Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules

Weflen, Andrew W.; Baier, Nina; Tang, Qing; Hof, Malon Van den; Blumberg, Richard S.; Lencer, Wayne I.; Massol, Ramiro

doi:10.1091/mbc.e13-04-0174

Cited by 85 publications

(90 citation statements)

References 44 publications

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“…From the results shown in the present study, we assume that the fate of multivalent immune complexes after FcgRIIdependent cellular uptake could also be fruitfully examined using a pH-dependent Ab against a multimeric Ag that forms immune complexes containing more than two Fc. Further studies could elucidate the differential intracellular trafficking of monomeric and multivalent immune complexes after FcgRII-mediated internalization (27). Considering that the Ag/Ab ratio, which changes during an immunological reaction, would affect the type of immune complex formed, further understanding of intracellular regulation of monomeric and multivalent immune complexes may provide some insight into the function of the immune complex (28).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…A previous study reported that monomeric red fluorescence protein-tagged FcRn expressed in the human endothelial cell line HMEC-1 is localized to both early endosomes and late endosomes/lysosomes, representing bidirectional transport of FcRn for recycling and constitutive degradation, respectively (Weflen et al, 2013). In this study, we also observed that a small fraction of FcRn-DsRed colocalizes with LAMP-1-positive late endosomes/lysosomes, and such colocalization significantly increases upon treatment of cells with lysosomal protease inhibitors, E64d/Leup/Pep.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Dynamics and Fate of a Humanized Anti–Interleukin-6 Receptor Monoclonal Antibody, Tocilizumab

Fujimoto¹,

Ida²,

Hirota³

et al. 2015

Mol Pharmacol

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Tocilizumab (TCZ), a humanized anti-interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, abrogates signal transducer protein gp130-mediated IL-6 signaling by competitively inhibiting the binding of IL-6 to the receptor, and shows clinical efficacy in autoimmune and inflammatory diseases. Despite accumulating evidence for therapeutic efficacy, the behavior and fate of TCZ at the cellular level remain largely unknown. To address this, we evaluated the endocytosis and intracellular trafficking of IL-6R in HeLa cells. The results of our study provide evidence that IL-6R is constitutively internalized from the cell surface by ligand or TCZ binding and the expression of gp130 in an independent manner and is targeted via endosomes without being significantly directed to the recycling pathway to, and degraded in, lysosomes. Furthermore, the cytoplasmic tail of IL-6R is required for constitutive endocytosis of the receptor, which is mediated by the clathrin and AP-2 complex. We further demonstrate that FcRn, whose function is to regulate the serum persistence of IgG, is confined primarily to early/recycling endosomes and rapidly transits between these compartments and late endosomes/ lysosomes without being degraded. Importantly, the expression of FcRn induces the segregation of TCZ from IL-6R, resulting in extensive colocalization of TCZ and FcRn in IL-6R-depleted endosomal compartments. Collectively, our results suggest that FcRn can accelerate the retrieval of the internalized TCZ, not only from endosomes but also from lysosomes. Our findings provide new insight into the mechanism by which the antibody internalized into cells is rescued from lysosomal degradation and into how its serum levels are maintained.

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“…Bispecific antigens like adalimumab, however, may also form large, cross-linked immune complexes. It remains open whether such cross- (25).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Piccand

Bessa

Schick

et al. 2015

AAPS J

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Abstract. The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immunetolerant offspring showed a slower adalimumab clearance (4.24±0.32 mL/day/kg) as compared to the control group (12.09±3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals.

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Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules

Cited by 85 publications

References 44 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

Intracellular Dynamics and Fate of a Humanized Anti–Interleukin-6 Receptor Monoclonal Antibody, Tocilizumab

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

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