Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice.
IgE-mediated hypersensitivity is central to the pathogenesis of asthma and other allergic diseases. Although neutralization of serum IgE with IgE-specific antibodies is in general an efficacious treatment for allergic asthma, one limitation of this approach is its lack of effect on IgE production. Here, we have developed a strategy to disrupt IgE production by generating monoclonal antibodies that target a segment of membrane IgE on human IgE-switched B cells that is not present in serum IgE. This segment is known as the M1' domain, and using genetically modified mice that contain the human M1' domain inserted into the mouse IgE locus, we demonstrated that M1'-specific antibodies reduced serum IgE and IgE-producing plasma cells in vivo, without affecting other immunoglobulin isotypes. M1'-specific antibodies were effective when delivered prophylactically and therapeutically in mouse models of immunization, allergic asthma, and Nippostrongylus brasiliensis infection, likely by inducing apoptosis of IgE-producing B cells. In addition, we generated a humanized M1'-specific antibody that was active on primary human cells in vivo, as determined by its reduction of serum IgE levels and IgE plasma cell numbers in a human PBMC-SCID mouse model. Thus, targeting of human IgE-producing B cells with apoptosis-inducing M1'-specific antibodies may be a novel treatment for asthma and allergy.
Brightbill
Hans D
HD
Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
Jeet
Surinder
S
Lin
Zhonghua
Z
Yan
Donghong
D
Zhou
Meijuan
M
Tan
Martha
M
Nguyen
Allen
A
Yeh
Sherry
S
Delarosa
Donnie
D
Leong
Steven R
SR
Wong
Terence
T
Chen
Yvonne
Y
Ultsch
Mark
M
Luis
Elizabeth
E
Ramani
Sree Ranjani
SR
Jackman
Janet
J
Gonzalez
Lino
L
Dennis
Mark S
MS
Chuntharapai
Anan
A
DeForge
Laura
L
Meng
Y Gloria
YG
Xu
Min
M
Eigenbrot
Charles
C
Lee
Wyne P
WP
Refino
Canio J
CJ
Balazs
Mercedesz
M
Wu
Lawren C
LC
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D007114:Immunization; D051379:Mice; D016513:Mice, SCID / Q000276:immunology*; D008822:Mice, Transgenic; D009559:Nippostrongylus / Q000187:drug effects / Q000276:immunology
D000906:Antibodies; D000911:Antibodies, Monoclonal
J Immunol. 1992 Jan 1;148(1):129-36
1727861
Allergy Proc. 1993 Nov-Dec;14(6):413-6
7512517
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Methods Enzymol. 1997;276:307-26
27754618
N Engl J Med. 1999 Dec 23;341(26):1966-73
10607813
J Exp Med. 1992 Jan 1;175(1):289-92
1370532
J Clin Invest. 1997 Mar 1;99(5):879-87
9062345
Cell Immunol. 1994 Sep;157(2):369-80
8069922
J Immunol. 1997 Feb 1;158(3):1438-45
9013989
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Immunol Rev. 1980;52:29-53
6790420
Blood. 1998 Mar 1;91(5):1633-43
9473229
Eur J Immunol. 1992 Jul;22(7):1827-34
1623926
Immunol Lett. 2005 Jan 31;96(2):187-94
15585322
J Immunol. 2008 Apr 15;180(8):5499-505
18390733
Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11392-7
15273292
J Immunol. 1985 May;134(5):3291-7
3980994
J Immunol. 2005 Oct 1;175(7):4167-73
16177053
Biotechnology (N Y). 1991 Jan;9(1):53-6
1370037
Allergy Asthma Proc. 2005 Nov-Dec;26(6):428-34
16541964
J Exp Med. 1995 Feb 1;181(2):515-25
7836908
Int Arch Allergy Appl Immunol. 1989;90 Suppl 1:45-50
2613352
J Immunol. 1995 Jan 1;154(1):209-18
7995941
Proc Natl Acad Sci U S A. 1990 May;87(9):3363-7
2185467
J Immunol. 1995 Aug 15;155(4):1930-41
7636244
Immunity. 2007 Feb;26(2):191-203
17292640
J Immunol. 1993 Jan 15;150(2):407-18
8419474
J Immunol. 1994 Jan 1;152(1):51-7
8254205
Nature. 2008 Jul 24;454(7203):445-54
18650915
J Exp Med. 1994 Jun 1;179(6):2023-6
8195724
Immunology. 1997 Jul;91(3):464-72
9301538
J Immunol. 1999 May 1;162(9):5624-30
10228046
Nat Rev Immunol. 2002 Dec;2(12):945-56
12461567
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7528-32
1881893
J Exp Med. 1983 Feb 1;157(2):772-88
6600492
J Allergy Clin Immunol. 2001 Mar;107(3):429-40
11240941
Eur J Immunol. 1987 Jul;17(7):981-90
3497044
Adv Immunol. 2007;95:83-110
17869611
EMBO J. 1982;1(9):1117-23
6329728
Int Arch Allergy Appl Immunol. 1983;71(2):182-4
6840875
Nat Rev Immunol. 2008 Mar;8(3):205-17
18301424
Nucleic Acids Res. 1995 Dec 11;23(23):4805-11
8532522
J Mol Biol. 1993 Feb 20;229(4):969-95
8095303
J Biol Chem. 2001 Mar 2;276(9):6591-604
11096108
Eur J Immunol. 1993 Jan;23(1):159-67
8419166
Nat Rev Immunol. 2002 Oct;2(10):773-86
12360215
Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1373-82
11567148
Proc Natl Acad Sci U S A. 1990 Oct;87(20):7829-33
2122447
J Exp Med. 1992 Jul 1;176(1):233-43
1613458
J Exp Med. 2004 Jun 21;199(12):1659-69
15210744
Mol Immunol. 1992 Oct;29(10):1159-64
1528190
Annu Rev Immunol. 1998;16:645-70
9597145
Eur J Immunol. 1996 Dec;26(12):3042-7
8977302
Trends Immunol. 2003 Jun;24(6):343-9
12810111
J Allergy Clin Immunol. 2004 Feb;113(2):297-302
14767445
Nat Med. 2009 Jul;15(7):766-73
19561618
Adv Immunol. 2007;93:63-119
17383539
Eur J Immunol. 1998 Feb;28(2):570-81
9521067
J Allergy Clin Immunol. 2005 Mar;115(3):S376-85
15753882
Trends Pharmacol Sci. 2002 Jul;23(7):316-24
12119152
J Exp Med. 2003 May 5;197(9):1125-39
12719481
J Immunol. 1983 Jan;130(1):350-6
6600186
J Immunol. 2005 Jan 15;174(2):817-26
15634903
J Allergy Clin Immunol. 2004 Sep;114(3):527-30
15356552
Int Arch Allergy Appl Immunol. 1991;95(2-3):202-6
1937922
J Immunol. 2009 Jun 15;182(12):8110-7
19494337
Clin Exp Allergy. 2009 Sep;39(9):1307-13
19489847
Annu Rev Immunol. 2003;21:579-628
12500981
Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):45-7
7613209
Int Immunol. 1995 Nov;7(11):1799-807
8580078