Recombinant Immunotoxins

Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Recombinant immunotoxins contain a recombinant antibody and a protein toxin, capable of killing a cell after internalization and transport of the toxin to the cytosol. Growth factor fusion toxins, including the approved molecule denileukin diftitox, contain a growth factor such as interleukin-2 and truncated toxin. Recombinant immunotoxins furthest along in clinical development are BL22 (CAT-3888) and HA22 (CAT-8015 or moxetumomab pasudotox) targeting CD22 and LMB-2 targeting CD25. These agents have induced complete and partial responses in patients with chemoresistant hairy cell leukemia (HCL) and partial responses with other hematologic malignancies. Clinical development is continuing with these and other agents for different forms of cancer.

Keywords

Monoclonal antibody Fusion toxin CD22 CD25 Diphtheria toxin Pseudomonas exotoxin Ricin KDEL receptor Fv Chronic lymphocytic leukemia Hairy cell leukemia Adult T-cell leukemia SS1P CD19 Mesothelin CD3 

Notes

Acknowledgments

The work regarding LMB-2, BL22, HA22, and SS1P was in part supported by the intramural program, NCI. Clinical development regarding BL22 and HA22 was in part funded by MedImmune, LLC.

References

  1. 1.
    Endo Y, Mitsui K, Motizuki M, Tsurugi K (1987) The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. J Biol Chem 262:5908–5912PubMedGoogle Scholar
  2. 2.
    Eiklid K, Olsnes S, Pihl A (1980) Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp Cell Res 126:321–326PubMedCrossRefGoogle Scholar
  3. 3.
    Yamaizumi M, Mekada E, Uchida T, Okada Y (1978) One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell 15:245–250PubMedCrossRefGoogle Scholar
  4. 4.
    Zamboni M, Brigotti M, Rambelli F, Montanaro L, Sperti S (1989) High pressure liquid chromatographic and fluorimetric methods for the determination of adenine released from ribosomes by ricin and gelonin. Biochem J 259:639–643PubMedGoogle Scholar
  5. 5.
    Carroll SF, Collier RJ (1987) 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 262:8707–8711PubMedGoogle Scholar
  6. 6.
    Van Ness BG, Howard JB, Bodley JW (1980) ADP-ribosylation of elongation factor 2 by diphtheria toxin. Isolation and properties of the novel ribosyl-amino acid and its hydrolysis products. J Biol Chem 255:10717–10720PubMedGoogle Scholar
  7. 7.
    Stirpe F, Sandvig K, Olsnes S, Pihl A (1982) Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257:13271–13277PubMedGoogle Scholar
  8. 8.
    Flavell DJ, Warnes S, Noss A, Flavell SU (1998) Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-SAPORIN immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia. Cancer Res 58:5787–5794PubMedGoogle Scholar
  9. 9.
    Uckun FM, Bellomy K, O’Neill K, Messinger Y, Johnson T, Chen CL (1999) Toxicity, biological activity, and pharmacokinetics of TXU (anti-CD7)-pokeweed antiviral protein in chimpanzees and adult patients infected with human immunodeficiency virus. J Pharmacol Exp Ther 291:1301–1307PubMedGoogle Scholar
  10. 10.
    Bernhard SL, Better M, Fishwild DM et al (1994) Cysteine analogs of recombinant barley ribosome inactivating protein form antibody conjugates with enhanced stability and potency in vitro. Bioconjug Chem 5:126–132PubMedCrossRefGoogle Scholar
  11. 11.
    Porro G, Bolognesi A, Caretto P et al (1993) In vitro and in vivo properties of an anti-CD5-momordin immunotoxin on normal and neoplastic T lymphocytes. Cancer Immunol Immunother 36:346–350PubMedCrossRefGoogle Scholar
  12. 12.
    Bolognesi A, Tazzari PL, Tassi C, Gromo G, Gobbi M, Stirpe F (1992) A comparison of anti-lymphocyte immunotoxins containing different ribosome-inactivating proteins and antibodies. Clin Exp Immunol 89:341–346PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Kreitman RJ (1997) Getting plant toxins to fuse. Leukemia Res 21:997–999CrossRefGoogle Scholar
  14. 14.
    Hwang J, FitzGerald DJ, Adhya S, Pastan I (1987) Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell 48:129–136PubMedCrossRefGoogle Scholar
  15. 15.
    Allured VS, Collier RJ, Carroll SF, McKay DB (1986) Structure of exotoxin A of Pseudomonas aeruginosa at 3.0 Angstrom resolution. Proc Natl Acad Sci USA 83:1320–1324PubMedCrossRefGoogle Scholar
  16. 16.
    Hessler JL, Kreitman RJ (1997) An early step in Pseudomonas exotoxin action is removal of the terminal lysine residue, which allows binding to the KDEL receptor. Biochemistry 36:14577–14582PubMedCrossRefGoogle Scholar
  17. 17.
    Kounnas MZ, Morris RE, Thompson MR, FitzGerald DJ, Strickland DK, Saelinger CB (1992) The α2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem 267:12420–12423PubMedGoogle Scholar
  18. 18.
    Chiron MF, Fryling CM, FitzGerald DJ (1994) Cleavage of Pseudomonas exotoxin and diphtheria toxin by a furin-like enzyme prepared from beef liver. J Biol Chem 269:18167–18176PubMedGoogle Scholar
  19. 19.
    Fryling C, Ogata M, FitzGerald D (1992) Characterization of a cellular protease that cleaves Pseudomonas exotoxin. Infect Immun 60:497–502PubMedCentralPubMedGoogle Scholar
  20. 20.
    Ogata M, Fryling CM, Pastan I, FitzGerald DJ (1992) Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol. J Biol Chem 267:25396–25401PubMedGoogle Scholar
  21. 21.
    McKee ML, FitzGerald DJ (1999) Reduction of furin-nicked Pseudomonas exotoxin A: an unfolding story. Biochemistry 38:16507–16513PubMedCrossRefGoogle Scholar
  22. 22.
    Theuer C, Kasturi S, Pastan I (1994) Domain II of Pseudomonas exotoxin A arrests the transfer of translocating nascent chains into mammalian microsomes. Biochemistry 33:5894–5900PubMedCrossRefGoogle Scholar
  23. 23.
    Theuer CP, Buchner J, FitzGerald D, Pastan I (1993) The N-terminal region of the 37-kDa translocated fragment of Pseudomonas exotoxin A aborts translocation by promoting its own export after microsomal membrane insertion. Proc Natl Acad Sci USA 90:7774–7778PubMedCrossRefGoogle Scholar
  24. 24.
    Webb TR, Cross SH, McKie L et al (2008) Diphthamide modification of eEF2 requires a J-domain protein and is essential for normal development. J Cell Sci 121:3140–3145PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Li M, Dyda F, Benhar I, Pastan I, Davies DR (1995) The crystal structure of Pseudomonas aeruginosa exotoxin domain III with nicotinamide and AMP: conformational differences with the intact exotoxin. Proc Natl Acad Sci USA 92:9308–9312PubMedCrossRefGoogle Scholar
  26. 26.
    Li M, Dyda F, Benhar I, Pastan I, Davies DR (1996) 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 93:6902–6906PubMedCrossRefGoogle Scholar
  27. 27.
    Han XY, Galloway DR (1995) Active site mutations of Pseudomonas aeruginosa exotoxin A – analysis of the His(440) residue. J Biol Chem 270:679–684PubMedCrossRefGoogle Scholar
  28. 28.
    Brinkmann U, Brinkmann E, Gallo M, Pastan I (1995) Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc Natl Acad Sci USA 92:10427–10431PubMedCrossRefGoogle Scholar
  29. 29.
    Keppler-Hafkemeyer A, Kreitman RJ, Pastan I (2000) Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies. Int J Cancer 87:86–94PubMedCrossRefGoogle Scholar
  30. 30.
    Decker T, Oelsner M, Kreitman RJ et al (2004) Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia cells by anti-CD22 immunotoxins. Blood 103:2718–2726PubMedCrossRefGoogle Scholar
  31. 31.
    Decker T, Oelsner M, Kreitman RJ, Salvatore G, Wang QC, Pastan I, Peschel C, Licht T (2004) Induction of Caspase-Dependent Programmed Cell Death in B-Cell Chronic Lymphocytic Leukemia Cells by Anti-CD22 Immunotoxins. Blood 103:2718–2726Google Scholar
  32. 32.
    Rolf JM, Gaudin HM, Eidels L (1990) Localization of the diphtheria toxin receptor-binding domain to the carboxyl-terminal Mr 6000 region of the toxin. J Biol Chem 265:7331–7337PubMedGoogle Scholar
  33. 33.
    Uchida T, Pappenheimer AM Jr, Harper AA (1972) Reconstitution of diphtheria toxin from two nontoxic cross-reacting mutant proteins. Science 175:901–903PubMedCrossRefGoogle Scholar
  34. 34.
    Uchida T, Pappenheimer AM Jr, Greany R (1973) Diphtheria toxin and related proteins I. Isolation and properties of mutant proteins serologically related to diphtheria toxin. J Biol Chem 248:3838–3844PubMedGoogle Scholar
  35. 35.
    Choe S, Bennett MJ, Fujii G et al (1992) The crystal structure of diphtheria toxin. Science 357:216–222Google Scholar
  36. 36.
    Williams DP, Wen Z, Watson RS, Boyd J, Strom TB, Murphy JR (1990) 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 265:20673–20677PubMedGoogle Scholar
  37. 37.
    Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E (1994) Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J 13:2322–2330PubMedGoogle Scholar
  38. 38.
    vanderSpek J, Cassidy D, Genbauffe F, Huynh PD, Murphy JR (1994) An intact transmembrane helix 9 is essential for the efficient delivery of the diphtheria toxin catalytic domain to the cytosol of target cells. J Biol Chem 269:21455–21459PubMedGoogle Scholar
  39. 39.
    Zhan H, Choe S, Huynh PD, Finkelstein A, Eisenberg D, Collier RJ (1994) Dynamic transitions of the transmembrane domain of diphtheria toxin: disulfide trapping and fluorescence proximity studies. Biochemistry 33:11254–11263PubMedCrossRefGoogle Scholar
  40. 40.
    Cabiaux V, Mindell J, Collier RJ (1993) Membrane translocation and channel-forming activities of diphtheria toxin are blocked by replacing isoleucine 364 with lysine. Infect Immun 61:2200–2202PubMedCentralPubMedGoogle Scholar
  41. 41.
    Kaul P, Silverman J, Shen WH et al (1996) Roles of Glu 349 and Asp 352 in membrane insertion and translocation by diphtheria toxin. Protein Sci 5:687–692PubMedCrossRefGoogle Scholar
  42. 42.
    Papini E, Schiavo G, Tomasi M, Colombatti M, Rappuoli R, Montecucco C (1987) Lipid interaction of diphtheria toxin and mutants with altered fragment B. 2. Hydrophobic photolabelling and cell intoxication. Eur J Biochem 169:637–644PubMedCrossRefGoogle Scholar
  43. 43.
    Moskaug JO, Stenmark H, Olsnes S (1991) Insertion of diphtheria toxin B-fragment into the plasma membrane at low pH. Characterization and topology of inserted regions. J Biol Chem 266:2652–2659PubMedGoogle Scholar
  44. 44.
    Wilson BA, Blanke SR, Reich KA, Collier RJ (1994) Active-site mutations of diphtheria toxin. Tryptophan 50 is a major determinant of NAD affinity. J Biol Chem 269:23296–23301PubMedGoogle Scholar
  45. 45.
    Bennett MJ, Eisenberg D (1994) Refined structure of monomeric diphtheria toxin at 2.3 A resolution. Protein Sci 3:1464–1475PubMedCrossRefGoogle Scholar
  46. 46.
    Holbourn KP, Shone CC, Acharya KR (2006) A family of killer toxins – exploring the mechanism of ADP-ribosylating toxins. FEBS J 273:4579–4593PubMedCrossRefGoogle Scholar
  47. 47.
    Thorburn A, Thorburn J, Frankel AE (2004) Induction of apoptosis by tumor cell-targeted toxins. Apoptosis 9:19–25PubMedCrossRefGoogle Scholar
  48. 48.
    Kondo T, FitzGerald D, Chaudhary VK, Adhya S, Pastan I (1988) Activity of immunotoxins constructed with modified Pseudomonas exotoxin A lacking the cell recognition domain. J Biol Chem 263:9470–9475PubMedGoogle Scholar
  49. 49.
    Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I (1989) Functional analysis of domains II, Ib, and III of Pseudomonas exotoxin. J Biol Chem 264:14256–14261PubMedGoogle Scholar
  50. 50.
    Kreitman RJ, Batra JK, Seetharam S, Chaudhary VK, FitzGerald DJ, Pastan I (1993) Single-chain immunotoxin fusions between anti-Tac and Pseudomonas exotoxin: relative importance of the two toxin disulfide bonds. Bioconjug Chem 4:112–120PubMedCrossRefGoogle Scholar
  51. 51.
    Williams DP, Parker K, Bacha P et al (1987) Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. Protein Eng 1:493–498PubMedCrossRefGoogle Scholar
  52. 52.
    Williams DP, Snider CE, Strom TB, Murphy JR (1990) 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 265:11885–11889PubMedGoogle Scholar
  53. 53.
    Chaudhary VK, FitzGerald DJ, Pastan I (1991) A proper amino terminus of diphtheria toxin is important for cytotoxicity. Biochem Biophys Res Commun 180:545–551PubMedCrossRefGoogle Scholar
  54. 54.
    Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I (1989) A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339:394–397PubMedCrossRefGoogle Scholar
  55. 55.
    Brinkmann U, Pai LH, FitzGerald DJ, Willingham M, Pastan I (1991) B3(Fv)-PE38KDEL, a single-chain immunotoxin that causes complete regression of a human carcinoma in mice. Proc Natl Acad Sci USA 88:8616–8620PubMedCrossRefGoogle Scholar
  56. 56.
    Brinkmann U, Reiter Y, Jung S, Lee B, Pastan I (1993) A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc Natl Acad Sci USA 90:7538–7542PubMedCrossRefGoogle Scholar
  57. 57.
    Reiter Y, Brinkmann U, Kreitman RJ, Jung S-H, Lee B, Pastan I (1994) Stabilization of the Fv fragments in recombinant immunotoxins by disulfide bonds engineered into conserved framework regions. Biochemistry 33:5451–5459PubMedCrossRefGoogle Scholar
  58. 58.
    Reiter Y, Kreitman RJ, Brinkmann U, Pastan I (1994) Cytotoxic and antitumor activity of a recombinant immunotoxin composed of disulfide-stabilized anti-Tac Fv fragment and truncated Pseudomonas exotoxin. Int J Cancer 58:142–149PubMedCrossRefGoogle Scholar
  59. 59.
    Studier FW, Moffatt BA (1986) Use of bacteriophage T7 polymerase to direct selective expression of cloned genes. J Mol Biol 189:113–130PubMedCrossRefGoogle Scholar
  60. 60.
    Chaudhary VK, Xu Y, FitzGerald D, Adhya S, Pastan I (1988) Role of domain II of Pseudomonas exotoxin in the secretion into the periplasm and medium by Escherichia coli. Proc Natl Acad Sci USA 85:2939–2943PubMedCrossRefGoogle Scholar
  61. 61.
    Bendel AE, Shao Y, Davies SM et al (1997) A recombinant fusion toxin targeted to the granulocyte-macrophage colony-stimulating factor receptor. Leuk Lymphoma 25:257PubMedGoogle Scholar
  62. 62.
    Buchner J, Pastan I, Brinkmann U (1992) A method for increasing the yield of properly folded recombinant fusion proteins: single-chain immunotoxins from renaturation of bacterial inclusion bodies. Anal Biochem 205:263–270PubMedCrossRefGoogle Scholar
  63. 63.
    Kreitman RJ, Pastan I (2000) Making fusion toxins to target leukemia and lymphoma. In: Francis GE, Delgado C (eds) Drug targeting, vol 25. Humana Press, Totowa, NJ, pp 215–226CrossRefGoogle Scholar
  64. 64.
    Kreitman RJ, Pastan I (1993) Purification and characterization of IL6-PE4E, a recombinant fusion of interleukin 6 with Pseudomonas exotoxin. Bioconjug Chem 4:581–585PubMedCrossRefGoogle Scholar
  65. 65.
    Kreitman RJ, Pastan I (1997) Recombinant toxins containing human granulocyte-macrophage colony-stimulating factor and either Pseudomonas exotoxin or diphtheria toxin kill gastrointestinal cancer and leukemia cells. Blood 90:252–259PubMedGoogle Scholar
  66. 66.
    Woo JH, Liu YY, Mathias A et al (2002) Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris. Protein Expr Purif 25:270–282PubMedCrossRefGoogle Scholar
  67. 67.
    Woo JH, Liu JS, Kang SH et al (2008) GMP production and characterization of the bivalent anti-human T cell immunotoxin, A-dmDT390-bisFv(UCHT1) for phase I/II clinical trials. Protein Expr Purif 58:1–11PubMedCrossRefGoogle Scholar
  68. 68.
    Foss F (2006) Clinical experience with denileukin diftitox (ONTAK). Semin Oncol 33:11–16CrossRefGoogle Scholar
  69. 69.
    Kuzel TM, Li S, Eklund J et al (2007) Phase II study of denileukin diftitox for previously treated indolent non-Hodgkin lymphoma: final results of E1497. Leuk Lymphoma 48:2397–2402PubMedCrossRefGoogle Scholar
  70. 70.
    Frankel AE, Surendranathan A, Black JH, White A, Ganjoo K, Cripe LD (2006) Phase II clinical studies of denileukin diftitox diphtheria toxin fusion protein in patients with previously treated chronic lymphocytic leukemia. Cancer 106:2158–2164PubMedCrossRefGoogle Scholar
  71. 71.
    Goldberg MR, Heimbrook DC, Russo P et al (1995) Phase I clinical study of recombinant oncotoxin TP40 in superficial bladder cancer. Clin Cancer Res 1:57–61PubMedGoogle Scholar
  72. 72.
    Garland L, Gitlitz B, Ebbinghaus S et al (2005) Phase I trial of intravenous IL-4 Pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor. J Immunother 28:376–381PubMedCrossRefGoogle Scholar
  73. 73.
    Kreitman RJ, Puri RK, Pastan I (1994) A circularly permuted recombinant interleukin 4 toxin with increased activity. Proc Natl Acad Sci USA 91:6889–6893PubMedCrossRefGoogle Scholar
  74. 74.
    Kreitman RJ, Puri RK, Pastan I (1995) Increased antitumor activity of a circularly permuted interleukin 4-toxin in mice with interleukin 4 receptor-bearing human carcinoma. Cancer Res 55:3357–3363PubMedGoogle Scholar
  75. 75.
    Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK (2000) Intratumoral administration of a recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high grade glioma. Clin Cancer Res 6:2157–2165PubMedGoogle Scholar
  76. 76.
    Vogelbaum MA, Sampson JH, Kunwar S et al (2007) Convection-enhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final safety results. Neurosurgery 61:1031–1037, discussion 1037–1038PubMedCrossRefGoogle Scholar
  77. 77.
    Kunwar S (2003) 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. Springer, Wien, Austria, pp 105–111CrossRefGoogle Scholar
  78. 78.
    Kunwar S, Prados MD, Chang SM et al (2007) Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 25:837–844PubMedCrossRefGoogle Scholar
  79. 79.
    Davey RT Jr, Boenning CM, Herpin BR et al (1994) Use of recombinant soluble CD4 Pseudomonas exotoxin, a novel immunotoxin, for treatment of persons infected with human immunodeficiency virus. J Infect Dis 170:1180–1188PubMedCrossRefGoogle Scholar
  80. 80.
    Frankel AE, Ramage J, Latimer A et al (1999) High-level expression and purification of the recombinant diphtheria fusion toxin DTGM for PHASE I clinical trials. Protein Expr Purif 16:190–201PubMedCrossRefGoogle Scholar
  81. 81.
    Hotchkiss CE, Hall PD, Cline JM et al (1999) Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys. Toxicol Appl Pharmacol 158:152–160PubMedCrossRefGoogle Scholar
  82. 82.
    Frankel AE, Powell BL, Hall PD, Case LD, Kreitman RJ (2002) 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 8:1004–1013PubMedGoogle Scholar
  83. 83.
    Frankel A, McCubrey J, Miller MS et al (2000) Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with acute phase chronic myeloid leukemia. Leukemia 14:576–585PubMedCrossRefGoogle Scholar
  84. 84.
    Urieto JO, Liu T, Black JH et al (2004) Expression and purification of the recombinant diphtheria fusion toxin DT388IL3 for phase I clinical trials. Protein Expr Purif 33:123–133PubMedCrossRefGoogle Scholar
  85. 85.
    Frankel A, Liu JS, Rizzieri D, Hogge D (2008) Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. Leuk Lymphoma 49:543–553PubMedCrossRefGoogle Scholar
  86. 86.
    Murphy JR, vanderSpek JC (1995) Targeting diphtheria toxin to growth factor receptors. Semin Cancer Biol 6:259–267PubMedCrossRefGoogle Scholar
  87. 87.
    Kodaka T, Uchiyama T, Ishikawa T et al (1990) Interleukin-2 receptor β-chain (p70-75) expressed on leukemic cells from adult T cell leukemia patients. Jpn J Cancer Res 81:902–908PubMedCrossRefGoogle Scholar
  88. 88.
    Yagura H, Tamaki T, Furitsu T et al (1990) Demonstration of high-affinity interleukin-2 receptors on B-chronic lymphocytic leukemia cells: functional and structural characterization. Blut 60:181–186PubMedCrossRefGoogle Scholar
  89. 89.
    Kreitman RJ, Pastan I (1994) Recombinant single-chain immunotoxins against T and B cell leukemias. Leuk Lymphoma 13:1–10PubMedGoogle Scholar
  90. 90.
    Robb RJ, Greene WC, Rusk CM (1984) Low and high affinity cellular receptors for interleukin 2. J Exp Med 160:1126–1146PubMedCrossRefGoogle Scholar
  91. 91.
    Gazzola M, Collins NH, Tafuri A, Keever CA (1992) Recombinant interleukin 3 induces interleukin 2 receptor expression on early myeloid cells in normal human bone marrow. Exp Hematol 20:201–208PubMedGoogle Scholar
  92. 92.
    Uchiyama TA, Broder S, Waldmann TA (1981) 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 126:1393–1397PubMedGoogle Scholar
  93. 93.
    Taniguchi T, Minami Y (1993) The IL2/IL-2 receptor system: a current overview. Cell 73:5–8PubMedCrossRefGoogle Scholar
  94. 94.
    Kreitman RJ, Pastan I (1995) Targeting Pseudomonas exotoxin to hematologic malignancies. Semin Cancer Biol 6:297–306PubMedCrossRefGoogle Scholar
  95. 95.
    Robbins DH, Margulies I, Stetler-Stevenson M, Kreitman RJ (2000) 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 6:693–700PubMedGoogle Scholar
  96. 96.
    Kreitman RJ, Bailon P, Chaudhary VK, FitzGerald DJP, Pastan I (1994) Recombinant immunotoxins containing anti-Tac(Fv) and derivatives of Pseudomonas exotoxin produce complete regression in mice of an interleukin-2 receptor-expressing human carcinoma. Blood 83:426–434PubMedGoogle Scholar
  97. 97.
    Kreitman RJ, Pastan I (1998) Accumulation of a recombinant immunotoxin in a tumor in vivo: fewer than 1000 molecules per cell are sufficient for complete responses. Cancer Res 58:968–975PubMedGoogle Scholar
  98. 98.
    Kobayashi H, Kao CK, Kreitman RJ et al (2000) Pharmacokinetics of In-111- and I-125-labeled antiTac single-chain Fv recombinant immunotoxin. J Nucl Med 41:755–762PubMedGoogle Scholar
  99. 99.
    Kreitman RJ, Wilson WH, White JD et al (2000) Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18:1614–1636Google Scholar
  100. 100.
    Kreitman RJ, Wilson WH, Robbins D et al (1999) Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood 94:3340–3348PubMedGoogle Scholar
  101. 101.
    Onda M, Kreitman RJ, Vasmatzis G, Lee B, Pastan I (1999) 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 163:6072–6077PubMedGoogle Scholar
  102. 102.
    Onda M, Willingham M, Wang Q et al (2000) 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 165:7150–7156PubMedGoogle Scholar
  103. 103.
    Zhang Y, Xiang L, Hassan R, Pastan I (2007) Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors. Proc Natl Acad Sci USA 104:17099–17104PubMedCrossRefGoogle Scholar
  104. 104.
    Crocker PR (2002) Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell-cell interactions and signalling. Curr Opin Struct Biol 12:609–615PubMedCrossRefGoogle Scholar
  105. 105.
    Amlot PL, Stone MJ, Cunningham D et al (1993) 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 82:2624–2633PubMedGoogle Scholar
  106. 106.
    Sausville EA, Headlee D, Stetler-Stevenson M et al (1995) Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study. Blood 85:3457–3465PubMedGoogle Scholar
  107. 107.
    Senderowicz AM, Vitetta E, Headlee D et al (1997) Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 126:882–885PubMedCrossRefGoogle Scholar
  108. 108.
    Messmann RA, Vitetta ES, Headlee D et al (2000) 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 [In Process Citation]. Clin Cancer Res 6:1302–1313PubMedGoogle Scholar
  109. 109.
    Kreitman RJ, Hansen HJ, Jones AL, FitzGerald DJP, Goldenberg DM, Pastan I (1993) Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab' induce regression of subcutaneous human B-cell lymphoma in mice. Cancer Res 53:819–825PubMedGoogle Scholar
  110. 110.
    Theuer CP, Kreitman RJ, FitzGerald DJ, Pastan I (1993) Immunotoxins made with a recombinant form of Pseudomonas exotoxin A that do not require proteolysis for activity. Cancer Res 53:340–347PubMedGoogle Scholar
  111. 111.
    Mansfield E, Chiron MF, Amlot P, Pastan I, FitzGerald DJ (1997) Recombinant RFB4 single-chain immunotoxin that is cytotoxic towards CD22-positive cells. Biochem Soc Trans 25:709–714PubMedGoogle Scholar
  112. 112.
    Mansfield E, Amlot P, Pastan I, FitzGerald DJ (1997) Recombinant RFB4 immunotoxins exhibit potent cytotoxic activity for CD22-bearing cells and tumors. Blood 90:2020–2026PubMedGoogle Scholar
  113. 113.
    Kreitman RJ, Wang QC, FitzGerald DJP, Pastan I (1999) 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 81:148–155PubMedCrossRefGoogle Scholar
  114. 114.
    Kreitman RJ, Margulies I, Stetler-Stevenson M, Wang QC, FitzGerald DJP, Pastan I (2000) Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) towards fresh malignant cells from patients with B-cell leukemias. Clin Cancer Res 6:1476–1487PubMedGoogle Scholar
  115. 115.
    Kreitman RJ, Wilson WH, Bergeron K et al (2001) Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. New Engl J Med 345:241–247PubMedCrossRefGoogle Scholar
  116. 116.
    Kreitman RJ, Squires DR, Stetler-Stevenson M et al (2005) Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies. J Clin Oncol 23:6719–6729PubMedCrossRefGoogle Scholar
  117. 117.
    Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D (2001) The natural history and clinico-pathological features of the variant form of hairy cell leukemia. Leukemia 15:184–186PubMedCrossRefGoogle Scholar
  118. 118.
    Saven A, Burian C, Koziol JA, Piro LD (1998) Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood 92:1918–1926PubMedGoogle Scholar
  119. 119.
    Kreitman RJ, Stetler-Stevenson M, Margulies I et al (2009) Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol 27:2983–2990PubMedCrossRefGoogle Scholar
  120. 120.
    Salvatore G, Beers R, Margulies I, Kreitman RJ, Pastan I (2002) Improved cytotoxic activity towards cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display. Clin Cancer Res 8:995–1002PubMedGoogle Scholar
  121. 121.
    Weldon JE, Xiang L, Chertov O et al (2009) A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity. Blood 113:3792–3800PubMedCrossRefGoogle Scholar
  122. 122.
    Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I (2008) An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Nat Acad Sci USA 105:11311–11316PubMedCrossRefGoogle Scholar
  123. 123.
    Hansen JK, Weldon JE, Xiang L, Beers R, Onda M, Pastan I (2010) A recombinant immunotoxin targeting CD22 with low immunogenicity, low nonspecific toxicity, and high antitumor activity in mice. J Immunother 33:297–304PubMedCrossRefGoogle Scholar
  124. 124.
    Vallera DA, Todhunter DA, Kuroki DW, Shu Y, Sicheneder A, Chen H (2005) A bispecific recombinant immunotoxin, DT2219, targeting human CD19 and CD22 receptors in a mouse xenograft model of B-cell leukemia/lymphoma. Clin Cancer Res 11:3879–3888PubMedCrossRefGoogle Scholar
  125. 125.
    Callard RE, Smith CM, Worman C, Linch D, Cawley JC, Beverley PC (1981) Unusual phenotype and function of an expanded subpopulation of T cells in patients with haemopoietic disorders. Clin Exp Immunol 43:497–505PubMedCentralPubMedGoogle Scholar
  126. 126.
    Martin PJ, Hansen JA, Torok-Storb B et al (1988) Effects of treating marrow with a CD3-specific immunotoxin for prevention of acute graft-versus-host disease. Bone Marrow Transplant 3:437–444PubMedGoogle Scholar
  127. 127.
    Thompson J, Hu H, Scharff J, Neville DM Jr (1995) An anti-CD3 single-chain immunotoxin with a truncated diphtheria toxin avoids inhibition by pre-existing antibodies in human blood. J Biol Chem 270:28037–28041PubMedCrossRefGoogle Scholar
  128. 128.
    Thompson J, Stavrou S, Weetall M et al (2001) Improved binding of a bivalent single-chain immunotoxin results in increased efficacy for in vivo T-cell depletion. Protein Eng 14:1035–1041PubMedCrossRefGoogle Scholar
  129. 129.
    Woo JH, Bour SH, Dang T et al (2008) Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390-bisFv(UCHT1). Cancer Immunol Immunother 57:1225–1239PubMedCrossRefGoogle Scholar
  130. 130.
    FitzGerald DJ, Padmanabhan R, Pastan I, Willingham MC (1983) Adenovirus-induced release of epidermal growth factor and pseudomonas toxin into the cytosol of KB cells during receptor-mediated endocytosis. Cell 32:607–617PubMedCrossRefGoogle Scholar
  131. 131.
    Chaudhary VK, FitzGerald DJ, Adhya S, Pastan I (1987) Activity of a recombinant fusion protein between transforming growth factor type α and Pseudomonas toxin. Proc Natl Acad Sci USA 84:4538–4542PubMedCrossRefGoogle Scholar
  132. 132.
    Siegall CB, Y-h X, Chaudhary VK, Adhya S, FitzGerald D, Pastan I (1989) Cytotoxic activities of a fusion protein comprised of TGFα and Pseudomonas exotoxin. FASEB J 3:2647–2652PubMedGoogle Scholar
  133. 133.
    Kreitman RJ, Chaudhary VK, Siegall CB, FitzGerald DJ, Pastan I (1992) Rational design of a chimeric toxin: an intramolecular location for the insertion of transforming growth factor-α within Pseudomonas exotoxin as a targeting ligand. Bioconjug Chem 3:58–62PubMedCrossRefGoogle Scholar
  134. 134.
    Kreitman RJ, Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I (1992) Properties of chimeric toxins with two recognition domains: interleukin 6 and transforming growth factor α at different locations in Pseudomonas exotoxin. Bioconjug Chem 3:63–68PubMedCrossRefGoogle Scholar
  135. 135.
    Sampson JH, Akabani G, Archer GE et al (2003) 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 65:27–35PubMedCrossRefGoogle Scholar
  136. 136.
    Foss FM, Saleh MN, Krueger JG, Nichols JC, Murphy JR (1998) Diphtheria toxin fusion proteins. In: Frankel AE (ed) Clinical applications of immunotoxins. Springer, Berlin, pp 63–81CrossRefGoogle Scholar
  137. 137.
    Pai LH, Wittes R, Setser A, Willingham MC, Pastan I (1996) Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin. Nat Med 2:350–353PubMedCrossRefGoogle Scholar
  138. 138.
    Posey JA, Khazaeli MB, Bookman MA et al (2002) A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors. Clin Cancer Res 8:3092–3099PubMedGoogle Scholar
  139. 139.
    Pai-Scherf LH, Villa J, Pearson D et al (1999) Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin Cancer Res 5:2311–2315PubMedGoogle Scholar
  140. 140.
    Azemar M, Schmidt M, Arlt F et al (2000) 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 86:269–275PubMedCrossRefGoogle Scholar
  141. 141.
    Azemar M, Djahansouzi S, Jager E et al (2003) Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2. Breast Cancer Res Treat 82:155–164PubMedCrossRefGoogle Scholar
  142. 142.
    Kreitman RJ (1995) Circularly permuted Interleukin 4 retains proliferative and binding activity. Cytokine 7:311–318PubMedCrossRefGoogle Scholar
  143. 143.
    Weber FW, Floeth F, Asher A et al (2003) 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. Springer, Wien, Austria, pp 93–103CrossRefGoogle Scholar
  144. 144.
    Parney IF, Kunwar S, McDermott M et al (2005) Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma. J Neurosurg 102:267–275PubMedCrossRefGoogle Scholar
  145. 145.
    Chang K, Pastan I (1996) Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA 93:136–140PubMedCrossRefGoogle Scholar
  146. 146.
    Palumbo C, Bei R, Procopio A, Modesti A (2008) Molecular targets and targeted therapies for malignant mesothelioma. Curr Med Chem 15:855–867PubMedCrossRefGoogle Scholar
  147. 147.
    Gubbels JA, Belisle J, Onda M et al (2006) Mesothelin-MUC16 binding is a high affinity. N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer 5:50PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Chang K, Pai LH, Pass H et al (1992) Monoclonal antibody K1 reacts with epithelial mesothelioma but not with lung adenocarcinoma. Am J Surg Pathol 16:259–268PubMedCrossRefGoogle Scholar
  149. 149.
    Chang K, Pastan I, Willingham MC (1992) Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas. Int J Cancer 51:548–554PubMedCrossRefGoogle Scholar
  150. 150.
    Kushitani K, Takeshima Y, Amatya VJ, Furonaka O, Sakatani A, Inai K (2007) Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma. Pathol Int 57:190–199PubMedCrossRefGoogle Scholar
  151. 151.
    Argani P, Iacobuzio-Donahue C, Ryu B et al (2001) Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res 7:3862–3868PubMedGoogle Scholar
  152. 152.
    Ryu B, Jones J, Blades NJ et al (2002) Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res 62:819–826PubMedGoogle Scholar
  153. 153.
    Hassan R, Wu C, Brechbiel MW, Margulies I, Kreitman RJ, Pastan I (1999) 111Indium-labeled Monoclonal antibody K1: biodistribution study in nude mice bearing a human carcinoma xenograft expressing mesothelin. Int J Cancer 80:559–563PubMedCrossRefGoogle Scholar
  154. 154.
    Hassan R, Viner J, Wang QC, Kreitman RJ, Pastan I (2000) Anti-tumor activity of K1-LysPE38QQR, an immunotoxin targeting mesothelin, a cell-surface antigen overexpressed in ovarian cancer and malignant mesothelioma. J Immunother 23:473–479PubMedCrossRefGoogle Scholar
  155. 155.
    Chowdhury PS, Chang K, Pastan I (1997) Isolation of anti-mesothelin antibodies from a phage display library. Mol Immunol 34:9–20PubMedCrossRefGoogle Scholar
  156. 156.
    Chowdhury PS, Pastan I (1999) Improving antibody affinity by mimicking somatic hypermutation in vitro. Nat Biotechnol 17:568–572PubMedCrossRefGoogle Scholar
  157. 157.
    Chowdhury PS, Viner JL, Beers R, Pastan I (1998) 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 anti-tumor activity. Proc Natl Acad Sci USA 95:669–674PubMedCrossRefGoogle Scholar
  158. 158.
    Chowdhury PS, Vasmatzis G, Lee B, Pastan I (1998) Improved stability and yield of a Fv-toxin fusion protein by computer design and protein engineering of the Fv. J Mol Biol 281:917–928PubMedCrossRefGoogle Scholar
  159. 159.
    Pastan I, Hassan R, FitzGerald DJP, Kreitman RJ (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6:559–565PubMedCrossRefGoogle Scholar
  160. 160.
    Hassan R, Bullock S, Premkumar A et al (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 13:5144–5149PubMedCrossRefGoogle Scholar
  161. 161.
    Kreitman RJ, Hassan R, FitzGerald DJ, Pastan I (2009) Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res 15:5274–5279PubMedCentralPubMedCrossRefGoogle Scholar
  162. 162.
    Zhang Y, Xiang L, Hassan R et al (2006) Synergistic anti-tumor activity of taxol and immunotoxin SS1P in tumor bearing mice. Clin Cancer Res 12:4695–4701PubMedCrossRefGoogle Scholar
  163. 163.
    Hassan R, Broaddus VC, Wilson S, Liewehr DJ, Zhang J (2007) Anti-mesothelin immunotoxin SS1P in combination with gemcitabine results in increased activity against mesothelin-expressing tumor xenografts. Clin Cancer Res 13:7166–7171PubMedCrossRefGoogle Scholar
  164. 164.
    Onda M, Nagata S, Fitzgerald DJ et al (2006) Characterization of the B cell epitopes associated with a truncated form of Pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. J Immunol 177:8822–8834PubMedGoogle Scholar
  165. 165.
    Roscoe DM, Jung SH, Benhar I, Pai L, Lee BK, Pastan I (1994) Primate antibody response to immunotoxin: serological and computer-aided analysis of epitopes on a truncated form of Pseudomonas exotoxin. Infect Immun 62:5055–5065PubMedCentralPubMedGoogle Scholar
  166. 166.
    Roscoe DM, Pai LH, Pastan I (1997) Identification of epitopes on a mutant form of Pseudomonas exotoxin using serum from humans treated with Pseudomonas exotoxin containing immunotoxins. Eur J Immunol 27:1459–1468PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Laboratory of Molecular BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA

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