Fcγ receptors as regulators of immune responses

Nimmerjahn, Falk; Ravetch, Jeffrey V.

doi:10.1038/nri2206

Cited by 2,485 publications

(2,686 citation statements)

References 134 publications

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“…The Fc region of IgG is capable of binding to many different Fc receptors, and the mechanism of action for many therapeutic antibodies relies on engagement with these Fc receptors. 39–41 It has been shown previously that mutations, even at positions distant from the Fc receptor binding site, can affect engagement of Fc with receptors such as FcγRI, FcγRIIa/b, FcγRIIIa, C1q, and/or TRIM21. While Fc receptor TRIM21 binds to a site that overlaps with the FcRn binding site on CH2-CH3, other receptors (such as Fcγ receptors and C1q) engage at the interface formed by the dimeric CH2 found in a fully assembled antibody.…”

Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously. Using this framework, we identified features that govern Fc-FcRn interactions and identified multiple distinct pathways for enhancing FcRn binding in a pH-specific manner. Network analysis provided a novel lens to study the allosteric impact of half-life-enhancing Fc mutations on FcγR engagement, which occurs distal to the FcRn binding site. Applying these principles, we engineered a panel of unique Fc variants that enhance FcRn binding while maintaining robust biophysical properties and wild type-like binding to activating receptors. An antibody harboring representative Fc designs demonstrates a half-life improvement of > 9 fold in transgenic mice and > 3.5 fold in cynomolgus monkeys, and maintains robust effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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“…Nevertheless, mAbs–Fc receptor interactions are crucial for the activation of the immune response (Nimmerjahn and Ravetch 2008). The complement component C1q (complement component 1, subcomponent q) can bind to the Fc portion of antibodies and cause the activation of a cascade resulting in complement‐dependent cytotoxicity (CDC).…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.

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“…Signaling via the activating receptors generally leads to the recruitment of signaling adaptor molecules (e.g. syk) to these receptors and downstream activation of PI3 kinase and other pathways [28] • . The net result is generally cellular activation, although it is now apparent that in some instances, some ITAM containing receptors can also mediate inhibitory signals [29].…”

Section: Recognition Of Cells Opsonized With Antibodies Is Mediated Imentioning

confidence: 99%

“…The net result is generally cellular activation, although it is now apparent that in some instances, some ITAM containing receptors can also mediate inhibitory signals [29]. Inhibitory Fcγ receptors contain an immune tyrosine inhibitory motif (ITIM) and inhibit signaling through the activating receptors by recruitment of phosphatases including inositol phosphatase SHIP and the tyrosine phosphatase SHP-1 [28]. Most FcγR bearing cells express both activating and inhibitory receptors.…”

Section: Recognition Of Cells Opsonized With Antibodies Is Mediated Imentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Current Opinion in Immunology

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Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

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Fcγ receptors as regulators of immune responses

Cited by 2,485 publications

References 134 publications

Extending human IgG half-life using structure-guided design

Extending human IgG half-life using structure-guided design

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Role of chaperones and FcγR in immunogenic death

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