title: Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice.
abstract: 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.
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Brightbill
authors.forename: Surinder
authors.initials: S
authors.lastname: Jeet
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Donghong
authors.initials: D
authors.lastname: Yan
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.forename: Martha
authors.initials: M
authors.lastname: Tan
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.forename: Sherry
authors.initials: S
authors.lastname: Yeh
authors.forename: Donnie
authors.initials: D
authors.lastname: Delarosa
authors.forename: Steven R
authors.initials: SR
authors.lastname: Leong
authors.forename: Terence
authors.initials: T
authors.lastname: Wong
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.forename: Sree Ranjani
authors.initials: SR
authors.lastname: Ramani
authors.forename: Janet
authors.initials: J
authors.lastname: Jackman
authors.forename: Lino
authors.initials: L
authors.lastname: Gonzalez
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: Anan
authors.initials: A
authors.lastname: Chuntharapai
authors.forename: Laura
authors.initials: L
authors.lastname: DeForge
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Canio J
authors.initials: CJ
authors.lastname: Refino
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
mesh_terms: 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
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal
references.citation: J Immunol. 1992 Jan 1;148(1):129-36
references.pmid: 1727861
references.citation: Allergy Proc. 1993 Nov-Dec;14(6):413-6
references.pmid: 7512517
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: N Engl J Med. 1999 Dec 23;341(26):1966-73
references.pmid: 10607813
references.citation: J Exp Med. 1992 Jan 1;175(1):289-92
references.pmid: 1370532
references.citation: J Clin Invest. 1997 Mar 1;99(5):879-87
references.pmid: 9062345
references.citation: Cell Immunol. 1994 Sep;157(2):369-80
references.pmid: 8069922
references.citation: J Immunol. 1997 Feb 1;158(3):1438-45
references.pmid: 9013989
references.citation: Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
references.pmid: 15299374
references.citation: Immunol Rev. 1980;52:29-53
references.pmid: 6790420
references.citation: Blood. 1998 Mar 1;91(5):1633-43
references.pmid: 9473229
references.citation: Eur J Immunol. 1992 Jul;22(7):1827-34
references.pmid: 1623926
references.citation: Immunol Lett. 2005 Jan 31;96(2):187-94
references.pmid: 15585322
references.citation: J Immunol. 2008 Apr 15;180(8):5499-505
references.pmid: 18390733
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11392-7
references.pmid: 15273292
references.citation: J Immunol. 1985 May;134(5):3291-7
references.pmid: 3980994
references.citation: J Immunol. 2005 Oct 1;175(7):4167-73
references.pmid: 16177053
references.citation: Biotechnology (N Y). 1991 Jan;9(1):53-6
references.pmid: 1370037
references.citation: Allergy Asthma Proc. 2005 Nov-Dec;26(6):428-34
references.pmid: 16541964
references.citation: J Exp Med. 1995 Feb 1;181(2):515-25
references.pmid: 7836908
references.citation: Int Arch Allergy Appl Immunol. 1989;90 Suppl 1:45-50
references.pmid: 2613352
references.citation: J Immunol. 1995 Jan 1;154(1):209-18
references.pmid: 7995941
references.citation: Proc Natl Acad Sci U S A. 1990 May;87(9):3363-7
references.pmid: 2185467
references.citation: J Immunol. 1995 Aug 15;155(4):1930-41
references.pmid: 7636244
references.citation: Immunity. 2007 Feb;26(2):191-203
references.pmid: 17292640
references.citation: J Immunol. 1993 Jan 15;150(2):407-18
references.pmid: 8419474
references.citation: J Immunol. 1994 Jan 1;152(1):51-7
references.pmid: 8254205
references.citation: Nature. 2008 Jul 24;454(7203):445-54
references.pmid: 18650915
references.citation: J Exp Med. 1994 Jun 1;179(6):2023-6
references.pmid: 8195724
references.citation: Immunology. 1997 Jul;91(3):464-72
references.pmid: 9301538
references.citation: J Immunol. 1999 May 1;162(9):5624-30
references.pmid: 10228046
references.citation: Nat Rev Immunol. 2002 Dec;2(12):945-56
references.pmid: 12461567
references.citation: Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7528-32
references.pmid: 1881893
references.citation: J Exp Med. 1983 Feb 1;157(2):772-88
references.pmid: 6600492
references.citation: J Allergy Clin Immunol. 2001 Mar;107(3):429-40
references.pmid: 11240941
references.citation: Eur J Immunol. 1987 Jul;17(7):981-90
references.pmid: 3497044
references.citation: Adv Immunol. 2007;95:83-110
references.pmid: 17869611
references.citation: EMBO J. 1982;1(9):1117-23
references.pmid: 6329728
references.citation: Int Arch Allergy Appl Immunol. 1983;71(2):182-4
references.pmid: 6840875
references.citation: Nat Rev Immunol. 2008 Mar;8(3):205-17
references.pmid: 18301424
references.citation: Nucleic Acids Res. 1995 Dec 11;23(23):4805-11
references.pmid: 8532522
references.citation: J Mol Biol. 1993 Feb 20;229(4):969-95
references.pmid: 8095303
references.citation: J Biol Chem. 2001 Mar 2;276(9):6591-604
references.pmid: 11096108
references.citation: Eur J Immunol. 1993 Jan;23(1):159-67
references.pmid: 8419166
references.citation: Nat Rev Immunol. 2002 Oct;2(10):773-86
references.pmid: 12360215
references.citation: Acta Crystallogr D Biol Crystallogr. 2001 Oct;57(Pt 10):1373-82
references.pmid: 11567148
references.citation: Proc Natl Acad Sci U S A. 1990 Oct;87(20):7829-33
references.pmid: 2122447
references.citation: J Exp Med. 1992 Jul 1;176(1):233-43
references.pmid: 1613458
references.citation: J Exp Med. 2004 Jun 21;199(12):1659-69
references.pmid: 15210744
references.citation: Mol Immunol. 1992 Oct;29(10):1159-64
references.pmid: 1528190
references.citation: Annu Rev Immunol. 1998;16:645-70
references.pmid: 9597145
references.citation: Eur J Immunol. 1996 Dec;26(12):3042-7
references.pmid: 8977302
references.citation: Trends Immunol. 2003 Jun;24(6):343-9
references.pmid: 12810111
references.citation: J Allergy Clin Immunol. 2004 Feb;113(2):297-302
references.pmid: 14767445
references.citation: Nat Med. 2009 Jul;15(7):766-73
references.pmid: 19561618
references.citation: Adv Immunol. 2007;93:63-119
references.pmid: 17383539
references.citation: Eur J Immunol. 1998 Feb;28(2):570-81
references.pmid: 9521067
references.citation: J Allergy Clin Immunol. 2005 Mar;115(3):S376-85
references.pmid: 15753882
references.citation: Trends Pharmacol Sci. 2002 Jul;23(7):316-24
references.pmid: 12119152
references.citation: J Exp Med. 2003 May 5;197(9):1125-39
references.pmid: 12719481
references.citation: J Immunol. 1983 Jan;130(1):350-6
references.pmid: 6600186
references.citation: J Immunol. 2005 Jan 15;174(2):817-26
references.pmid: 15634903
references.citation: J Allergy Clin Immunol. 2004 Sep;114(3):527-30
references.pmid: 15356552
references.citation: Int Arch Allergy Appl Immunol. 1991;95(2-3):202-6
references.pmid: 1937922
references.citation: J Immunol. 2009 Jun 15;182(12):8110-7
references.pmid: 19494337
references.citation: Clin Exp Allergy. 2009 Sep;39(9):1307-13
references.pmid: 19489847
references.citation: Annu Rev Immunol. 2003;21:579-628
references.pmid: 12500981
references.citation: Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):45-7
references.pmid: 7613209
references.citation: Int Immunol. 1995 Nov;7(11):1799-807
references.pmid: 8580078