title: Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies.
abstract: Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for medical use, although a related molecule, denileukin diftitox, composed of interleukin-2 fused to truncated diphtheria toxin, is approved for relapsed/refractory cutaneous T-cell lymphoma. Recombinant immunotoxins which have been tested in patients with chemotherapy-pretreated hematologic malignancies include LMB-2 (anti-CD25), BL22 (CAT-3888, anti-CD22) and HA22 (CAT-8015, anti-CD22), each containing an Fv fragment fused to truncated Pseudomonas exotoxin. Major responses were observed with LMB-2 in adult T-cell leukemia, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, Hodgkin's disease, and hairy cell leukemia (HCL). BL22 resulted in a high complete remission rate in patients with HCL, particularly those without excessive tumor burden. HA22, an improved version of BL22 with higher affinity to CD22, is now undergoing phase I testing in HCL, CLL, non-Hodgkin's lymphoma, and pediatric acute lymphoblastic leukemia.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37/5124b, 9000 Rockville Pike, Bethesda, MD 20892, USA. kreitmar@mail.nih.gov
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
mesh_terms: D002986:Clinical Trials as Topic; D004167:Diphtheria Toxin / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000276:immunology; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007956:Leukocidins / Q000494:pharmacology; D008954:Models, Biological; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000627:therapeutic use*; D014118:Toxins, Biological / Q000494:pharmacology
chemical_list: D004167:Diphtheria Toxin; D000922:Immunotoxins; D007956:Leukocidins; C510238:Pseudomonas aeruginosa Cytotoxins; D011994:Recombinant Proteins; D014118:Toxins, Biological
references.citation: Biochem Soc Trans. 2006 Feb;34(Pt 1):1-6
references.pmid: 16246167
references.citation: J Mol Biol. 1986 May 5;189(1):113-30
references.pmid: 3537305
references.citation: FEBS J. 2006 Oct;273(20):4579-93
references.pmid: 16956368
references.citation: Proc Natl Acad Sci U S A. 1980 Sep;77(9):5419-23
references.pmid: 6968912
references.citation: EMBO J. 1994 May 15;13(10):2322-30
references.pmid: 8194524
references.citation: Leuk Res. 1997 Oct;21(10):997-9
references.pmid: 9403010
references.citation: Cancer Res. 1995 Aug 1;55(15):3357-63
references.pmid: 7614471
references.citation: Blood. 2002 Feb 15;99(4):1320-6
references.pmid: 11830482
references.citation: Protein Expr Purif. 2008 Mar;58(1):1-11
references.pmid: 18160309
references.citation: Leukemia. 1994 Nov;8(11):2019-20
references.pmid: 7967746
references.citation: J Biol Chem. 1980 Nov 25;255(22):10717-20
references.pmid: 7000782
references.citation: J Clin Oncol. 1989 Feb;7(2):168-72
references.pmid: 2783731
references.citation: Clin Cancer Res. 2000 Apr;6(4):1476-87
references.pmid: 10778980
references.citation: J Biol Chem. 1994 Sep 16;269(37):23296-301
references.pmid: 8083236
references.citation: Clin Lymphoma. 2002 Mar;2 Suppl 1:S19-23
references.pmid: 11970766
references.citation: Protein Eng. 1987 Dec;1(6):493-8
references.pmid: 3334101
references.citation: Biochem J. 1995 Apr 1;307 ( Pt 1):29-37
references.pmid: 7717988
references.citation: Blood. 2007 May 15;109(10):4168-70
references.pmid: 17227830
references.citation: Clin Cancer Res. 2005 Feb 15;11(4):1545-50
references.pmid: 15746059
references.citation: Infect Immun. 1992 Feb;60(2):497-502
references.pmid: 1730481
references.citation: Ann Intern Med. 1997 Jun 1;126(11):882-5
references.pmid: 9163289
references.citation: Protein Sci. 1994 Sep;3(9):1464-75
references.pmid: 7833808
references.citation: J Biol Chem. 1994 Jul 8;269(27):18167-76
references.pmid: 8027078
references.citation: Clin Cancer Res. 2000 Apr;6(4):1302-13
references.pmid: 10778955
references.citation: Exp Cell Res. 1980 Apr;126(2):321-6
references.pmid: 7363949
references.citation: Blood. 1993 Aug 15;82(4):1277-87
references.pmid: 7688993
references.citation: J Clin Oncol. 2004 Oct 15;22(20):4095-102
references.pmid: 15353540
references.citation: Proc Natl Acad Sci U S A. 1986 Mar;83(5):1320-4
references.pmid: 3006045
references.citation: Neurosurgery. 2007 Nov;61(5):1031-7; discussion 1037-8
references.pmid: 18091279
references.citation: Blood. 1997 Jul 1;90(1):252-9
references.pmid: 9207460
references.citation: Leukemia. 1994 Jul;8(7):1153-6
references.pmid: 7913513
references.citation: Biochem Biophys Res Commun. 1991 Oct 31;180(2):545-51
references.pmid: 1953725
references.citation: J Clin Oncol. 1995 Apr;13(4):974-82
references.pmid: 7707126
references.citation: Mol Microbiol. 1997 Feb;23(3):445-57
references.pmid: 9044279
references.citation: Blood. 2003 Aug 15;102(4):1458-65
references.pmid: 12714494
references.citation: N Engl J Med. 2001 Jul 26;345(4):241-7
references.pmid: 11474661
references.citation: J Biol Chem. 1992 Jun 25;267(18):12420-3
references.pmid: 1618748
references.citation: Protein Expr Purif. 2004 Jan;33(1):123-33
references.pmid: 14680969
references.citation: Leuk Lymphoma. 1994;14 Suppl 1:1-12
references.pmid: 7820038
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8616-20
references.pmid: 1924323
references.citation: J Biol Chem. 1992 Dec 15;267(35):25396-401
references.pmid: 1460035
references.citation: Cancer Res. 1998 Mar 1;58(5):968-75
references.pmid: 9500458
references.citation: Exp Hematol. 1992 Feb;20(2):201-8
references.pmid: 1371965
references.citation: Mol Cancer Ther. 2008 Sep;7(9):2924-32
references.pmid: 18790773
references.citation: Leuk Lymphoma. 2008 Mar;49(3):543-53
references.pmid: 18297533
references.citation: J Exp Med. 1959 Feb 1;109(2):145-63
references.pmid: 13620845
references.citation: Bioconjug Chem. 1993 Nov-Dec;4(6):581-5
references.pmid: 8305530
references.citation: Best Pract Res Clin Haematol. 2003 Mar;16(1):15-31
references.pmid: 12670462
references.citation: Leukemia. 2003 Jan;17(1):45-51
references.pmid: 12529659
references.citation: Curr Pharm Des. 2009;15(2):153-72
references.pmid: 19149610
references.citation: Bioconjug Chem. 1993 Mar-Apr;4(2):112-20
references.pmid: 7873642
references.citation: Leuk Lymphoma. 2007 Dec;48(12):2397-402
references.pmid: 17943599
references.citation: Best Pract Res Clin Haematol. 2003 Mar;16(1):57-68
references.pmid: 12670465
references.citation: J Clin Oncol. 2001 Jan 15;19(2):376-88
references.pmid: 11208829
references.citation: Infect Immun. 1993 May;61(5):2200-2
references.pmid: 7683003
references.citation: Leuk Lymphoma. 2002 Apr;43(4):885-8
references.pmid: 12153180
references.citation: Int J Cancer. 1994 Jul 1;58(1):142-9
references.pmid: 8014011
references.citation: J Nucl Med. 2000 Apr;41(4):755-62
references.pmid: 10768579
references.citation: J Biol Chem. 1995 Nov 24;270(47):28037-41
references.pmid: 7499288
references.citation: Science. 1972 Feb 25;175(4024):901-3
references.pmid: 4621498
references.citation: J Biol Chem. 1990 Sep 25;265(27):16311-7
references.pmid: 1975810
references.citation: J Immunol. 2000 Dec 15;165(12):7150-6
references.pmid: 11120846
references.citation: Hematol Oncol Clin North Am. 2006 Oct;20(5):1051-63
references.pmid: 16990106
references.citation: Clin Cancer Res. 2006 May 1;12(9):2804-11
references.pmid: 16675574
references.citation: Blood. 1999 Jun 1;93(11):3678-84
references.pmid: 10339474
references.citation: Biochemistry. 1994 May 10;33(18):5451-9
references.pmid: 7910034
references.citation: Curr Pharm Des. 2008;14(21):2022
references.pmid: 18691112
references.citation: Methods Mol Med. 2000;25:215-26
references.pmid: 21318848
references.citation: Blood. 1994 Jan 15;83(2):426-34
references.pmid: 8286741
references.citation: Bioconjug Chem. 1992 Jan-Feb;3(1):63-8
references.pmid: 1616951
references.citation: Blood. 1995 Jun 15;85(12):3457-65
references.pmid: 7780133
references.citation: Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6902-6
references.pmid: 8692916
references.citation: J Biol Chem. 1989 Aug 25;264(24):14256-61
references.pmid: 2503515
references.citation: Blood. 1999 Nov 15;94(10):3340-8
references.pmid: 10552943
references.citation: J Immunol. 1999 Dec 1;163(11):6072-7
references.pmid: 10570296
references.citation: Blood. 1993 Nov 1;82(9):2624-33
references.pmid: 8219217
references.citation: J Immunol. 2006 Dec 15;177(12):8822-34
references.pmid: 17142785
references.citation: Biochem J. 1989 May 1;259(3):639-43
references.pmid: 2730579
references.citation: J Biol Chem. 1990 May 5;265(13):7331-7
references.pmid: 2332431
references.citation: Clin Exp Immunol. 1981 Mar;43(3):497-505
references.pmid: 7026093
references.citation: Cancer Res. 1993 Jan 15;53(2):340-7
references.pmid: 8417828
references.citation: Apoptosis. 2004 Jan;9(1):19-25
references.pmid: 14739595
references.citation: Nature. 1992 May 21;357(6375):216-22
references.pmid: 1589020
references.citation: Leukemia. 2005 Feb;19(2):176-82
references.pmid: 15592433
references.citation: Ann Intern Med. 1978 Nov;89(5 Pt 1):677-83
references.pmid: 717940
references.citation: Leuk Lymphoma. 2002 May;43(5):953-9
references.pmid: 12148905
references.citation: Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3555-61
references.pmid: 14506141
references.citation: Leuk Lymphoma. 1994 Mar;13(1-2):1-10
references.pmid: 8025511
references.citation: Int J Cancer. 2000 Jul 1;87(1):86-94
references.pmid: 10861457
references.citation: Blood. 2008 Apr 1;111(7):3830-7
references.pmid: 18230757
references.citation: Blood. 1990 Jul 1;76(1):157-62
references.pmid: 2364167
references.citation: Leukemia. 2008 Mar;22(3):487-95
references.pmid: 18094718
references.citation: Clin Cancer Res. 1999 Sep;5(9):2311-5
references.pmid: 10499598
references.citation: Clin Cancer Res. 2002 Apr;8(4):995-1002
references.pmid: 11948105
references.citation: J Biol Chem. 1991 Feb 5;266(4):2652-9
references.pmid: 1990012
references.citation: J Clin Oncol. 1998 Sep;16(9):3007-15
references.pmid: 9738569
references.citation: J Cell Sci. 2008 Oct 1;121(Pt 19):3140-5
references.pmid: 18765564
references.citation: Clin Cancer Res. 1999 Jul;5(7):1665-70
references.pmid: 10430066
references.citation: Blood. 1997 Sep 1;90(5):2020-6
references.pmid: 9292538
references.citation: Toxicol Appl Pharmacol. 1999 Jul 15;158(2):152-60
references.pmid: 10406930
references.citation: J Biol Chem. 2005 Jan 7;280(1):607-17
references.pmid: 15491997
references.citation: Science. 1970 Jul 3;169(3940):68-70
references.pmid: 4986716
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11311-6
references.pmid: 18678888
references.citation: Clin Cancer Res. 2005 May 15;11(10):3879-88
references.pmid: 15897589
references.citation: J Immunother. 2005 Jul-Aug;28(4):376-81
references.pmid: 16000956
references.citation: Biochemistry. 1994 May 17;33(19):5894-900
references.pmid: 8180218
references.citation: Clin Cancer Res. 2002 May;8(5):1004-13
references.pmid: 12006512
references.citation: J Clin Oncol. 2000 Apr;18(8):1622-36
references.pmid: 10764422
references.citation: J Biol Chem. 1987 Jun 25;262(18):8707-11
references.pmid: 2885323
references.citation: Cell. 1986 Dec 5;47(5):641-8
references.pmid: 3536124
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10427-31
references.pmid: 7479798
references.citation: Cancer Res. 1993 Feb 15;53(4):819-25
references.pmid: 8428363
references.citation: J Biol Chem. 1987 Apr 25;262(12):5908-12
references.pmid: 3571242
references.citation: Blood. 2009 Apr 16;113(16):3792-800
references.pmid: 18988862
references.citation: J Clin Oncol. 2009 Jun 20;27(18):2983-90
references.pmid: 19414673
references.citation: Clin Cancer Res. 1995 Jan;1(1):57-61
references.pmid: 9815887
references.citation: Hematol Oncol Clin North Am. 2006 Oct;20(5):1099-108
references.pmid: 16990110
references.citation: Leuk Lymphoma. 1997 Apr;25(3-4):381-5
references.pmid: 9168448
references.citation: Am J Clin Pathol. 2005 Jan;123(1):132-8
references.pmid: 15762289
references.citation: Int J Cancer. 1999 Mar 31;81(1):148-55
references.pmid: 10077166
references.citation: J Biol Chem. 1973 Jun 10;248(11):3838-44
references.pmid: 4196584
references.citation: Cell. 1993 Apr 9;73(1):5-8
references.pmid: 8462103
references.citation: J Biol Chem. 1990 Nov 25;265(33):20673-7
references.pmid: 2243114
references.citation: Anal Biochem. 1992 Sep;205(2):263-70
references.pmid: 1332541
references.citation: Acta Neurochir Suppl. 2003;88:105-11
references.pmid: 14531568
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7774-8
references.pmid: 8356083
references.citation: Infect Immun. 1994 Nov;62(11):5055-65
references.pmid: 7927788
references.citation: J Biol Chem. 1988 Jul 5;263(19):9470-5
references.pmid: 3132465
references.citation: Leuk Lymphoma. 1999 Oct;35(3-4):347-54
references.pmid: 10706459
references.citation: Blood. 1998 Sep 15;92(6):1918-26
references.pmid: 9731048
references.citation: Eur J Biochem. 1987 Dec 15;169(3):637-44
references.pmid: 3691512
references.citation: J Infect Dis. 1994 Nov;170(5):1180-8
references.pmid: 7963711
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7538-42
references.pmid: 8356052
references.citation: Clin Cancer Res. 2000 Jun;6(6):2157-65
references.pmid: 10873064
references.citation: Semin Oncol. 2000 Apr;27(2 Suppl 5):32-6
references.pmid: 10877049
references.citation: Cell. 1987 Jan 16;48(1):129-36
references.pmid: 3098436
references.citation: J Clin Oncol. 2003 Mar 1;21(5):891-6
references.pmid: 12610190
references.citation: Protein Expr Purif. 1999 Jun;16(1):190-201
references.pmid: 10336877
references.citation: J Biol Chem. 1988 Dec 15;263(35):18650-6
references.pmid: 3143716
references.citation: Am J Clin Pathol. 2003 Feb;119(2):213-7
references.pmid: 12579991
references.citation: Proc Natl Acad Sci U S A. 1988 Mar;85(6):1922-6
references.pmid: 3126499
references.citation: Br J Haematol. 2000 Oct;111(1):277-9
references.pmid: 11091212
references.citation: Nature. 1989 Jun 1;339(6223):394-7
references.pmid: 2498664
references.citation: Blood. 2004 Apr 1;103(7):2718-26
references.pmid: 14525789
references.citation: Semin Cancer Biol. 1995 Oct;6(5):259-67
references.pmid: 8562903
references.citation: J Clin Oncol. 2007 Mar 1;25(7):837-44
references.pmid: 17327604
references.citation: Hematol Oncol Clin North Am. 2006 Oct;20(5):1075-86
references.pmid: 16990108
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6719-29
references.pmid: 16061911
references.citation: Protein Expr Purif. 2002 Jul;25(2):270-82
references.pmid: 12135560
references.citation: Biochemistry. 1994 Sep 20;33(37):11254-63
references.pmid: 7537085
references.citation: Jpn J Cancer Res. 1990 Sep;81(9):902-8
references.pmid: 2121691
references.citation: Biochem Soc Trans. 1997 May;25(2):709-14
references.pmid: 9191188
references.citation: J Biol Chem. 1995 Jan 13;270(2):679-84
references.pmid: 7822295
references.citation: Rev Clin Exp Hematol. 2002 Dec;6(4):366-88; discussion 449-50
references.pmid: 12823778
references.citation: Cancer Immunol Immunother. 2008 Aug;57(8):1225-39
references.pmid: 18256829
references.citation: Clin Cancer Res. 2000 Feb;6(2):693-700
references.pmid: 10690555
references.citation: Proc Natl Acad Sci U S A. 1988 May;85(9):2939-43
references.pmid: 3283735
references.citation: Leukemia. 2000 Aug;14(8):1436-43
references.pmid: 10942240
references.citation: J Biol Chem. 1990 Jul 15;265(20):11885-9
references.pmid: 2195027
references.citation: Leukemia. 2001 Jan;15(1):184-6
references.pmid: 11243388
references.citation: J Exp Med. 1988 Feb 1;167(2):612-22
references.pmid: 3126255
references.citation: J Biol Chem. 1994 Aug 26;269(34):21455-9
references.pmid: 8063778
references.citation: Blut. 1990 Mar;60(3):181-6
references.pmid: 2180499
references.citation: Best Pract Res Clin Haematol. 2003 Mar;16(1):41-56
references.pmid: 12670464
references.citation: Semin Cancer Biol. 1995 Oct;6(5):297-306
references.pmid: 8562907
references.citation: Cancer. 2006 May 15;106(10):2158-64
references.pmid: 16586495
references.citation: Cancer Immunol Immunother. 2003 May;52(5):328-37
references.pmid: 12700948
references.citation: Protein Eng. 2001 Dec;14(12):1035-41
references.pmid: 11809934
references.citation: N Engl J Med. 2001 Nov 15;345(20):1500-1
references.pmid: 11794207
references.citation: Arch Pathol Lab Med. 2002 Nov;126(11):1430-3
references.pmid: 12421153
references.citation: J Exp Med. 1984 Oct 1;160(4):1126-46
references.pmid: 6090574
references.citation: Leukemia. 2000 Apr;14(4):576-85
references.pmid: 10764142
references.citation: Bone Marrow Transplant. 1988 Sep;3(5):437-44
references.pmid: 2973360
references.citation: Leuk Res. 1980;4(6):547-59
references.pmid: 7206776
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6889-93
references.pmid: 8041715
references.citation: Curr Pharm Des. 2008;14(21):2040-50
references.pmid: 18691114
references.citation: Cell. 1978 Sep;15(1):245-50
references.pmid: 699044
references.citation: Leuk Lymphoma. 1997 Apr;25(3-4):257-70
references.pmid: 9168436
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9308-12
references.pmid: 7568123
references.citation: Protein Sci. 1996 Apr;5(4):687-92
references.pmid: 8845758
references.citation: Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6
references.pmid: 16516670
references.citation: Eur J Immunol. 1997 Jun;27(6):1459-68
references.pmid: 9209499
references.citation: Biochem Biophys Res Commun. 1979 Sep 12;90(1):320-6
references.pmid: 496982
references.citation: J Immunol. 1981 Apr;126(4):1393-7
references.pmid: 6970774
references.citation: Blood. 2001 Jan 15;97(2):528-35
references.pmid: 11154233
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(1):308-12
references.pmid: 2104981
references.citation: Cancer. 2005 Dec 1;104(11):2442-8
references.pmid: 16245328