Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies.
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.
Kreitman
Robert J
RJ
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37/5124b, 9000 Rockville Pike, Bethesda, MD 20892, USA. kreitmar@mail.nih.gov
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
D004167:Diphtheria Toxin; D000922:Immunotoxins; D007956:Leukocidins; C510238:Pseudomonas aeruginosa Cytotoxins; D011994:Recombinant Proteins; D014118:Toxins, Biological
Biochem Soc Trans. 2006 Feb;34(Pt 1):1-6
16246167
J Mol Biol. 1986 May 5;189(1):113-30
3537305
FEBS J. 2006 Oct;273(20):4579-93
16956368
Proc Natl Acad Sci U S A. 1980 Sep;77(9):5419-23
6968912
EMBO J. 1994 May 15;13(10):2322-30
8194524
Leuk Res. 1997 Oct;21(10):997-9
9403010
Cancer Res. 1995 Aug 1;55(15):3357-63
7614471
Blood. 2002 Feb 15;99(4):1320-6
11830482
Protein Expr Purif. 2008 Mar;58(1):1-11
18160309
Leukemia. 1994 Nov;8(11):2019-20
7967746
J Biol Chem. 1980 Nov 25;255(22):10717-20
7000782
J Clin Oncol. 1989 Feb;7(2):168-72
2783731
Clin Cancer Res. 2000 Apr;6(4):1476-87
10778980
J Biol Chem. 1994 Sep 16;269(37):23296-301
8083236
Clin Lymphoma. 2002 Mar;2 Suppl 1:S19-23
11970766
Protein Eng. 1987 Dec;1(6):493-8
3334101
Biochem J. 1995 Apr 1;307 ( Pt 1):29-37
7717988
Blood. 2007 May 15;109(10):4168-70
17227830
Clin Cancer Res. 2005 Feb 15;11(4):1545-50
15746059
Infect Immun. 1992 Feb;60(2):497-502
1730481
Ann Intern Med. 1997 Jun 1;126(11):882-5
9163289
Protein Sci. 1994 Sep;3(9):1464-75
7833808
J Biol Chem. 1994 Jul 8;269(27):18167-76
8027078
Clin Cancer Res. 2000 Apr;6(4):1302-13
10778955
Exp Cell Res. 1980 Apr;126(2):321-6
7363949
Blood. 1993 Aug 15;82(4):1277-87
7688993
J Clin Oncol. 2004 Oct 15;22(20):4095-102
15353540
Proc Natl Acad Sci U S A. 1986 Mar;83(5):1320-4
3006045
Neurosurgery. 2007 Nov;61(5):1031-7; discussion 1037-8
18091279
Blood. 1997 Jul 1;90(1):252-9
9207460
Leukemia. 1994 Jul;8(7):1153-6
7913513
Biochem Biophys Res Commun. 1991 Oct 31;180(2):545-51
1953725
J Clin Oncol. 1995 Apr;13(4):974-82
7707126
Mol Microbiol. 1997 Feb;23(3):445-57
9044279
Blood. 2003 Aug 15;102(4):1458-65
12714494
N Engl J Med. 2001 Jul 26;345(4):241-7
11474661
J Biol Chem. 1992 Jun 25;267(18):12420-3
1618748
Protein Expr Purif. 2004 Jan;33(1):123-33
14680969
Leuk Lymphoma. 1994;14 Suppl 1:1-12
7820038
Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8616-20
1924323
J Biol Chem. 1992 Dec 15;267(35):25396-401
1460035
Cancer Res. 1998 Mar 1;58(5):968-75
9500458
Exp Hematol. 1992 Feb;20(2):201-8
1371965
Mol Cancer Ther. 2008 Sep;7(9):2924-32
18790773
Leuk Lymphoma. 2008 Mar;49(3):543-53
18297533
J Exp Med. 1959 Feb 1;109(2):145-63
13620845
Bioconjug Chem. 1993 Nov-Dec;4(6):581-5
8305530
Best Pract Res Clin Haematol. 2003 Mar;16(1):15-31
12670462
Leukemia. 2003 Jan;17(1):45-51
12529659
Curr Pharm Des. 2009;15(2):153-72
19149610
Bioconjug Chem. 1993 Mar-Apr;4(2):112-20
7873642
Leuk Lymphoma. 2007 Dec;48(12):2397-402
17943599
Best Pract Res Clin Haematol. 2003 Mar;16(1):57-68
12670465
J Clin Oncol. 2001 Jan 15;19(2):376-88
11208829
Infect Immun. 1993 May;61(5):2200-2
7683003
Leuk Lymphoma. 2002 Apr;43(4):885-8
12153180
Int J Cancer. 1994 Jul 1;58(1):142-9
8014011
J Nucl Med. 2000 Apr;41(4):755-62
10768579
J Biol Chem. 1995 Nov 24;270(47):28037-41
7499288
Science. 1972 Feb 25;175(4024):901-3
4621498
J Biol Chem. 1990 Sep 25;265(27):16311-7
1975810
J Immunol. 2000 Dec 15;165(12):7150-6
11120846
Hematol Oncol Clin North Am. 2006 Oct;20(5):1051-63
16990106
Clin Cancer Res. 2006 May 1;12(9):2804-11
16675574
Blood. 1999 Jun 1;93(11):3678-84
10339474
Biochemistry. 1994 May 10;33(18):5451-9
7910034
Curr Pharm Des. 2008;14(21):2022
18691112
Methods Mol Med. 2000;25:215-26
21318848
Blood. 1994 Jan 15;83(2):426-34
8286741
Bioconjug Chem. 1992 Jan-Feb;3(1):63-8
1616951
Blood. 1995 Jun 15;85(12):3457-65
7780133
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6902-6
8692916
J Biol Chem. 1989 Aug 25;264(24):14256-61
2503515
Blood. 1999 Nov 15;94(10):3340-8
10552943
J Immunol. 1999 Dec 1;163(11):6072-7
10570296
Blood. 1993 Nov 1;82(9):2624-33
8219217
J Immunol. 2006 Dec 15;177(12):8822-34
17142785
Biochem J. 1989 May 1;259(3):639-43
2730579
J Biol Chem. 1990 May 5;265(13):7331-7
2332431
Clin Exp Immunol. 1981 Mar;43(3):497-505
7026093
Cancer Res. 1993 Jan 15;53(2):340-7
8417828
Apoptosis. 2004 Jan;9(1):19-25
14739595
Nature. 1992 May 21;357(6375):216-22
1589020
Leukemia. 2005 Feb;19(2):176-82
15592433
Ann Intern Med. 1978 Nov;89(5 Pt 1):677-83
717940
Leuk Lymphoma. 2002 May;43(5):953-9
12148905
Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3555-61
14506141
Leuk Lymphoma. 1994 Mar;13(1-2):1-10
8025511
Int J Cancer. 2000 Jul 1;87(1):86-94
10861457
Blood. 2008 Apr 1;111(7):3830-7
18230757
Blood. 1990 Jul 1;76(1):157-62
2364167
Leukemia. 2008 Mar;22(3):487-95
18094718
Clin Cancer Res. 1999 Sep;5(9):2311-5
10499598
Clin Cancer Res. 2002 Apr;8(4):995-1002
11948105
J Biol Chem. 1991 Feb 5;266(4):2652-9
1990012
J Clin Oncol. 1998 Sep;16(9):3007-15
9738569
J Cell Sci. 2008 Oct 1;121(Pt 19):3140-5
18765564
Clin Cancer Res. 1999 Jul;5(7):1665-70
10430066
Blood. 1997 Sep 1;90(5):2020-6
9292538
Toxicol Appl Pharmacol. 1999 Jul 15;158(2):152-60
10406930
J Biol Chem. 2005 Jan 7;280(1):607-17
15491997
Science. 1970 Jul 3;169(3940):68-70
4986716
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11311-6
18678888
Clin Cancer Res. 2005 May 15;11(10):3879-88
15897589
J Immunother. 2005 Jul-Aug;28(4):376-81
16000956
Biochemistry. 1994 May 17;33(19):5894-900
8180218
Clin Cancer Res. 2002 May;8(5):1004-13
12006512
J Clin Oncol. 2000 Apr;18(8):1622-36
10764422
J Biol Chem. 1987 Jun 25;262(18):8707-11
2885323
Cell. 1986 Dec 5;47(5):641-8
3536124
Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10427-31
7479798
Cancer Res. 1993 Feb 15;53(4):819-25
8428363
J Biol Chem. 1987 Apr 25;262(12):5908-12
3571242
Blood. 2009 Apr 16;113(16):3792-800
18988862
J Clin Oncol. 2009 Jun 20;27(18):2983-90
19414673
Clin Cancer Res. 1995 Jan;1(1):57-61
9815887
Hematol Oncol Clin North Am. 2006 Oct;20(5):1099-108
16990110
Leuk Lymphoma. 1997 Apr;25(3-4):381-5
9168448
Am J Clin Pathol. 2005 Jan;123(1):132-8
15762289
Int J Cancer. 1999 Mar 31;81(1):148-55
10077166
J Biol Chem. 1973 Jun 10;248(11):3838-44
4196584
Cell. 1993 Apr 9;73(1):5-8
8462103
J Biol Chem. 1990 Nov 25;265(33):20673-7
2243114
Anal Biochem. 1992 Sep;205(2):263-70
1332541
Acta Neurochir Suppl. 2003;88:105-11
14531568
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7774-8
8356083
Infect Immun. 1994 Nov;62(11):5055-65
7927788
J Biol Chem. 1988 Jul 5;263(19):9470-5
3132465
Leuk Lymphoma. 1999 Oct;35(3-4):347-54
10706459
Blood. 1998 Sep 15;92(6):1918-26
9731048
Eur J Biochem. 1987 Dec 15;169(3):637-44
3691512
J Infect Dis. 1994 Nov;170(5):1180-8
7963711
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7538-42
8356052
Clin Cancer Res. 2000 Jun;6(6):2157-65
10873064
Semin Oncol. 2000 Apr;27(2 Suppl 5):32-6
10877049
Cell. 1987 Jan 16;48(1):129-36
3098436
J Clin Oncol. 2003 Mar 1;21(5):891-6
12610190
Protein Expr Purif. 1999 Jun;16(1):190-201
10336877
J Biol Chem. 1988 Dec 15;263(35):18650-6
3143716
Am J Clin Pathol. 2003 Feb;119(2):213-7
12579991
Proc Natl Acad Sci U S A. 1988 Mar;85(6):1922-6
3126499
Br J Haematol. 2000 Oct;111(1):277-9
11091212
Nature. 1989 Jun 1;339(6223):394-7
2498664
Blood. 2004 Apr 1;103(7):2718-26
14525789
Semin Cancer Biol. 1995 Oct;6(5):259-67
8562903
J Clin Oncol. 2007 Mar 1;25(7):837-44
17327604
Hematol Oncol Clin North Am. 2006 Oct;20(5):1075-86
16990108
J Clin Oncol. 2005 Sep 20;23(27):6719-29
16061911
Protein Expr Purif. 2002 Jul;25(2):270-82
12135560
Biochemistry. 1994 Sep 20;33(37):11254-63
7537085
Jpn J Cancer Res. 1990 Sep;81(9):902-8
2121691
Biochem Soc Trans. 1997 May;25(2):709-14
9191188
J Biol Chem. 1995 Jan 13;270(2):679-84
7822295
Rev Clin Exp Hematol. 2002 Dec;6(4):366-88; discussion 449-50
12823778
Cancer Immunol Immunother. 2008 Aug;57(8):1225-39
18256829
Clin Cancer Res. 2000 Feb;6(2):693-700
10690555
Proc Natl Acad Sci U S A. 1988 May;85(9):2939-43
3283735
Leukemia. 2000 Aug;14(8):1436-43
10942240
J Biol Chem. 1990 Jul 15;265(20):11885-9
2195027
Leukemia. 2001 Jan;15(1):184-6
11243388
J Exp Med. 1988 Feb 1;167(2):612-22
3126255
J Biol Chem. 1994 Aug 26;269(34):21455-9
8063778
Blut. 1990 Mar;60(3):181-6
2180499
Best Pract Res Clin Haematol. 2003 Mar;16(1):41-56
12670464
Semin Cancer Biol. 1995 Oct;6(5):297-306
8562907
Cancer. 2006 May 15;106(10):2158-64
16586495
Cancer Immunol Immunother. 2003 May;52(5):328-37
12700948
Protein Eng. 2001 Dec;14(12):1035-41
11809934
N Engl J Med. 2001 Nov 15;345(20):1500-1
11794207
Arch Pathol Lab Med. 2002 Nov;126(11):1430-3
12421153
J Exp Med. 1984 Oct 1;160(4):1126-46
6090574
Leukemia. 2000 Apr;14(4):576-85
10764142
Bone Marrow Transplant. 1988 Sep;3(5):437-44
2973360
Leuk Res. 1980;4(6):547-59
7206776
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6889-93
8041715
Curr Pharm Des. 2008;14(21):2040-50
18691114
Cell. 1978 Sep;15(1):245-50
699044
Leuk Lymphoma. 1997 Apr;25(3-4):257-70
9168436
Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9308-12
7568123
Protein Sci. 1996 Apr;5(4):687-92
8845758
Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6
16516670
Eur J Immunol. 1997 Jun;27(6):1459-68
9209499
Biochem Biophys Res Commun. 1979 Sep 12;90(1):320-6
496982
J Immunol. 1981 Apr;126(4):1393-7
6970774
Blood. 2001 Jan 15;97(2):528-35
11154233
Proc Natl Acad Sci U S A. 1990 Jan;87(1):308-12
2104981
Cancer. 2005 Dec 1;104(11):2442-8
16245328