Fc receptors (FcRs) are membrane proteins that bind with antibody Fc regions and help in regulating the body’s immune response. A variety of Fc receptors (Figure 1) selectively bind the Fc region of specific antibodies (Table 1) . When these antibodies are attached to disease-causing pathogens or infected cells, the Fc receptors can mediate their destruction by antibody-dependent cellular phagocytosis (ADCP) or antibody-dependent cell-mediated cytotoxicity (ADCC, Figure 2 ). The Fc region can also interact with complement proteins to induce complement-dependent cytotoxicity (CDC). The interaction of Fc receptors with complement proteins results in a wide range of modulated immune responses. Due to the central role of Fc receptors in regulating antibody function, binding kinetics of new antibodies may be tested using Fc receptor-expressing cell lines when developing antibody-based drugs and therapies.
Fc gamma receptors (FcγRs) (Figure 1) bind Immunoglobulin G antibodies (IgGs), and can enhance or inhibit IgG-based immune responses [1-5]. In the field of tumor biology and development of antibody therapies for cancer, the ADCC function of FcγRs has gained prominence. ADCC is initiated when FcγRs expressed on the surface of natural killer (NK) or other types of effector cells such as macrophages recognize and bind with the Fc domain of antibodies which are attached to the surface of tumor cells. The interaction with FcγRs (most often FcγRIIIA) with these bound antibodies releases perforins and granzymes from the effector cells, resulting in the lysis of the tumor cells (Figure 2). FcγRs make good targets for antibody-based therapies for cancers as they can assist in the destruction of diseased cells by ADCC . Cell lines expressing FcγRs are often used to determine effectiveness of antibody drugs developed to treat various types of cancers and autoimmune diseases.
Some FcγRs have several polymorphic variants due to point mutations. The FcγR variant expressed by an individual can affect their chance of developing certain diseases such as SARS and ulcerative colitis, as well as the disease intensity (Table 1) [7-26]. FcγR variants can also determine a patient’s response to antibody-based drugs and therapies. Therefore, cell lines expressing FcγR polymorphisms are useful for developing personalized medicine.
Another type of Fc receptor, the neonatal Fc receptor (FcRn) is indicated in increasing the stability of antibodies and serum proteins such as albumins . FcRn binds IgGs and albumins in a pH-dependent mechanism and mediates their transcytosis across polarized membranes . FcRn is present in a variety of cells, including placental cells which transport IgGs from the mother to the developing fetus . Cell lines expressing FcRn are useful screening tools to study transcytosis and in vitro clearance of antibody-based drugs.
- Single-clone cell lines for stable and consistent receptor expression on host cell surface.
- Polymorphic versions of popular FcγRs available for targeted drug development.
- Use of human receptors expressed in CHO-K1 host cell line for in vitro drug testing.
- Determination of binding affinity of antibody-based drug candidates.
- Determination of the half-life of antibody-based drug candidates.
- Determination of the drug candidate’s mechanism of action in vitro.
- Research and development of personalized medicine.
Figure 1. Human FcRγ and FcRn receptors.
This figure illustrates human FcRγ and FcRn receptors embedded in the cell membrane. The function of the FcRγ receptors is affected by their structures. The FcγRI, FcγRIIa, FcγRIIc and FcγRIIIa are primarily activating receptors, as they express immunoreceptor tyrosine activating motifs (ITAMs, brown circles) on their α or associated γ chains. On the other hand, the inhibitory receptor FcγRIIb expresses an immunoreceptor tyrosine inhibitory motif (ITIM). The FcγRIIIb receptor is a GPI-anchored protein which expresses neither ITAM nor ITIM motifs, but instead conducts signal transduction through associations with other Fc receptors. The FcRn receptor is structurally a heterodimer consisting of an α chain and a β2-microglobulin (β2m), both of which are important for the receptor’s expression on the cell surface, as well as for optimal IgG binding activity [3-5].
Table 1. Human FcRγ and FcRn receptors.
|FcγRI||FcγRIIa||FcγRIIb||FcγRIIc||FcγRIIIa||FcγRIIIb||Neonatal Fc receptor|
|-||Histidine (H131)||Arginine (R131)||-||-||Valine (V158)||Phenylalanine (F158)||-||-|
|Immunoglobulin subclass binding|
IgG2 (lower affinity than H131),
IgG2 (low affinity),
IgG2 (low affinity),
|Higher affinity to all human IgGs than F158||Lower affinity to all human IgGs than V158||IgG1,
|Monocytes, macrophages, neutrophils, dendritic cells, mast cells||Basophils, eosinophils, monocytes, macrophages, neutrophils, dendritic cells, mast cells||Basophils, eosinophils, monocytes, macrophages, neutrophils, dendritic cells, mast cells||B-cells, basophils, dendritic cells, mast cells||Natural Killer (NK) cells, monocytes, macrophages, neutrophils||Natural Killer (NK) cells, monocytes, macrophages||Natural Killer (NK) cells, monocytes, macrophages||Neutrophils, basophils, eosinophils||monocytes, macrophages, neutrophils, dendritic cells, endothelium, synctiotrophoblasts|
|Activation||Recycling, transport, uptake|
|Link to diseases|
|-||H131 variant is associated with less severe infection with encapsulated microorganisms including more severe SARS (Severe Acute Respiratory Syndrome) infection , Kawasaki disease , ulcerative colitis , Guillain–Barré syndrome .||R131 variant associated with more severe infection due to encapsulated microorganisms including SARS ; Immune thrombocytopenic purpura ; Systemic lupus erythematosus (SLE) ; IgA nephropathy [13,14]||Lupus [12,15]; Atopy ||Kawasaki Disease ||Arthritis [18, 19]; Crohn’s disease ||Arthritis [18, 19]; Crohn’s disease ; Systemic lupus erythematosus (SLE) ; Behçet's disease [22, 23]||Wegener’s granulomatosis ||-|
FcRγ and FcRn alleles, immunoglobulin binding affinities, expression, function, and link to diseases [7-24].
Figure 2. Antibody-dependent cellular cytotoxicity (ADCC).
This figure illustrates how the FcRγ receptors on natural killer (NK) cells mediate destruction of antibody-marked cancer cells by the process of ADCC .
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