Targeting FcRn to Generate Antibody-Based Therapeutics

Ward, E. Sally; Ober, Raimund J.

doi:10.1016/j.tips.2018.07.007

Cited by 85 publications

(78 citation statements)

References 100 publications

(139 reference statements)

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“…IgG can bind to multiple types of activating FcgRs that can promote numerous effector functions, such as antibody-dependent cytotoxicity and opsonization, as well as an inhibitory FcgR, FcgRIIb, that plays an immunomodulatory role (Bournazos and Ravetch, 2017). FcRn is responsible for endosomal recycling of IgG and thereby ensuring that IgG has a long (3 week) serum half-life (Ward and Ober, 2018). A large fraction of IgE is bound to FcεRI, a high-affinity receptor abundant on mast cells and basophils; engagement of IgE by cognate antigen activates FcεRI and promotes degranulation of these cells leading to the rapid release of inflammatory mediators in immediate-type hypersensitivity (Kinet, 1999).…”

Section: Isotype Switchingmentioning

confidence: 99%

B Cell Responses: Cell Interaction Dynamics and Decisions

Cyster

Allen

2019

Cell

681

634

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B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short-and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.

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Section: Isotype Switchingmentioning

confidence: 99%

B Cell Responses: Cell Interaction Dynamics and Decisions

Cyster

Allen

2019

Cell

681

634

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“…It is therefore possible that these differences could engage other Fc-specific processes that alter their transcytosis by FcRn. Accordingly, the four human IgG subclasses (IgG1-4) were assessed separately as their Fc domains are conserved but only IgG3 exhibits a mutation on the FcRn binding motif 6 . Also, because glycosylation has been speculated to alter BEC permeability 27 , an aglycosylated IgG1 was assessed.…”

Section: Igg Transcytosis Across Ibecs Is Not Receptor-mediated Givementioning

confidence: 99%

“…electrostatic adsorption) processes. The mechanisms regulating the preference for luminal or abluminal shuttling by FcRn remain to be determined, but are likely tissue and organ-specific 6,8,9 . Accordingly, FcRn functionality in BECs may not mirror those reported for other endo-or epithelium (e.g.…”

mentioning

confidence: 99%

Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn

Ruano-Salguero

Lee

2020

Sci Rep

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The blood-brain barrier (BBB) hinders the brain delivery of therapeutic immunoglobulin γ (igG) antibodies. Evidence suggests that IgG-specific processing occurs within the endothelium of the BBB, but any influence on transcytosis remains unclear. Here, involvement of the neonatal Fc receptor (FcRn), which mediates IgG recycling and transcytosis in peripheral endothelium, was investigated by evaluating the transcytosis of IgGs with native or reduced FcRn engagement across human induced pluripotent stem cell-derived brain endothelial-like cells. Despite differential trafficking, the permeability of all tested IgGs were comparable and remained constant irrespective of concentration or competition with excess IgG, suggesting IgG transcytosis occurs nonspecifically and originates from fluid-phase endocytosis. Comparison with the receptor-enhanced permeability of transferrin indicates that the phenomena observed for IgG is ubiquitous for most macromolecules. However, increased permeability was observed for macromolecules with biophysical properties known to engage alternative endocytosis mechanisms, highlighting the importance of biophysical characterizations in assessing transcytosis mechanisms.The brain endothelial cells (BECs) that form the main structural component of the blood-brain barrier (BBB) are central to the protection of brain parenchyma. Unique from peripheral endothelium, BECs exhibit substantially reduced permeability of most bloodborne molecules 1 . Accordingly, this restrictive physiology also poses a formidable obstacle in the brain delivery of therapeutic molecules 2 . In particular, conventional immunoglobulin γ (IgG) antibody-based passive immunotherapies, which are structurally and functionally similar to endogenous IgGs, only demonstrate brain uptake of 0.1-0.3% of the injected dose 3,4 . Despite the need to improve the brain delivery of conventional therapeutic IgGs 5 , progress is hindered by the current lack of understanding regarding their interactions with BECs.IgG-endothelium interactions in the periphery are dominated by the neonatal fragment crystallizable (Fc) receptor (FcRn). Following internalization of circulating IgG, the acidic microenvironment of endosomal compartments enables FcRn to bind and recycle IgG back to the lumen in a pH-dependent manner 6 . FcRn-mediated recycling therefore limits lysosomal degradation and contributes to the extended serum half-life of IgGs. However, FcRn can also mediate the abluminal transcytosis of IgG, which is exemplified in the transfer of maternal IgG across the placental endothelium. In this regard, FcRn is a unique transcytosis receptor, e.g. compared to the transferrin receptor (TfR) 7 , as it can shuttle its ligand bidirectionally to either cell surface (i.e. luminal recycling or abluminal transcytosis) 8 . Traditional transcytosis pathways are categorized as fluid-phase (e.g. macropinocytosis) or adsorptive-mediated, which occur via specific (e.g. receptor-mediated transcytosis (RMT)) or nonspecific (e.g. electrostatic adsorption) processes....

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“…The therapeutic actions of mAbs can take many forms—neutralization of the target such as cytokines in autoimmune disease, clearance of the target such as virus in infection or immunoglobulin (Ig)E in allergy, induction of innate effector cell activation that leads to target destruction by direct killing or the induction of apoptosis and the induction of adaptive immunity. Most therapeutic mAbs are IgG in origin and the heavy‐chain subclass determines many of their biological properties including their long plasma half‐life3; complement activation, which is important in the action of some cytotoxic mAbs4‐6 and importantly engagement by their fragment crystallizable (Fc) region with specific cell surface receptors, called FcγR, the subject of this review.…”

Section: Introductionmentioning

confidence: 99%

“…This review focuses on the cell‐based effector functions that arise from the interaction of IgG with the classical human leukocyte FcγR 7. Although beyond the scope of this review, it should be noted that the IgG‐Fc portion dictates other aspects of an antibody’s biology, including its serum half‐life mediated by the neonatal FcR (FcRn), 3 the activation of complement C1,8 antiviral protection via the intracellular receptor TRIM219 and interactions with the Fc receptor‐like family 10…”

Section: Introductionmentioning

confidence: 99%

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

et al. 2020

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The human fragment crystallizable (Fc)c receptor (R) interacts with antigencomplexed immunoglobulin (Ig)G ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FccR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralize or remove small macromolecules such as cytokines or other Igs. The use of mAb therapeutics has also revealed a "scaffolding" role for FccR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FccR function and the complexity of the relationships between FccRs and antibodies is fueling efforts to develop more potent "next-gen" therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FccRs or the inhibitory FccRIIb or alternatively, for the ablation of FccR interaction altogether. This review touches on recent aspects of FccR and IgG immunobiology and its relationship with the present and future actions of therapeutic mAbs.

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Targeting FcRn to Generate Antibody-Based Therapeutics

Cited by 85 publications

References 100 publications

B Cell Responses: Cell Interaction Dynamics and Decisions

B Cell Responses: Cell Interaction Dynamics and Decisions

Antibody transcytosis across brain endothelial-like cells occurs nonspecifically and independent of FcRn

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

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