Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics.
Immunogenicity of non-human proteins with useful therapeutic properties has prevented their development for use in the therapy of disease. However, this class of proteins could be very useful, if their immunogenicity could be markedly reduced so that many treatment cycles could be administered. One approach to reduce the immunogenicity of foreign proteins is to identify B cell epitopes on the protein and eliminate them by mutagenesis. In this article, theoretical aspects and experimental evidence for the feasibility of B cell epitope removal is reviewed. A special focus is given to our results with deimmunization of recombinant immunotoxins in which Fvs are fused to a 38kDa portion of the bacterial protein, Pseudomonas exotoxin A (PE38). Immunotoxins targeting CD22 and CD25 have produced complete remissions in many patients with drug resistant Hairy Cell Leukemia and are being evaluated in other malignancies. Experimental data summarized in this review indicates that removal of B cell epitopes is a practical approach for making less immunogenic protein therapeutics from non-human functional proteins. This approach requires grouping of the epitopes to identify targets for deimmunization followed by quantitative analysis of the decrease in affinity produced by the mutations in B cell epitopes.
Nagata
Satoshi
S
Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57105, USA. nagatas@sanfordhealth.org
Pastan
Ira
I
D000818:Animals; D000915:Antibody Affinity; D000937:Antigen-Antibody Reactions; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006801:Humans; D000922:Immunotoxins / Q000276:immunology; D016296:Mutagenesis; D017354:Point Mutation; D011487:Protein Conformation; D011506:Proteins / Q000276:immunology*
D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D000922:Immunotoxins; D011506:Proteins
Nat Rev Immunol. 2007 Jun;7(6):485-90
17479127
Immunol Cell Biol. 2001 Oct;79(5):507-11
11564159
Curr Opin Mol Ther. 2004 Feb;6(1):10-6
15011776
Adv Immunol. 2000;75:159-208
10879284
J Immunol. 1975 Apr;114(4):1302-6
46896
Annu Rev Immunol. 1993;11:331-60
8476565
Nature. 1986 May 29-Jun 4;321(6069):522-5
3713831
Biochemistry. 1964 Jul;3:996-1008
14214095
J Mol Biol. 1971 Feb 14;55(3):379-400
5551392
J Immunol Methods. 1992 Feb 14;147(1):125-34
1311735
Methods Mol Biol. 1996;66:55-66
8959704
Mol Immunol. 2007 Feb;44(5):1029-41
16647121
Immunol Invest. 1992 Oct;21(6):523-38
1385323
Immunol Invest. 1997 Jun;26(4):473-89
9246567
Proc Natl Acad Sci U S A. 2005 May 31;102(22):7946-51
15905329
Clin Exp Immunol. 1972 Sep;12(1):121-32
5083460
Am J Obstet Gynecol. 2007 Jan;196(1):7-15
17240220
Science. 1987 Mar 6;235(4793):1184-90
3823878
Immunogenetics. 2005 Jun;57(5):326-36
15895191
J Mol Recognit. 2002 Sep-Oct;15(5):240-7
12447900
Cell. 1990 May 18;61(4):553-6
1693095
J Immunol Methods. 1997 Aug 7;206(1-2):43-52
9328567
Assay Drug Dev Technol. 2007 Oct;5(5):655-62
17939757
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2719-24
10716997
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D777-80
16381978
N Engl J Med. 2001 Jul 26;345(4):241-7
11474661
J Immunol. 1987 Jan 1;138(1):213-9
2431055
Semin Immunol. 1989 Sep;1(1):5-12
15630954
Protein Sci. 2001 Mar;10(3):491-503
11344318
Methods Enzymol. 1991;203:176-201
1722270
Circulation. 1996 Jul 15;94(2):197-206
8674179
Expert Opin Biol Ther. 2006 Jan;6(1):1-7
16370909
Science. 1985 Sep 6;229(4717):932-40
2410982
Int J Cardiol. 2003 Oct;91(2-3):115-27
14559121
J Pharm Biomed Anal. 2008 Dec 15;48(5):1267-81
18993008
Int J Med Microbiol. 2004 Apr;293(7-8):577-82
15149034
J Immunol Methods. 1992 Jun 24;150(1-2):77-90
1613260
J Immunol. 2006 Dec 15;177(12):8822-34
17142785
Protein J. 2004 Jan;23(1):39-52
15115181
Anal Chem. 2001 Feb 1;73(3):471-80
11217749
J Theor Biol. 2004 Dec 21;231(4):535-48
15488530
Clin Ther. 2007 Apr;29(4):683-90
17617291
Nat Rev Drug Discov. 2008 Jan;7(1):21-39
18097458
Nature. 1986 Aug 21-27;322(6081):747-8
2427953
Thromb Haemost. 2008 May;99(5):874-82
18449416
Protein Sci. 1994 Dec;3(12):2351-7
7538848
Thromb Haemost. 1994 Aug;72(2):297-301
7831668
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11311-6
18678888
J Immunotoxicol. 2006 Sep 1;3(3):151-6
18958695
J Mol Biol. 1992 Aug 5;226(3):851-65
1380563
Nature. 1984 Sep 13-19;311(5982):123-6
6206398
Anal Chem. 1997 Jan 15;69(2):175-82
8997894
J Mol Recognit. 2004 Mar-Apr;17(2):132-43
15027033
Protein Sci. 2005 Jan;14(1):246-8
15576553
J Exp Med. 1994 Nov 1;180(5):1889-900
7964465
Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2264-71
8637861
Amino Acids. 2007 Sep;33(3):423-8
17252308
Methods Mol Biol. 2009;524:3-20
19377933
Blood. 2000 Aug 15;96(4):1425-32
10942387
Annu Rev Biochem. 1990;59:439-73
2197980
Mol Immunol. 1997 Aug-Sep;34(12-13):843-53
9464520
Annu Rev Med. 2007;58:221-37
17059365
Nat Rev Cancer. 2006 Jul;6(7):559-65
16794638
J Immunol. 1992 Nov 15;149(10):3260-72
1431104
Clin Ther. 2002 Nov;24(11):1720-40; discussion 1719
12501870
J Immunol Methods. 2004 Sep;292(1-2):141-55
15350519
Transplantation. 2005 Feb 15;79(3 Suppl):S8-S11
15699753
Curr Protoc Immunol. 2004 May;Chapter 9:Unit 9.4
18432936
Adv Exp Med Biol. 2008;640:198-207
19065793
Nature. 1984 Dec 13-19;312(5995):643-6
6095115
Science. 1989 Jun 2;244(4908):1081-5
2471267
Nat Biotechnol. 2007 May;25(5):555-61
17483842
Orthop Rev. 1992 Sep;21(9):1034-42, 1130-1
1437254
Proc Natl Acad Sci U S A. 1984 Nov;81(21):6851-5
6436822
Biologicals. 2001 Sep-Dec;29(3-4):209-13
11851317
Methods Mol Biol. 2009;524:335-44
19377956
J Immunol Methods. 2003 Jul;278(1-2):127-44
12957402
Prog Clin Biol Res. 1980;47:107-17
6163155
J Clin Oncol. 2005 Sep 20;23(27):6719-29
16061911
Trends Biotechnol. 2006 Jun;24(6):274-80
16631266
Transplantation. 2006 Feb 15;81(3):308-15
16477212
Mol Immunol. 2009 Feb;46(5):840-7
18947876
Br J Cancer. 2004 Jun 14;90(12):2402-10
15162148
Scand J Immunol. 1996 Nov;44(5):478-84
8947599
Immunity. 1994 Jun;1(3):167-78
7534202
Annu Rev Immunol. 1994;12:117-39
8011279
J Mol Recognit. 2007 Mar-Apr;20(2):75-82
17205610
Protein Sci. 2006 Nov;15(11):2558-67
17001032
Immunol Invest. 1999 Mar-May;28(2-3):89-101
10484684
Blood. 2008 Jan 1;111(1):338-43
17895404
J Virol. 2005 Oct;79(19):12148-63
16160142
Int J Pharm. 2003 Nov 6;266(1-2):3-16
14559389
BMC Bioinformatics. 2008 Dec 02;9:514
19055730