title: FcγRΙΙB controls the potency of agonistic anti-TNFR mAbs.
abstract: Isotype plays a crucial role in therapeutic monoclonal antibody (mAb) function, mediated in large part through differences in Fcγ receptor (FcγR) interaction. Monoclonal Abs such as rituximab and alemtuzumab, which bind target cells directly, are designed for efficient recruitment of immune effector cells through their activatory FcγR engagement to mediate maximal target cell killing. In this setting, binding to inhibitory FcγRIIB is thought to inhibit function, making mAbs with high activatory/inhibitory (A/I) FcγR binding ratios, such as mouse IgG2a and human IgG1, the first choice for this role. In contrast, exciting new data show that agonistic mAbs directed against the tumour necrosis factor receptor superfamily member CD40 require interaction with FcγRIIB for in vivo function. Such ligation activates antigen-presenting cells, promotes myeloid and CTL responses and potentially stimulates effective anti-cancer immunity. It appears that the role of FcγRIIB is to mediate mAb hyper-crosslinking to allow CD40 downstream intracellular signalling. Previous work has shown that mAbs directed against other TNFR family members, Fas and death receptor 5 and probably death receptor 4, also require FcγRIIB hyper-crosslinking to promote target cell apoptosis, suggesting a common mechanism of action. In mouse models, IgG1 is optimal for these agents as it binds to FcγRIIB with tenfold higher affinity than IgG2a and hence has a relatively low A:I FcγR binding ratio. In contrast, human IgG isotypes have a universally low affinity for FcγRIIB, but in the case of human IgG1, engineering the Fc to increase its affinity for FcγRIIB can potentially overcome this problem. Thus, modifying the A/I binding ratio of human IgG Fc can be used to optimise different types of therapeutic activity by enhancing cytotoxic or hyper-crosslinking function.
authors.affiliation: Antibody and Vaccine Group, MP88, Cancer Sciences Unit, Faculty of Medicine, Southampton University Hospital, Tremona Road, Southampton, SO16 0XA, UK. alw1@soton.ac.uk
authors.forename: Ann L
authors.initials: AL
authors.lastname: White
authors.forename: H T Claude
authors.initials: HT
authors.lastname: Chan
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Beers
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011485:Protein Binding; D017452:Receptors, IgG / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D017452:Receptors, IgG; D018124:Receptors, Tumor Necrosis Factor
references.citation: J Clin Oncol. 2003 Nov 1;21(21):3940-7
references.pmid: 12975461
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Curr Opin Pharmacol. 2004 Aug;4(4):360-7
references.pmid: 15251129
references.citation: Blood. 2010 Jun 24;115(25):5191-201
references.pmid: 20223920
references.citation: J Immunol. 2001 Apr 15;166(8):4891-8
references.pmid: 11290766
references.citation: N Engl J Med. 2007 Jul 5;357(1):39-51
references.pmid: 17611206
references.citation: Aliment Pharmacol Ther. 2005 Jul 15;22(2):111-22
references.pmid: 16011669
references.citation: Blood. 2009 Apr 16;113(16):3716-25
references.pmid: 19018092
references.citation: Clin Exp Immunol. 2009 Jul;157(1):9-19
references.pmid: 19659765
references.citation: Blood. 2011 Sep 1;118(9):2530-40
references.pmid: 21768293
references.citation: J Immunol. 2003 Jul 15;171(2):562-8
references.pmid: 12847219
references.citation: Science. 2003 Aug 1;301(5633):640-3
references.pmid: 12855817
references.citation: Nat Med. 2000 Apr;6(4):443-6
references.pmid: 10742152
references.citation: Int Immunol. 1999 Jan;11(1):11-20
references.pmid: 10050669
references.citation: Science. 2011 Mar 25;331(6024):1612-6
references.pmid: 21436454
references.citation: Blood. 2008 Aug 15;112(4):1205-13
references.pmid: 18495955
references.citation: J Clin Oncol. 2009 Mar 1;27(7):1122-9
references.pmid: 19164213
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128
references.citation: J Exp Med. 2006 Mar 20;203(3):743-53
references.pmid: 16520392
references.citation: Blood. 2008 Aug 1;112(3):711-20
references.pmid: 18497318
references.citation: Int Rev Immunol. 2012 Aug;31(4):279-88
references.pmid: 22804572
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Nat Biotechnol. 2005 Sep;23(9):1073-8
references.pmid: 16151394
references.citation: J Immunol. 2002 Mar 15;168(6):2720-8
references.pmid: 11884438
references.citation: J Leukoc Biol. 2000 Jan;67(1):2-17
references.pmid: 10647992
references.citation: Haematologica. 2010 May;95(5):845-8
references.pmid: 20133895
references.citation: Haematologica. 2010 Jan;95(1):135-43
references.pmid: 19773256
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: J Exp Med. 2012 Feb 13;209(2):201-9
references.pmid: 22330682
references.citation: Mol Immunol. 2008 Sep;45(15):3926-33
references.pmid: 18691763
references.citation: Blood. 2002 Feb 1;99(3):754-8
references.pmid: 11806974
references.citation: J Exp Med. 2003 Apr 21;197(8):955-66
references.pmid: 12707299
references.citation: J Clin Oncol. 2008 Apr 10;26(11):1789-96
references.pmid: 18347005
references.citation: J Clin Oncol. 2009 Sep 10;27(26):4371-7
references.pmid: 19636010
references.citation: J Exp Med. 2004 Feb 16;199(4):437-48
references.pmid: 14769851
references.citation: J Immunol. 2011 Aug 15;187(4):1754-63
references.pmid: 21742972
references.citation: Cancer Immun. 2012;12:13
references.pmid: 22896758
references.citation: Science. 2005 Dec 2;310(5753):1510-2
references.pmid: 16322460
references.citation: J Clin Oncol. 2007 Mar 1;25(7):876-83
references.pmid: 17327609
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1083-8
references.pmid: 17317815
references.citation: Science. 2011 Aug 19;333(6045):1030-4
references.pmid: 21852502
references.citation: Semin Oncol. 1999 Oct;26(5 Suppl 14):52-7
references.pmid: 10561018
references.citation: Nat Rev Immunol. 2010 May;10(5):317-27
references.pmid: 20414205
references.citation: J Exp Med. 2004 Jun 21;199(12):1659-69
references.pmid: 15210744
references.citation: Immunity. 2005 Jul;23(1):41-51
references.pmid: 16039578
references.citation: Eur J Immunol. 1994 Nov;24(11):2714-9
references.pmid: 7525301
references.citation: Nature. 2011 Dec 21;480(7378):480-9
references.pmid: 22193102
references.citation: Nat Rev Immunol. 2010 May;10(5):328-43
references.pmid: 20414206
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16723-8
references.pmid: 21933959
references.citation: J Immunol Methods. 2001 Feb 1;248(1-2):139-47
references.pmid: 11223075
references.citation: Blood. 2011 Jul 14;118(2):358-67
references.pmid: 21444918
references.citation: Annu Rev Immunol. 1998;16:111-35
references.pmid: 9597126
references.citation: Drug Discov Today. 2007 Nov;12(21-22):898-910
references.pmid: 17993407
references.citation: Nat Med. 1999 May;5(5):548-53
references.pmid: 10229232
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):10966-71
references.pmid: 22723355
references.citation: Cancer Cell. 2011 Jan 18;19(1):101-13
references.pmid: 21251615
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6181-6
references.pmid: 22474370