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Your Position: Home > Insights > Overview of Fc Receptors: classification and functions
Overview of Fc Receptors: classification and functions
Release time: 2021-10-20 Source: ACROBiosystems Read: 2601

Fc receptors (FcRs) are a group of glycoproteins belonging to the immunoglobulin  superfamily and are organized into classes, such as Fc alpha receptors (FcαRs), Fc gamma receptors (FcγRs) and Fc epsilon receptors (FcεRs). Communication of IgG antibodies with the immune system is controlled and mediated by FcγRs, which relay the information sensed and gathered by antibodies to the immune system. IgG is the most studied and best characterized of the Igs and is divided into four distinct subclasses (IgG1, IgG2, IgG3, IgG4), each with differences in sequence and structure, binding properties to FcγRs and effector functions.

       Figure1. Four subtypes of IgG exist in humans: IgG1, IgG2, IgG3, IgG4. Conserved Asn 297 amino acids in the Fc region with N-glycans attached (shown in yellow), Heavy chains are shown in green, and light chains are shown in blue and purple.


The four subtypes are named based on their respective abundance in serum with IgG1 being the most abundant. IgG antibodies consist of two Fab regions that can bind both an antigen molecule and the Fc region which interact with the FcγRs, joined by a highly flexible hinge region. IgG1 has the highest affinity to all FcγRs, leading to significant effector functions, such as ADCC, ADCP, and CDC. Although human IgG3 can also mediate competent effector functions, it has a very long hinge region and complex disulfide bonds, resulting in significantly greater polymorphism, which may increase the risk of immunogenicity. Therefore, the IgG3 isotype is rarely chosen in antibody therapeutics. In comparison, IgG2 and IgG4 induce significantly weaker or no ADCC and CDC.


Based on the differences in structure, function, and affinity for IgG binding, FcγRs are classified into three major groups: FcγRI/CD64, FcγRII/CD32 (FcγRIIa, FcγRIIb and FcγRIIc) and FcγRIII/CD16 (FcγRIIIa and FcγRIIIb). Among them, FcγRI, FcγRIIa, and FcγRIIIa are activating receptors containing the signal transduction motif, immunoreceptor tyrosine-based activation motif (ITAM), in the γ subunit of FcγRI and FcγRIIIa, or in the cytoplasmic tail of FcγRIIa. In contrast, FcγRIIb is an inhibitory receptor. Cross-linking of FcγRIIb leads to the phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) and inhibitory signaling transduction.

Figure 2 Fc–FcγRs interactions and FcγRs expression across cell subsets in human.    For cell-type expression, + indicates constitutive expression, +* indicates inducible expression and − indicates no expression. For relative affinities, +++ indicates lower than 1 μM, ++ indicates 1–10 μM, + indicates 10–100 μM, +/− indicates higher than 100 μM and n.b. indicates no binding. †Indicates binding observed with no affinity reported.


FcγRI (Fc gamma receptor I, CD64)


FcγRI is a high-affinity Fc receptor for both the monomeric IgG and immune complex (IC). The affinities of FcγRI to IgG1 or IgG4 are similar (1–10 nM KD). In contrast,  FcγRI has no binding to IgG2. FcγRI is mainly expressed on monocytes/macrophages, dendritic cells (DCs), and activated neutrophils. One of the major functions of FcγRI is to activate myeloid cells to phagocytose IgG1 and IgG-bound target cells via ADCP. Due to high-affinity binding of FcγRI to monomeric IgG and high serum concentrations of IgG (∼15 mg/mL), it is believed that most FcγRI is occupied by endogenous IgG. However, a recent study has shown that stimulation of myeloid cells with cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), could induce the clustering of FcγRI and increase the binding of FcγRI to ICs. Multiple studies have also shown that FcγRI plays an important role in modulating immune responses in autoimmune diseases, inflammation, and antibody therapy.


FcγRII (Fc gamma receptor II, CD32)


FcγRII is the receptor most widely expressed on hematopoietic cells among FcγRs. FcγRII includes FcγRIIA, FcγRIIB and FcγRIIC isoforms. FcγRIIA, expressed on monocytes, macrophages, neutrophils, and platelets is more largely expressed on immune cells than FcγRIIC that has been identified on NK cells. FcγRIIA initiates endocytosis, phagocytosis, ADCC, and inflammatory mediator release. By contrast, FcγRIIB, expressed on B cells, basophils, mast cells, monocytes, macrophages and DC transduce inhibitory signals that down-regulate immune functions triggered by activating receptors, when co-ligated with the latter receptors.


FcγRIII (Fc gamma receptor III, CD16)


Two different FcγRIII isoforms have been identified. FcγRIIIB is a glycosyl-phosphatidylinositol (GPI) anchored- FcγRIIIB expressed on neutrophils and involved in degranulation and generation of reactive oxygen intermediates by these cells. FcγRIIIA is a transmembrane isoform expressed on NK cells and a small subpopulation of T lymphocytes as well as on monocytes and macrophages, although at low levels in the latter case. FcγRIIIA is involved in ADCC, phagocytosis, endocytosis and cytokine release.


While the mouse IgG system differs from the human in important ways (mice express IgG1, IgG2a, IgG2b and IgG3, all with different affinities for mouse FcγRs compared with human), with higher affinity Fc–FcγRs engagement by the mouse IgG2a isotype for activating FcγRs than that of human IgG1.

Figure 3 Fc–FcγRs interactions and FcγRs expression across cell subsets in mouse.  For cell-type expression, + indicates constitutive expression, +* indicates inducible expression and − indicates no expression. For relative affinities, +++ indicates lower than 1 μM, ++ indicates 1–10 μM, + indicates 10–100 μM, +/− indicates higher than 100 μM and n.b. indicates no binding. †Indicates binding observed with no affinity reported.


In mice, only FcγRI, FcγRIIB, and FcγRIIIA human equivalents have been described. Mouse FcγRI and FcγRIIIA (termed FcγRIII) exhibit the same activating properties as their human counterparts. These two mouse receptors bind IgG with a high and a low affinity, respectively. Mouse FcγRIIB (termed FcγRII) is also a low affinity receptor that exhibits inhibitory functions as the human FcγRIIB that contains an ITIM. All mouse FcγRs can bind human IgG1 and IgG3 subclasses, in addition to mouse IgG1, IgG2a, and IgG2b subclasses. Among these subclasses, IgG2a is a strong binder of FcγRI, as compared to IgG1 and IgG2b which preferentially bind FcγRIIB and FcγRIII, to which IgG2a also binds. Whether a specific mouse Fc receptor for mouse IgG3 exists is still a matter of controversy, although it has been claimed that this subclass could bind mouse FcγRI.


Summary


FcγRs are expressed mostly on leukocytes and they are the class of receptors most relevant for the function of therapeutic antibodies. FcγRs are divided into three types, FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16). They have traditionally been categorized according to their affinity for specific IgG subclasses and the type of signaling pathway that they trigger; that is, whether it is inhibitory or activating. In general, FcγRI has been considered to be a high-affinity receptor that binds both monomeric IgG and immune complexes, whereas the affinity of FcγRII and FcγRIII for IgGs is low and intermediate, respectively.


Engineering the Fc region of IgG mAbs or IgG-like bispecific antibodies to modulate IgG/FcγRs interactions is a major goal of current studies on therapeutic antibodies. The development and manufacture of therapeutic antibodies, including Fc (crystallizable fragment) fusion proteins, represent a significant segment of the biopharmaceutical industry and have resulted in substantial benefits to public health. In conclusion, binding of the antibody Fc-hinge region to FcγRs has been shown to exert a profound impact on antibody function and in vivo efficacy.


ACROBiosystems offers a comprehensive collection of recombinant Fc receptor proteins, including their common variants, to expedite your antibody drug development.


The use of biotin labeling can make your assay development much easier. We offer a variety of “ready-to-use” biotinylated Fc receptors. These proteins are produced using our in-house developed labeling techniques, which confers high bioactivity and minimal batch-to-batch variation. In addition, we have developed a series of Fc receptors of other species, which are suitable for the screening of non-humanized antibodies or the species cross reaction.

Advantages of Fc receptor protein products

Expressed by HEK293 Cells: post-translational modification and proper protein folding

Multiple species: Human, Mouse, Cynomolgus/Rhesus macaque, Rat, Porcine, Rabbit, Feline, Bovine, can be fully applied to different cross species experiments

High purity: SDS-PAGE verification purity>95%, SEC-MALS verification purity>90%

Low endotoxin: <1.0 EU/µg

High stability: strict quality control to ensure high batch-to-batch consistency

Biotinylated Fc Receptor proteins labeled with AvitagTM offered: the labeling efficiency is high, and the labeling site is specific and clear, which is suitable for ELISA/SPR/BLI detection based on binding to streptavidin in the process of drug development and optimization process

Affinity verified by SPR & BLI: activity guaranteed, and protocols offered free of charge

Product list
   (All Fc receptors are expressed from HEK293)
  • FcRn

  • FcγR

  • FcεR

MoleculeCat. No.HostProduct DescriptionStructure
FcRn (FCGRT & B2M)FCM-H5286HEK293Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (SPR & BLI & MALS verified)Hot
FCM-H8286HEK293Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag, ultra sensitivity (primary amine labeling) (SPR verified)
FCM-H82W4HEK293Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein,,His Tag&Strep II Tag (SPR & BLI & MALS verified)Hot
FCM-H82W7HEK293Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein, His,(MALS & SPR verified)
FCN-H52W7HEK293Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag (SPR & BLI & MALS verified)Hot
FCM-M52W2HEK293Mouse FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Twin-Strep Tag (MALS & BLI verified)
FCM-M52W8HEK293Mouse FcRn / FCGRT&B2M Heterodimer Protein, His Tag (MALS & BLI verified)
FCM-M82W5HEK293Biotinylated Mouse FcRn / FCGRT&B2M Heterodimer Protein, His,(MALS & BLI verified)
FCM-M82W6HEK293Biotinylated Mouse FcRn / FCGRT&B2M Heterodimer Protein,,His Tag&Twin-Strep Tag (MALS & BLI-verified)
FCM-R5287HEK293Rat FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & SPR verified)
FCM-R82W7HEK293Biotinylated Rat FcRn / FCGRT&B2M Heterodimer Protein,,His Tag&Strep II Tag (MALS & SPR verified)
FCM-R52W5HEK293Rabbit FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Tag Free (MALS & SPR verified)
FCM-C5284HEK293Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & BLI verified)
FCM-C52W9HEK293Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His Tag (MALS & BLI verified)
FCM-C82W3HEK293Biotinylated Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His,(MALS & SPR verified)
FCM-C82W5HEK293Biotinylated Cynomolgus / Rhesus macaque FcRn Heterodimer Protein, His,&Strep II Tag (SPR & BLI verified)
FCM-P5280HEK293Porcine FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & SPR verified)
FCN-F82W3HEK293Biotinylated Feline FcRn / FCGRT&B2M Heterodimer Protein, His,(MALS & SPR verified)
FCN-B82W3HEK293Biotinylated Bovine FcRn / FCGRT&B2M Heterodimer Protein, His,(MALS & SPR verified)
MoleculeCat. No.HostProduct DescriptionStructure
Fc gamma RIIIA / CD16aCD8-H52H4HEK293Human Fc gamma RIIIA / CD16a (V176) Protein, His Tag (SPR & BLI & MALS verified)
CDA-H5220HEK293Human Fc gamma RIIIA / CD16a (F176) Protein, His Tag (SPR & BLI & MALS verified)
CDA-H5290HEK293Human Fc gamma RIIIA / CD16a (V176) Protein, SUMO,His Tag (MALS verified)
CDA-H52S1HEK293Human Fc gamma RIIIA / CD16a (V176) Protein, HSA,His Tag (MALS verified)
CDA-H82E8HEK293Biotinylated Human Fc gamma RIIIA / CD16a (F176) Protein,,His Tag (SPR & BLI & MALS verified)
CDA-H82E9HEK293Biotinylated Human Fc gamma RIIIA / CD16a (V176) Protein, ,His Tag (SPR & BLI verified)
Fc gamma RI / CD64FCA-H52H1HEK293Human Fc gamma RI / CD64 Protein, His Tag (MALS verified)
FCA-H82E8HEK293Biotinylated Human Fc gamma RI / CD64 Protein, His,(MALS verified)
CD4-M5227HEK293Mouse Fc gamma RI / CD64 Protein, His Tag (MALS & BLI verified)
CD4-M82E7HEK293Biotinylated Mouse Fc gamma RI / CD64 Protein, His,(MALS verified)
FCA-C82E8HEK293Biotinylated Cynomolgus Fc gamma RI / CD64 Protein, His,(MALS & BLI verified)
Fc gamma RIIB / CD32bCDB-M52H7HEK293Mouse Fc gamma RIIB / CD32b Protein, His Tag (SPR & BLI & MALS verified)Hot
CDB-M82E8HEK293Biotinylated Mouse Fc gamma RIIB / CD32b Protein,,His Tag (SPR & BLI & MALS verified)
CDB-C5224HEK293Cynomolgus Fc gamma RIIB / CD32b Protein, His Tag (MALS & SPR verified)
CDB-C82E4HEK293Biotinylated Cynomolgus Fc gamma RIIB / CD32b Protein, His,(SPR & BLI & MALS verified)
Fc gamma RIIB/C / CD32b/cCDB-H5228HEK293Human Fc gamma RIIB/C / CD32b/c Protein, His Tag (SPR & BLI & MALS verified)Hot
CDB-H5298HEK293Human Fc gamma RIIB/C / CD32b/c Protein, SUMO,His Tag (MALS & BLI verified)
CDB-H52S9HEK293Human Fc gamma RIIB/C / CD32b/c Protein, HSA,His Tag (MALS verified)
CDB-H82E0HEK293Biotinylated Human Fc gamma RIIB/C / CD32b/c Protein,,His Tag (SPR & BLI & MALS verified)Hot
Fc gamma RIIA / CD32aCD1-H5223HEK293Human Fc gamma RIIA / CD32a (H167) Protein, His Tag (SPR & BLI & MALS verified)Hot
CDA-H5221HEK293Human Fc gamma RIIA / CD32a (R167) Protein, His Tag (MALS & BLI verified)Hot
CDA-H82E6HEK293Biotinylated Human Fc gamma RIIA / CD32a (H167) Protein,,His Tag (SPR & BLI & MALS verified)Hot
CDA-H82E7HEK293Biotinylated Human Fc gamma RIIA / CD32a (R167) Protein, ,His Tag (SPR & BLI & MALS verified)
CDA-R52H5HEK293Rat Fc gamma RIIA / CD32a Protein, His Tag (MALS & SPR verified)
CDA-C52H7HEK293Cynomolgus Fc gamma RIIA / CD32a Protein, His Tag (SPR & BLI & MALS verified)
CDA-C82E5HEK293Biotinylated Cynomolgus Fc gamma RIIA / CD32a Protein, His,(SPR & BLI & MALS verified)
CDA-R52H4HEK293Rhesus macaque Fc gamma RIIA / CD32a Protein, His Tag (SPR & BLI & MALS verified)
Fc gamma RIII / CD16CDA-M52H8HEK293Mouse Fc gamma RIII / CD16 Protein, His Tag (SPR & BLI & MALS verified)
FC6-M82E0HEK293Biotinylated Mouse Fc gamma RIII / CD16 Protein, His,(MALS verified)
FC6-C52H9HEK293Cynomolgus Fc gamma RIII / CD16 Protein, His Tag (MALS & BLI verified)
FC6-C82E0HEK293Biotinylated Cynomolgus Fc gamma RIII / CD16 Protein, His,(MALS & BLI verified)
FC6-R52H6HEK293Rhesus macaque Fc gamma RIII / CD16 Protein, His Tag (SPR & BLI & MALS verified)
Fc gamma RIIIB / CD16b (NA1)CDB-H5227HEK293Human Fc gamma RIIIB / CD16b (NA1) Protein, His Tag (SPR & BLI & MALS verified)
CDB-H5296HEK293Human Fc gamma RIIIB / CD16b (NA1) Protein, SUMO,His Tag (MALS & BLI-verified)
CDB-H82E4HEK293Biotinylated Human Fc gamma RIIIB / CD16b (NA1) Protein, His,(SPR & BLI & MALS verified)
Fc gamma RIIIB / CD16b (NA2)CDB-H5222HEK293Human Fc gamma RIIIB / CD16b (NA2) Protein, His Tag (SPR & BLI & MALS verified)
CDB-H5294HEK293Human Fc gamma RIIIB / CD16b (NA2) Protein, SUMO,His Tag (MALS & BLI-verified)
CDB-H82EaHEK293Biotinylated Human Fc gamma RIIIB / CD16b (NA2) Protein, His,(SPR & BLI & MALS verified)
Fc gamma RIV / CD16-2FC4-M52H3HEK293Mouse Fc gamma RIV / CD16-2 Protein, His Tag (MALS verified)
FC4-M82E8HEK293Biotinylated Mouse Fc gamma RIV / CD16-2 Protein, His,(BLI verified)
MoleculeCat. No.HostProduct DescriptionStructure
CD23CD3-H5249HEK293Human CD23 / Fc epsilon RII Protein, His Tag (MALS verified)
CD3-H82Q5HEK293Biotinylated Human CD23 / Fc epsilon RII Protein, His,(MALS verified)
Fc epsilon RI alphaFCA-H5228HEK293Human Fc epsilon RI alpha Protein, His Tag (MALS verified)
FCA-H5259HEK293Human Fc epsilon RI alpha Protein, Fc Tag (MALS & BLI verified)


 

More Fc Receptors related information

>>> Why Fc Receptors Are So Important?

>>> Role of FcRn as a therapeutic target



References

1. Jerrard M Hayes, Mark R Wormald et al. Fc gamma receptors: glycobiology and therapeutic prospects. Journal of Inflammation Research. 2016, 9:209–219.

2. Bryan C Barnhart, Michael Quigley. Role of Fc–FcγR interactions in the antitumor activity of therapeutic antibodies. Immunology and Cell Biology. 2017, 95, 340–346.

3. Gestur Vidarsson, Gillian Dekkers. IgG subclasses and allotypes: from structure to effector functions. Frontiers in Immunology.2014, 5(520).

4. Sophie Siberil, Charles-Antoine Dutertre et al. FcγR: The key to optimize therapeutic antibodies? Critical Reviews in Oncology/Hematology. 2007, 62,26–33.

5. Xin Chen, Xiaomin Song et al. FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy. Frontiers in Immunology.2019,10.

6. Xu-Rong Jiang, An Song et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nature Review, Drug Discovery.2011,10.

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