epitopes on a mutant form of Pseudomonas exotoxin using serum from humans treated with Pseudomonas exotoxin containing immunotoxins.Eur J Immunol. 1997;27:1459–1468.

    Article  CAS  PubMed  Google Scholar 

  280. Roscoe DM, Jung SH, Benhar I, Pai L, Lee BK, Pastan I. Primate antibody response to immunotoxin: serological and computer-aided analysis of epitopes on a truncated form of Pseudomonas exotoxin.Infect Immun. 1994;62:5055–5065.

    CAS  PubMed  PubMed Central  Google Scholar 

  281. Nagata S, Numata Y, Onda M, et al. Rapid grouping of monoclonal antibodies based on their topographical epitopes by a label-free competitive immunoassay.J Immunol Methods. 2004;292:141–155.

    Article  CAS  PubMed  Google Scholar 

  282. Pai LH, FitzGerald DJ, Tepper M, Schacter B, Spitalny G, Pastan I. Inhibition of antibody response to Pseudomonas exotoxin and an immunotoxin containing Pseudomonas exotoxin by 15-deoxyspergualin in mice.Cancer Res. 1990;50:7750–7753.

    CAS  PubMed  Google Scholar 

  283. Siegall CB, Haggerty HG, Warner GL, et al. Prevention of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumor efficacy.J Immunol. 1997;159:5168–5173.

    CAS  PubMed  Google Scholar 

  284. Gelber EE, Vitetta ES. Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.Clin Cancer Res. 1998;4:1297–1304.

    CAS  PubMed  Google Scholar 

  285. Hassan R, Williams-Gould J, Watson T, Pai-Scherf L, Pastan I. Pretreatment with rituximab does not inhibit the human immune response against the immunogenic protein LMB-1.Clin Cancer Res. 2004;10:16–18.

    Article  CAS  PubMed  Google Scholar 

  286. Baluna R, Rizo J, Gordon BE, Ghetie V, Vitetta ES. Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome.Proc Natl Acad Sci USA. 1999;96:3957–3962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Baluna R, Coleman E, Jones C, Ghetie V, Vitetta ES. The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: insights into toxin-mediated vascular damage.Exp Cell Res. 2000;258:417–424.

    Article  CAS  PubMed  Google Scholar 

  288. Onda M, Nagata S, Tsutsumi Y, et al. Lowering the isoelectric point of the Fv portion of recombinant immunotoxins leads to decreased nonspecific animal toxicity without affecting antitumor activity.Cancer Res. 2001;61:5070–5077.

    CAS  PubMed  Google Scholar 

  289. Grossbard ML, Lambert JM, Goldmacher VS, et al. Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.J Clin Oncol. 1993;11:726–737.

    Article  CAS  PubMed  Google Scholar 

  290. Grossbard ML, Fidias P, Kinsella J, et al. Anti-B4-blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma.Br J Haematol. 1998;102:509–515.

    Article  CAS  PubMed  Google Scholar 

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  1. Clinical Immunotherapy Section, Laboratory of Molecular Biology, Centers for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 5124B, 20892-4255, Bethesda, MD

    Robert J. Kreitman

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Published: August 18, 2006

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Kreitman, R.J. Immunotoxins for targeted cancer therapy. AAPS J 8, 63 (2006). https://doi.org/10.1208/aapsj080363

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