FcγRIIb on Liver Sinusoidal Endothelium Clears Small Immune Complexes

Ganesan, Latha P.; Kim, Jonghan; Wu, Yun; Mohanty, Sudhasri; Phillips, Gary; Birmingham, Daniel J.; Robinson, John M.; Anderson, Clark L.

doi:10.4049/jimmunol.1202017

Cited by 140 publications

(196 citation statements)

References 41 publications

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“…Whereas Ag clearance was largely maintained in FcR g-chain knockout mice and FcgRIII knockout mice, it was clearly diminished in FcgRII knockout mice, demonstrating that FcgRII, which is an inhibitory FcgR, is the main contributor to intracellular uptake of monomeric immune complexes in vivo. Although it has long been said that FcgRII could take multivalent immune complexes up into the cell in a noninflammatory way (13), to our knowledge this is the first report revealing that inhibitory FcgRIIb can efficiently internalize monomeric immune complexes without cross-linking the receptor in vivo. Furthermore, studies using PH-mIgG1-Fy in FcgRIII knockout mice and PH-v12 in hFcgRIIb Tg mice (Abs with enhanced binding to FcgRII/III in mice or FcgRIIb in humans, respectively) showed that Ag clearance was accelerated without shortening Ab half-life (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…However, the in vivo behavior of multivalent immune complexes still remains to be elucidated. It has been said that multivalent immune complexes were eliminated by FcgR in vivo and the fact that multivalent immune complexes are constitutively eliminated through FcgRII expressed on liver sinusoidal endothelial cells in mice (11)(12)(13)(14)(15) indicates that multivalent immune complexes bound to mFcgRII would be internalized and transferred to lysosome in vivo. Alternatively, it was also shown by an in vitro study that hFcgRIIb has a recycling capability and that an immune complex internalized by hFcgRIIb is constitutively recycled to the cell surface after internalization (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, a monomeric immune complex containing a single Fc, that is, a complex of 1:1 or 1:2 formed by one Ab with one or two Ags, is not internalized by FcgR, because the monovalent interaction between Fc and FcgR is weak (11)(12)(13)(14)(15). Moreover, studies have shown that FcgR does not affect the clearance of Ab itself, which suggests that FcgR does not contribute to the internalization and clearance of monomeric immune complex in vivo (16,17).…”

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confidence: 99%

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Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering

Iwayanagi¹,

Igawa²,

Maeda³

et al. 2015

The Journal of Immunology

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Fc engineering can modulate the Fc–FcγR interaction and thus enhance the potency of Abs that target membrane-bound Ags, but it has not been applied to Abs that target soluble Ags. In this study, we revealed a previously unknown function of inhibitory FcγRII in vivo and, using an Ab that binds to Ag pH dependently, demonstrated that the function can be exploited to target soluble Ag. Because pH-dependent Ab dissociates Ag in acidic endosome, its Ag clearance from circulation reflects the cellular uptake rate of Ag/Ab complexes. In vivo studies showed that FcγR but not neonatal FcR contributes to Ag clearance by the pH-dependent Ab, and when Fc binding to mouse FcγRII and III was increased, Ag clearance was markedly accelerated in wild-type mice and FcR γ-chain knockout mice, but the effect was diminished in FcγRII knockout mice. This demonstrates that mouse FcγRII efficiently promotes Ab uptake into the cell and its subsequent recycling back to the cell surface. Furthermore, when a human IgG1 Fc variant with selectively increased binding to human FcγRIIb was tested in human FcγRIIb transgenic mice, Ag clearance was accelerated without compromising the Ab half-life. Taken together, inhibitory FcγRIIb was found to play a prominent role in the cellular uptake of monomeric Ag/Ab immune complexes in vivo, and when the Fc of a pH-dependent Ab was engineered to selectively enhance human FcγRIIb binding, the Ab could accelerate soluble Ag clearance from circulation. We assume such a function would enhance the therapeutic potency of Abs that target soluble Ags.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering

Iwayanagi¹,

Igawa²,

Maeda³

et al. 2015

The Journal of Immunology

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“…After 10 to 30 minutes, the rounded morphology of B cells was lost and RFP fluorescence appeared more diffuse, possibly reflecting B cell death and/or degradation. The liver contains Kupffer cells (KCs), a population of highly phagocytic tissular macrophages, lining the sinusoids and expressing FcRs (11). When mice were injected with clodronate liposomes, a treatment that efficiently removed KCs (Figure 2A), anti-CD20 treatment was no longer effective (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

The mechanism of anti-CD20–mediated B cell depletion revealed by intravital imaging

Montalvão¹,

Garcia²,

Celli³

et al. 2013

J. Clin. Invest.

164

151

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Anti-CD20 Ab therapy has proven successful for treating B cell malignancies and a number of autoimmune diseases. However, how anti-CD20 Abs operate in vivo to mediate B cell depletion is not fully understood. In particular, the anatomical location, the type of effector cells, and the mechanism underlying anti-CD20 therapy remain uncertain. Here, we found that the liver is a major site for B cell depletion and that recirculation accounts for the decrease in B cell numbers observed in secondary lymphoid organs. Using intravital imaging, we established that, upon anti-CD20 treatment, Kupffer cells (KCs) mediate the abrupt arrest and subsequent engulfment of B cells circulating in the liver sinusoids. KCs were also effective in depleting malignant B cells in a model of spontaneous lymphoma. Our results identify Ab-dependent cellular phagocytosis by KCs as a primary mechanism of anti-CD20 therapy and provide an experimental framework for optimizing the efficacy of therapeutic Abs. IntroductionAnti-CD20 therapy mediates the depletion of B cells and represents a breakthrough in the treatment of B cell malignancies and autoimmune disorders (1-3). Multiple underlying mechanisms have been proposed, including complement-dependent cytotoxicity, Ab-dependent cell-mediated cytotoxicity, and Ab-dependent cellular phagocytosis. Preclinical studies have highlighted the importance of Fc receptor-dependent (FcR-dependent) processes for B cell depletion (4, 5), a finding consistent with the observed influence of FcR polymorphism on the efficiency of anti-CD20 therapy in humans (6). Many immune cells, including NK cells, macrophages, and monocytes, kill anti-CD20-coated B cells in vitro and/or are required for depletion in murine models (4,5,7). Paradoxically, despite more than 15 years of clinical experience, the anatomical location, the precise immune cell type, and the mechanism underlying anti-CD20 therapy remain incompletely understood (8). Addressing these questions remains critical to facilitate the design of improved therapeutic Abs. Here, we used a combination of surgical procedures, intravital 2-photon imaging, and a spontaneous tumor model to uncover the mechanism by which anti-CD20 injection results in the clearance of normal and malignant B cells.

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“…2B versus Fig. 3) is consistent with a mechanism for rapid hepatic elimination of ICs (Løvdal et al, 2000;Ganesan et al, 2012).…”

Section: Resultsmentioning

confidence: 49%

The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

Brunn

Mauze

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Administration of biologics to enhance T-cell function is part of a rapidly growing field of cancer immunotherapy demonstrated by the unprecedented clinical success of several immunoregulatory receptor targeting antibodies. While these biologic agents confer significant anti-tumor activity through targeted immune response modulation, they can also elicit broad immune responses potentially including the production of anti-drug antibodies (ADAs). DTA-1, an agonist monoclonal antibody against GITR, is a highly effective anti-tumor treatment in preclinical models. We demonstrate that repeated dosing with murinized DTA-1 (mDTA-1) generates ADAs with corresponding reductions in drug exposure and engagement of GITR on circulating CD31 CD4 1 T cells, due to rapid hepatic drug uptake and catabolism. Mice implanted with tumors after induction of preexisting mDTA-1 ADA show no anti-tumor efficacy when given 3 mg/kg mDTA-1, an efficacious dose in naive mice. Nonetheless, increasing mDTA-1 treatment to 30 mg/kg in ADA-positive mice restores mDTA-1 exposure and GITR engagement on circulating CD3

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FcγRIIb on Liver Sinusoidal Endothelium Clears Small Immune Complexes

Cited by 140 publications

References 41 publications

Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering

Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering

The mechanism of anti-CD20–mediated B cell depletion revealed by intravital imaging

The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

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