Objective. Current modalities used in the treatment of cancer often cause unacceptable damage to normal tissue. Toxins targeted toward tumor cells by antibodies or growth factors have the potential to selectively kill tumor cells while leaving normal tissue intact. The purpose of this review is to provide background information on targeted toxins and current clinical studies for this new class of anti-cancer compounds.
Data sources. A MEDLINE search was conducted using the term “immunotoxins.” Relevant articles were also obtained by the systematic examination of article references.
Data synthesis. The toxins Pseudomonas exotoxin, diphtheria toxin, and ricin toxin are often used as targeted toxins. Deletion or mutation of the binding domains of these toxins decreased binding of the toxins to normal tissues. Antibodies or growth factors can be used as targeting moiety, and the resulting agents are called immunotoxins or fusion proteins, respectively. DNA technology and chemical modifications of the toxin as well as the antibody moiety led to smaller and less immunogenic targeted toxins. Smaller targeted toxins are less toxic and penetrate further into the tumor. The summary of several targeted toxins elicited during clinical trials in this review makes it clear that several targeted toxins are potential agents for the treatment of various cancers, although some problems still need to be overcome. These problems include toxicity, immunogenicity, cross-reactivity of the targeted toxin with life-sustaining tissue, heterogenicity of tumor cells, and limited tumor penetration.
Ehrlich P.Collected Studies on Immunity. Vol. 2. New York: John Wiley & Sons; 1906.
2.
Pastan I, Chaudhary V, Fitzgerald DJ.Recombinant toxins as novel therapeutic agents. Annu Rev Biochem. 1992;61:331-354.
3.
Brinkmann U, Pastan L.Immunotoxins against cancer. Biochim Biophys Acta. 1994;1198:27-45.
4.
Bodey B, Siegel SE, Kaiser HE.Human cancer detection and immunotherapy with conjugated and non-conjugated monoclonal antibodies. Anticancer Res. 1996;16:661-674.
5.
Brinkmann U.Recombinant immunotoxins: protein engineering for cancer therapy. Mol Med Today. 1996;2:439-446.
6.
Ghetie V, Vitetta, ES.Immunotoxins in the therapy of cancer: from bench to clinic. Pharmacol Ther. 1994;63:209-234.
7.
Fitzgerald D.Why toxins! Semin Cancer Biol. 1996;7:87-95.
8.
Pastan I.Targeted therapy of cancer with recombinant immunotoxins. Biochim Biophys Acta. 1997;1333:C1-C6.
9.
Sznol M, Holmlund J.Antigen-specific agents in development. Semin Oncol. 1997;24:173-186.
10.
Frankel EA, Fitzgerald D, Siegall C, et al.Advances in immunotoxin biology and therapy: a summary of the fourth international symposium on immunotoxins. Cancer Res. 1995;56:926-932.
11.
Trush RT, Lark LR, Clinchy BC, et al.Immunotoxins: an update. Annu Rev Immunol. 1996;14:49-71.
12.
Blythman HE, Casellas P, Gros O, et al.Immunotoxins: hybrid molecules of monoclonal antibodies and a toxin subunit specifically kill tumour cells. Nature. 1981;290:145-146.
13.
Jansen FK, Blythman HE, Carriere D, et al.Immunotoxins: hybrid molecules combining high specificity and potent cytotoxicity. Immunol Rev.1982;62:185-216.
14.
Pastan IH, Pai LH, Brinkmann U, et al.Recombinant toxins: new therapeutic agents for cancer. Ann N Y Acad Sci. 1995;758:345-354.
Pai LH, Batra JK, Fitzgerald DJ, et al.Anti-tumor activities of immunotoxins made of monoclonal antibody B3 and various forms of Pseudomonas exotoxin. Proc Natl Acad Sci USA.1991;88:3358-3362.
27.
Pai LH, Bookman MA, Ozols RF, et al.Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer. J Clin Oncol. 1991;9: 2095-2103.
28.
Debinski W, Karlsson B, Lindholm L, et al.Monoclonal antibody C242-Psuedomonas exotoxin A: a specific and potent immunotoxin with antitumor activity on a human colon cancer xenograft in nude mice. J Clin Invest. 1992;90:405-411.
29.
Kreitman RJ, Hansen HJ, Jones AL, et al.Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab9 induce regression of subcutaneous human B-cell lymphoma in mice. Cancer Res. 1993;53:819-825.
30.
Thorpe PE, Wallace PM, Knowles PP, et al.New coupling agents for the synthesis of immunotoxins containing a hindered disulfide bond with improved stability in vivo. Cancer Res. 1987;47:5924-5931.
31.
Huston JS, Levinson D, Mudgett-Hunter M, et al.Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA. 1988;85:5879-5883.
32.
Bird RE, Hardman KD, Jacobson JW, et al.Single-chain antigen-binding proteins. Science. 1988;242:423-426.
33.
Glockshuber R, Malia M, Pfitzinger I, et al.A comparison of strategies to stabilize immunoglobulin Fv fragments. Biochemistry. 1990;29:1362-1367.
34.
Brinkmann U, Reiter Y, Jung SH, et al.A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc Natl Acad Sci USA. 1993;90:7538-7342.
35.
O’Hara M, Brown AN, Hussain K, et al.Cytotoxicity of a recombinant ricin-A-chain fusion protein containing a proteolytical cleavable spacer sequence. FEBS Lett. 1990;273:200-204.
36.
Skerra A, Pluckthun A.Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science. 1988;240:1038-1041.
37.
Gray CL, Smith DH, Baldridge JS, et al.Cloning, nucleotide sequence, and expression in Escherichia coli of the exotoxin A structural gene of Pseudomonas aeruginosa. Proc Natl Acad Sci USA. 1984;81:2645-2649.
Hwang J, Fitzgerald DJ, Adhya S, et al.Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expression in E. coli. Cell. 1987;48:129-136.
41.
Kreitman RJ, Batra JK, Seetharam S, et al.Single-chain immunotoxin fusions between anti-Tac and Pseudomonas exotoxin: relative importance of the two toxin disulfide bonds. Bioconjug Chem. 1993;4:112-120.
42.
Chiron MF, Fryling CM, Fitzgerald DJ.Cleavage of Pseudomonasexotoxin and diphtheria toxin by a furin-like protease prepared from beef liver. J Biol Chem. 1994;269:18167-18176.
43.
Feener EP, Shen WC, Ryser JP.Cleavage of disulfide bonds in endocytosed macromolecules: a processing not associated with lysosomes or endosomes. J Biol Chem. 1990;265:18780-18785.
44.
Jinno Y, Ogata M, Pastan I, et al.Domain II mutants of Pseudo-monas exotoxin deficient in translocation. J Biol Chem. 1989; 264:15953-15959.
45.
Chaudhary VK, Jinno Y, Fitzgerald D, et al.Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity. Proc Natl Acad Sci USA. 1990;87: 308-312.
46.
Seetharam S, Chaudhary VK, Fitzgerald D, et al.Increased cytotoxic activity of Pseudomonas exotoxin and two chimeric toxins ending in KDEL. J Biol Chem. 1991;266:17376-17381.
47.
Batra JK, Jinno Y, Chaudhary VK, et al.Anti-tumor activity in mice of an immunotoxin made with anti-transferrin receptor and a recombinant form of Pseudomonas exotoxin. Proc Natl Acad Sci USA. 1989;86:8545-8549.
48.
Batra JK, Kasprzyk PH, Bird RE, et al.Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci USA. 1992;89:5867-5871.
49.
Debinski W, Pastan I.Monovalent immunotoxin containing truncated form of Pseudomonas exotoxin as potent antitumor agent. Cancer Res. 1992;52:1-7.
50.
Theuer CP, Kreitman RJ, Fitzgerald DJ, et al.Immunotoxins made with a recombinant form of Pseudomonas exotoxin A that do not require proteolysis for activity. Cancer Res. 1993;53:340-347.
51.
Collier RJ.Structure-activity relationships in diphtheria toxin and Pseudomonas aeruginosa exotoxin A. Cancer Treat Res. 1988; 37:25-35.
52.
Choe S, Bennett MJ, Fuji H, et al.The crystal structure of diphtheria toxin. Nature. 1992;357:216-222.
53.
Naglich JG, Metherall JE, Russell DW, et al.Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell. 1992;69:1051-1061.
54.
Ryser RH, Mandel R, Ghani F.Cell surface sulfhydryls are required for the cytotoxicity of diphtheria toxin but not of ricin in Chinese hamster ovary cells. J Biol Chem. 1991;266:18438-18442.
55.
vanderSpek JC, Mindell JA, Finkelstein A, et al.Structure/function analysis of the transmembrane domain of DAB389-interleukin-2, an interleukin-2 receptor-targeted fusion protein: the amphipathic helical region of the transmembrane domain is essential for the efficient delivery of the catalytic domain to the cytosol of target cells. J Biol Chem. 1993;268:12077-12082.
56.
Sandvig D, Olsnes S.Rapid entry of nicked diphtheria toxin into cells at low pH: characterization of the entry process and effects of low pH on the toxin molecule. J Biol Chem. 1981;256:9068-9076.
57.
Blewitt MG, Zhao FM, McKeever B, et al.Fluorescence characterization of the low pH-induced change in diphtheria toxin conformation: effect of salt. Biochem Biophys Res Commun.1984;120:286-290.
58.
Blewitt MG, Chung LA, London E.Effect of pH on the conformation of diphtheria toxin and its implication for membrane penetration. Biochemistry. 1984;24:2458-2464.
59.
Sandvig K, Olsnes S.Diphtheria toxin entry into cells is facilitated by low pH. J Cell Biol. 1980;87:828-832.
60.
Draper RK, Simon MI.The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lyosomal involvement. J Cell Biol. 1980;87:849-854.
61.
Zalman LS, Wisnieski BJ.Mechanism of insertion of diphtheria toxin: peptide entry and pore size determination for membrane penetration. Biochemistry. 1984;24:5458-5464.
62.
Hu VW, Holmes RK.Evidence for direct insertion of fragments A and B of diphtheria toxin into model membranes. J Biol Chem.1984;259:12226-12233.
63.
Montecucco C, Shiavo G, Tomasi M.pH-dependence of the phospholipid interaction of diphtheria-toxin fragments. Biochem J. 1985;231:123-128.
64.
Greenfield L, Johnson VH, Youle RJ.Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science. 1987;238:536-539.
65.
Chadwick DE, Jamal N, Messner HA, et al.Differential sensitivity of human myeloma cell lines and normal bone marrow colony-forming cells to a recombinant diphtheria toxin-interleukin 6 fusion protein. Br J Haematol. 1993;85:25-36.
66.
Woodworth TG.Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis and recent onset insulin-dependent diabetes mellitus. Clin Exp Rheumatol. 1993; 11(suppl):S177-S180.
67.
Pappenheimer AM Jr.Diphtheria toxin. Annu Rev Biochem.1977;46:69-94.
68.
Endo Y.Mechanism of action of ricin and related toxins on the inactivation of eukaryotic ribosomes. Cancer Treat Res. 1988;37: 75-89.
69.
Endo Y, Mitsui K, Dambert JM.The site of action of six different ribosome-inactivating proteins from plants on eukaryotic ribosomes: the RNA N-glycosidase activity of the proteins. Biochem Biophys Res Commun. 1988;150:1032-1036.
70.
Lamb FI, Roberts LM, Lord JM.Nucleotide sequence of cloned cDNA coding for preproricin. Eur J Biochem. 1985;148:265-270.
71.
Olsnes S, Pihl A.Toxic lectins and related proteins. In: Cohen P, van Heyningen S, eds. Molecular Action of Toxins and Viruses. New York: Elsevier Biomedical Press; 1982:51-105.
72.
Fu T, Burbage C, Tagge EP, et al.Ricin toxin contains three lectin sites which contribute to its in vivo toxicity. Int J Immunopharmacol. 1996;18:685-692.
73.
Pelham HRB, Roberts LM, Lord JM.Toxin entry: how reversible is the secretory pathway?Trends Cell Biol. 1992;2:183-185.
74.
Wales R, Chaddock JA, Roberts LM, et al.Addition of an ER retention signal to the ricin A chain increases the cytotoxicity of the holotoxin. Exp Cell Res. 1992;203:1-4.
75.
Wales R, Roberts LM, Lord JM.Addition of an endoplasmic reticulum retrieval sequence to ricin A chain significantly increases its cytotoxicity to mammalian cells. J Biol Chem. 1993; 268:23986-23990.
76.
Thorpe PE, Detre SI, Foxwell BMJ, et al.Modification of the carbohydrate in ricin with metaperiodate-cyanoborohydride mixtures: effects on toxicity and in vivo distribution. Eur J Biochem.1985;147:197-206.
77.
Thorpe PE, Ross WC, Brown AN, et al.Blockade of the galactose-binding sites of ricin by its linkage to antibody: specific cytotoxic effects of the conjugates. Eur J Biochem. 1984;140:63-71.
78.
Lambert JM, McIntyre G, Gauthier N, et al.The galactose-binding sites of the cytotoxic lectin ricin can be chemically blocked in high yields with reactive ligands prepared by chemical modifications of glycopeptides containing triantennary N-linked oligosaccharides. Biochemistry. 1991;30:3234-3247.
79.
Blakey DC, Skilleter DN, Price RJ, et al.Uptake of native and deglycosylated ricin A-chain immunotoxins by mouse liver parenchymal and non-parenchymal cells in vitro and in vivo. Biochim Biophys Acta. 1988;968:172-178.
80.
Skilleter DN, Paine AJ, Stirpe F.A comparison of the accumulation of ricin by hepatic parenchymal and non-parenchymal cells and its inhibition of protein synthesis. Biochim Biophys Acta.1981;677:495-500.
81.
Thorpe PE, Wallace PM, Knowles PP, et al.Improved anti-tumor effects of immunotoxins prepared with deglycosylated ricin A chain and hindered disulfide linkages. Cancer Res. 1988;48: 6396-6403.
82.
Harkonen S, Stoudemire J, Mischak R, et al.Toxicity and immunogenicity of monoclonal anti-melanoma antibody-ricin A chain immunotoxin in rats. Cancer Res. 1987;47:1377-1382.
83.
Piatak M, Lane JA, Laird W, et al.Expression of soluble and fully functional ricin A chain in Escherichia coli is temperature sensitive. J Biol Chem. 1988;263:4837-4843.
84.
Olsnes S, Pihl A.Isolation and properties of abrin: a toxic protein inhibiting protein synthesis. Evidence for different biological functions of its two constituent-peptide chains. Eur J Biochem.1973;35:179-185.
Lord JM, Hartley MR, Roberts LM.Ribosome inactivating proteins of plants. Semin Cell Biol. 1991;2:15-22.
87.
Irvin JD.Purification and partial characterization of the antiviral protein Phytolacca americana which inhibits eukaryotic protein synthesis. Arch Biochem Biophys. 1975;169:522-528.
88.
Soria MR, Benatti L, Nitti G, et al.Studies on ribosome inactivating proteins from Saponaria officinalis. Targeted Diagn Ther. 1992; 7:193-212.
89.
Stirpe F, Olsnes S, Pihl A.Gelonin, a new inhibitor of protein synthesis, nontoxic to intact cells: Isolation, characterization, and preparation of cytotoxic complexes with concanavalin A. J Biol Chem. 1980;255:6947-6953.
90.
Willingham MC, Fitzgerald DJ, Pastan I.Pseudomonas exotoxin coupled to a monoclonal antibody against ovarian cancer inhibits the growth of human ovarian cancer cells in a mouse model. Proc Natl Acad Sci USA. 1987;84:2474-2478.
91.
Frankel AE, Ring DB, Tringale F, et al.Tissue distribution of breast cancer-associated antigens defined by monoclonal antibodies. J Biol Response Mod. 1985;4:273-286.
92.
Gould BJ, Borowitz MJ, Groves ES, et al.Phase I study of an anti-breast cancer immunotoxin by continuous infusion: report of a targeted toxic effect not predicted by animal studies. J Natl Cancer Inst. 1989;81:775-781.
93.
Weiner LM, O’Dwyer J, Kitson J, et al.Phase I evaluation of an anti-breast carcinoma monoclonal antibody 260F9-recombinant ricin A chain immunoconjugate. Cancer Res. 1989;49:4062-4067.
94.
Reiter Y, Pai LH, Brinkmann U, et al.Antitumor activity and pharmacokinetics in mice of a recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Cancer Res. 1994;54: 2714-2718.
95.
Reiter Y, Brinkmann U, Jung SH, et al.Improved binding and antitumor activity of a recombinant anti-ErbB2 immunotoxin by disulfide stabilization of the Fv fragment. J Biol Chem. 1994;269: 18327-18331.
96.
Chaudhary VK, Queen C, Junghas RP, et al.A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature. 1989;339:394-397.
97.
Kreitman R, Pastan I.Recombinant single-chain immunotoxins against T and B cell leukemias. Leuk Lymphoma. 1994;13:1-10.
98.
Kreitman R, Pastan I.Targeting Pseudomonas exotoxin to hematologic malignancies. Semin Cancer Biol. 1995;6:297-306.
99.
Kuan C, Pastan I.Improved antitumor activity of a recombinant anti-LewisY immunotoxin not requiring proteolytic activation. Proc Natl Acad Sci USA. 1996;93:974-978.
100.
Benhar I, Pastan I.Cloning, expression, and characterization of the Fv fragments of the anticarbohydrate monoclonal antibodies B1 and B5 as single-chain immunotoxins. Protein Eng. 1994;7: 1509-1515.
101.
Benhar I, Reiter Y, Pai LH, et al.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.
102.
Maurer-Gebhard M, Smidt M, Azemar M, et al.Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells. Cancer Res. 1998;58:2661-2666.
103.
Siegall C, Chace D, Mixan B, et al.In vitro and in vivo characterization of BR96 sFv-PE40: a single-chain immunotoxin fusion protein that cures human breast carcinoma xenografts in athymic mice and rats. J Immunol. 1994;152:2377-2384.
104.
Schroff RW, Foon KA, Beatty SM, et al.Human antimurine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res. 1985;45:879-885.
105.
Shawler DL, Bartholomew RM, Smith LM, et al.Human immune responses to multiple injections of murine monoclonal IgG. J Immunol. 1985;135:1530-1535.
106.
Traub UC, DeJager RL, Primus FJ, et al.Anti-idiotypic antibodies in cancer patients receiving monoclonal antibody to carcinoembryonic antigen. Cancer Res. 1988;48:4002-4006.
107.
Durrant LG, Byers VS, Scannon PJ, et al.Humoral immune responses to XMMCO-791-RTA immunotoxin in colorectal cancer patients. Clin Exp Immunol. 1989;75:258-264.
108.
Pai LH, Gallo MG, Fitzgerald DJ, et al.Antitumor activity of a transforming growth factor a-Pseudomonas exotoxin fusion protein (TGF-a-PE40). Cancer Res. 1991;51:2808-2812.
109.
Lorberboum-Galski H, Fitzgerald D, Chaudhary V, et al.Cytotoxic activity of an interleukin 2-Pseudomonas exotoxin chimeric protein produced in Escherichia coli. Proc Natl Acad Sci USA.1988;85:1922-1926.
110.
Kreitman RJ, Chaudhary VK, Siegall CB, et al.Rational design of a chimeric toxin: an intramolecular location for the insertion of transforming growth factor a within Pseudomonas exotoxin as a targeting ligand. Bioconjug Chem. 1992;3:58-62.
111.
Siegall CB, Fitzgerald DJ, Pastan I.Selective killing of tumor cells using EGF or TGF a-Pseudomonas exotoxin chimeric molecules. Semin Cancer Biol. 1990;1:345-350.
112.
Nichols J, Foss F, Kuzel TM, et al.Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies. Eur J Cancer. 1997;33:S34-S36.
113.
Strauchen JA, Breakstone BA.IL-2 receptor expression in human lymphoid lesions: immunohistochemical study of 166 cases. Am J Pathol. 1987;126:506-512.
114.
Grossbard ML, Freedman AS, Ritz J, et al.Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion. Blood. 1992;79:576-586.
115.
Soler-Rodriguez AM, Uhr JW, Richardson J, et al.The toxicity of chemically deglycosylated ricin A-chain in mice. Int J Immunopharmacol. 1992;14:281-291.
116.
Soler-Rodriguez AM, Ghetie MA, Oppenheimer-Marks N, et al.Ricin A-chain and ricin A-chain immunotoxins rapidly damage human endothelial cells: implications for vascular leak syndrome. Exp Cell Res. 1993;206:227-239.
117.
Baluna R, Vitetta ES.Vascular leak syndrome: a side effect of immunotherapy. Immunopharmacology. 1997;37:117-132.
118.
Grossbard M, Nadler LM.Immunotoxin therapy of lymphoid neoplasms. Semin Hematol. 1994;31:88-97.
119.
Siegall CB, Liggitt D, Chace D, et al.Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity. Proc Natl Acad Sci USA. 1994;91:9514-9518.
120.
Baluna R, Ghetie V, Oppenheimer-Marks N, et al.Fibronectin inhibits the cytotoxic effect of ricin A chain on endothelial cells. Int J Immunopharmacol. 1996;18:355-361.
121.
DeFouw DO, Brown KL, Feinberg RN.Canine jugular vein endothelial cell monolayers in vitro: vasomediator-activated diffusive albumin pathway. J Vasc Res. 1993;30:154-160.
122.
Hinshaw DB, Burger JM, Beals TF, et al.Actin polymerization in cellular oxidant injury. Arch Biochem Biophys. 1991;288:311-316.
123.
Amlot P, Stone M, 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.
124.
Vitetta ES, Stone M, Amlot P, et al.A phase I immunotoxin trial in patients with B cell lymphoma. Cancer Res. 1991;51:4052-4058.
125.
Strugar JG, Criscuolo GR, Rothbart D, et al.Vascular endothelial growth/permeability factor expression in human glioma specimens: correlation with vasogenic brain edema and tumor-associated cysts. J Neurosurg. 1995;83:682-689.
126.
Dolberg-Stolik OC, Putterman C, Rubinow A, et al.Idiopathic capillary leak syndrome complicated by massive rhabdomyolysis. Chest. 1993;104:123-126.
127.
Lindstrom AL, Erlandsen SL, Kersey JH, et al.An in vitro model for toxin-mediated vascular leak syndrome: ricin toxin A chain increases the permeability of human endothelial cell monolayers. Blood. 1997;90:2323-2334.
128.
Yokota T, Milenic DE, Whitlow M, et al.Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 1992;52:3402-3408.
129.
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.
130.
Pai LH, Wittes R, Setser A, et al.Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudo-monas exotoxin. Nat Med. 1996;2:350-353.
131.
Lynch TJ Jr, 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.
132.
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.
133.
Schnell R, Hatwig MT, Radszuhn A, et al.A clinical phase-I trial of an anti-CD25 deglycosylated ricin A chain immunotoxin in patients with refractory Hodgkin’s disease. Blood. 1995;10(suppl1):55a-55a.
134.
Morrison SL, Johnson MJ, Herzenberg LA, et al.Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA. 1984;81:6851-6855.
135.
Shaw DR, Khazaeli MB, Lobuglio AF.Biological activity of mouse/human chimeric antibodies of the four human IgG subclasses with specificity for a tumor-associated antigen. Proc Am Assoc Cancer Res. 1988;29:421-421.
136.
Jones PT, Dear PH, Foote J, et al.Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature. 1986;321:522-525.
137.
Shaw DR, Khazaeli MB, Sin LK, et al.Characterization of a mouse/human chimeric monoclonal antibody (17-1A) to a colon cancer tumor-associated antigen. J Immunol. 1987;138:4534-4538.
138.
Selvaggi D, Saria EA, Schwartz R, et al.Phase I/II study of murine monoclonal antibody-ricin A chain (XOMAZYME-Mel) immuno-conjugate plus cyclosporin A in patients with metastatic melanoma. J Immunother. 1993;13:201-207.
139.
Oratz R, Speyer JL, Wernz JC, et al.Anti-melanoma monoclonal antibody ricin A chain immunoconjugate (XMMME001-RTA) plus cyclophosphamide in the treatment of metastatic malignant melanoma: results of a phase I trial. J Biol Response Mod.1990;9:345-354.
140.
Pai L, Fitzgerald D, Tepper M, et al.Inhibition of antibody response to Pseudomonas exotoxin and an immunotoxin containing Pseudomonas exotoxin by 15-deoxyspergualin in mice. Cancer Res. 1990;50:7750-7760.
141.
Noon E, Shanahan S, Linsley P, et al.Reduction in the murine anti-immunotoxin antibody response using novel immunosuppressive agents. Proceedings of the Fourth International Symposium on Immunotoxins. Myrtle Beach, SC; June 8-10, 1995: 150-150. Abstract.
142.
Lenschow DJ, Zeng Y, Thistleyhwaite JR, et al.Long-term survival of xenogenic pancreatic islet grafts induced by CTLA4Ig. Science.1992;257:789-792.
143.
Linsley PS, Wallace PM, Johnson MG, et al.Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257:792-795.
144.
Gadina M, Newton DL, Rybak SM, et al.Humanized immunotoxins. Ther Immunol. 1994;1:59-64.
145.
Roscoe D, Jung S, Benhar I, et al.Primate antibody response to immunotoxin: serological and computer-aided analysis of epitopes on a truncated form of Pseudomonas exotoxin. Infect Immun. 1994;62:5055-5060.
146.
Roscoe DM, Pai H, 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.
147.
Lemley P, Amanatides P, Wright D.Identification and characterization of a monoclonal antibody that neutralizes ricin toxicity in vitro and in vivo. Hybridoma. 1994;13:417-422.
148.
Benhar I, Wang QC, Fitzgerald DJ, et al.Pseudomonas exotoxin mutants: replacement of surface-exposed residues in domain III with cysteine residues that can be modified with polyethylene glycol in a site-specific manner. J Biol Chem. 1994;269:13398-13404.
149.
Jain RK.Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev.1990;9:253-266.
150.
Fujimori K, Covell DG, Fletcher JE, et al.Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab9)2, and Fab in tumors. Cancer Res. 1989;49:5656-5663.
151.
Spitler LE, del Rio M, Khentigan A, et al.Therapy of patients with malignant melanoma using a monoclonal anti-melanoma antibody-ricin A chain immunotoxin. Cancer Res. 1987;47:1717-1723.
152.
Spitler LE.Clinical studies: solid tumors. Cancer Treat Res.1988;37:493-514.
153.
Byers VS, Rodvien R, Grant K, et al.Phase I study of monoclonal antibody-ricin A chain immunotoxin XomaZyme-791 in patients with metastatic colon cancer. Cancer Res. 1989;49:6153-6160.
154.
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.
155.
McLaughlin P, Murray JL, Rosenblum M.Phase I trial of anti-B4- blocked ricin (B4br) by 8-day continuous infusion (CI). Proc Am Assoc Cancer Res. 1994;35:251-251.
156.
Foss F, Nichols J, Parker K.Phase I/II trial of DAB389-IL-2 in patients with NHL, HD, and CTCL. Proceedings of the Fourth International Symposium on Immunotoxins. Myrtle Beach, SC; June 8-10, 1995:159-159. Abstract.
157.
Kuzel T, Foss F, LeMaistre C, et al.Phase I trial of a diphtheria toxin (DT) fusion protein for the treatment of interleukin-2 receptors (IL-2R) expressing hematologic neoplasm. Blood. 1995; 86:274a-274a.
158.
Foss F, Borkowski T, Gilliom M, et al.Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study. Blood. 1994;84:1765-1774.
159.
Woodworth TG, Nichols JC.Recombinant fusion toxins: a new class of targeted biologic therapeutics. Cancer Treat Res. 1993; 68:145-160.
160.
Strom T, Kelley V, Murphy J, et al.Interleukin-2 receptor-directed therapies: antibody- or cytokine-based targeting molecules. Adv Nephrol Necker Hosp. 1994;23:347-356.
161.
Hertler AA, Schlossman DM, Borowitz MJ.A phase I study of T101-ricin A chain immunotoxin in refractory chronic lymphocytic leukemia. J Biol Response Mod. 1988;7:97-113.
162.
LeMaistre CF, Rosen S, Frankel A, et al.Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma. Blood. 1991;78:1173-1182.
163.
Bookman M, Godfrey S, Padavic K, et al.Anti-transferrin receptor immunotoxin (IT) therapy: phase I intraperitoneal (i.p.) trial. Proc Am Soc Clin Oncol. 1990;9:187-187.
164.
Laske D, Muraszko K, Oldfield E, et al.Intraventricular immunotoxin therapy for leptomeningeal neoplasia. Neurosurgery. 1997; 41:1039-1049.
165.
Laske D, Oldfield E, Youle RJ.Immunotoxins for brain tumor therapy. Proceedings of the Fourth International Symposium on Immunotoxins. Myrtle Beach, SC; June 8-10, 1995:166-166. Abstract.
166.
Lynch TJ Jr, 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.
167.
Uckun F.B43-pokeweed antiviral protein (B43-PAP) immunotoxin. Proceedings of the Fourth International Symposium on Immunotoxins. Myrtle Beach, SC; June 8-10, 1995:162-162. Abstract.
168.
Uckun F.Annotation: immunotoxins for the treatment of leukaemia. Br J Haematol. 1993;85:435-438.
