FcγRIIB (CD32B) antibodies enhance immune responses through activating FcγRs

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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Identifiers

ORCID for Robert J. Oldham: orcid.org/0000-0002-8007-1145

ORCID for Martin C. Taylor: orcid.org/0009-0007-1696-4401

ORCID for Sonya James: orcid.org/0000-0002-0032-5935

ORCID for Yury Bogdanov: orcid.org/0000-0003-4667-5890

ORCID for Mark S. Cragg: orcid.org/0000-0003-2077-089X

ORCID for Ali Roghanian: orcid.org/0000-0003-1316-4218

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