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FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs

FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs
FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs
Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory Fc gamma receptor (FcγRIIB/CD32B; referred to as FcγRII/CD32 in mice) restrains the immune response, specifically through regulating immunoglobulin G (IgG) effector functions. FcγRII-deficient mice demonstrate elevated incidence and severity of autoimmunity and increased responses to immunization and infections. To explore the potential of FcγRIIB as a target for augmenting vaccines, we tested the ability of monoclonal antibodies (mAb) against mouse FcγRII and human FcγRIIB to enhance humoral responses in preclinical models. We used wild-type (WT), FcγR-deficient, and human FcγRIIB transgenic (Tg) mice with either a functional intracellular domain (hFcγRIIB Tg) or lacking immunoreceptor tyrosine-based inhibitory motif (ITIM) signalling capacity (NoTIM). Targeting mouse FcγRII and human FcγRIIB with antibodies significantly augmented humoral immune responses against experimental antigens and enhanced tumour clearance in vivo. Surprisingly, mAbs without a functional Fc (N297Q; referred to as Fc-null) lacked efficacy. Similarly, blocking FcγRII in mice lacking activating FcγRs failed to enhance immune responses. Conversely, blocking both signalling-competent and signalling-defective (NoTIM) FcγRIIB in Tg mice with a WT, but not Fc-null, FcγRIIB mAb equally enhanced immunity. These data indicate the redundancy of inhibitory signalling in potentiating immune responses in vivo. Collectively, our data suggest that mAb-targeting of FcγRIIB stabilizes mAb Fc and enhances immune responses via Fc-mediated crosslinking of activating FcγRs, irrespective of the inhibitory function of FcγRIIB. These findings support a strategy to boost immune responses in immunization protocols.
0009-9104
Simpson, Alexander P.
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Oldham, Robert J.
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Cox, Kerry L.
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Taylor, Martin C.
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James, Sonya
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Bogdanov, Yury
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Glennie, Martin J.
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Frendeus, Bjorn
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Cragg, Mark S.
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Roghanian, Ali
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Simpson, Alexander P.
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Oldham, Robert J.
844b9bff-16f0-4577-abba-b35afd02b923
Cox, Kerry L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Taylor, Martin C.
9e6d2e6d-5e00-4610-8ec6-5f117296124a
James, Sonya
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Bogdanov, Yury
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Glennie, Martin J.
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Frendeus, Bjorn
3c6a6739-3319-4ae5-8019-d54470e2f444
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Roghanian, Ali
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Simpson, Alexander P., Oldham, Robert J., Cox, Kerry L., Taylor, Martin C., James, Sonya, Bogdanov, Yury, Glennie, Martin J., Frendeus, Bjorn, Cragg, Mark S. and Roghanian, Ali (2025) FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs. Clinical and Experimental Immunology, 219 (1), [uxaf015]. (doi:10.1093/cei/uxaf015).

Record type: Article

Abstract

Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory Fc gamma receptor (FcγRIIB/CD32B; referred to as FcγRII/CD32 in mice) restrains the immune response, specifically through regulating immunoglobulin G (IgG) effector functions. FcγRII-deficient mice demonstrate elevated incidence and severity of autoimmunity and increased responses to immunization and infections. To explore the potential of FcγRIIB as a target for augmenting vaccines, we tested the ability of monoclonal antibodies (mAb) against mouse FcγRII and human FcγRIIB to enhance humoral responses in preclinical models. We used wild-type (WT), FcγR-deficient, and human FcγRIIB transgenic (Tg) mice with either a functional intracellular domain (hFcγRIIB Tg) or lacking immunoreceptor tyrosine-based inhibitory motif (ITIM) signalling capacity (NoTIM). Targeting mouse FcγRII and human FcγRIIB with antibodies significantly augmented humoral immune responses against experimental antigens and enhanced tumour clearance in vivo. Surprisingly, mAbs without a functional Fc (N297Q; referred to as Fc-null) lacked efficacy. Similarly, blocking FcγRII in mice lacking activating FcγRs failed to enhance immune responses. Conversely, blocking both signalling-competent and signalling-defective (NoTIM) FcγRIIB in Tg mice with a WT, but not Fc-null, FcγRIIB mAb equally enhanced immunity. These data indicate the redundancy of inhibitory signalling in potentiating immune responses in vivo. Collectively, our data suggest that mAb-targeting of FcγRIIB stabilizes mAb Fc and enhances immune responses via Fc-mediated crosslinking of activating FcγRs, irrespective of the inhibitory function of FcγRIIB. These findings support a strategy to boost immune responses in immunization protocols.

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Accepted/In Press date: 11 March 2025
e-pub ahead of print date: 16 March 2025
Published date: 2 May 2025

Identifiers

Local EPrints ID: 502084
URI: http://eprints.soton.ac.uk/id/eprint/502084
ISSN: 0009-9104
PURE UUID: 39387474-10c2-425a-941b-b9fc36700676
ORCID for Robert J. Oldham: ORCID iD orcid.org/0000-0002-8007-1145
ORCID for Martin C. Taylor: ORCID iD orcid.org/0009-0007-1696-4401
ORCID for Sonya James: ORCID iD orcid.org/0000-0002-0032-5935
ORCID for Yury Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Ali Roghanian: ORCID iD orcid.org/0000-0003-1316-4218

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Date deposited: 16 Jun 2025 16:46
Last modified: 04 Sep 2025 02:09

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Contributors

Author: Alexander P. Simpson
Author: Robert J. Oldham ORCID iD
Author: Kerry L. Cox
Author: Martin C. Taylor ORCID iD
Author: Sonya James ORCID iD
Author: Yury Bogdanov ORCID iD
Author: Bjorn Frendeus
Author: Mark S. Cragg ORCID iD
Author: Ali Roghanian ORCID iD

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