FcγRIIB controls the potency of agonistic anti-TNFR mAbs
FcγRIIB controls the potency of agonistic anti-TNFR mAbs
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 Fc←RIIB 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.
Anti-CD40, isotype, immunomodulatory, cancer therapy, CIMT 2012Immunomodulatory anti-
941-948
White, Ann L.
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Chan, H. T. Claude
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French, Ruth R.
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Beers, Stephen A.
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Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Johnson, Peter W. M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Glennie, Martin J.
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May 2013
White, Ann L.
b8c81272-e959-4acb-bbfe-1adc8a6c43f0
Chan, H. T. Claude
b109c93f-7e9a-44ee-ad12-da757b1b11fc
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Johnson, Peter W. M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
White, Ann L., Chan, H. T. Claude, French, Ruth R., Beers, Stephen A., Cragg, Mark S., Johnson, Peter W. M. and Glennie, Martin J.
(2013)
FcγRIIB controls the potency of agonistic anti-TNFR mAbs.
Cancer Immunology Immunotherapy, 62 (5), .
(doi:10.1007/s00262-013-1398-6).
(PMID:23543215)
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 Fc←RIIB 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.
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e-pub ahead of print date: 31 March 2013
Published date: May 2013
Keywords:
Anti-CD40, isotype, immunomodulatory, cancer therapy, CIMT 2012Immunomodulatory anti-
Organisations:
Cancer Sciences
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Local EPrints ID: 350764
URI: http://eprints.soton.ac.uk/id/eprint/350764
ISSN: 0340-7004
PURE UUID: b7db9d52-a96a-433d-ae8e-55384f4061b4
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Date deposited: 05 Apr 2013 09:36
Last modified: 15 Mar 2024 03:08
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Author:
Ann L. White
Author:
H. T. Claude Chan
Author:
Ruth R. French
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