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  • Review Article
  • Published:

Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond

Key Points

  • Antibodies produced by the humoral arm of the adaptive immune system induce powerful effector responses of the innate immune system.

  • Many of these effector responses are induced and regulated by the binding of antigen and antibody immune complexes to Fc receptors (FcRs).

  • These powerful effector responses can be dysregulated in autoimmune disease, causing major, clinically significant, tissue-destroying inflammation. Equally, these responses can be harnessed by therapeutic antibodies for the targeted destruction of antibody-coated targets.

  • FcRs of human leukocytes are cell surface receptors that specifically interact with the Fc portion of antibodies. This interaction is most avid and biologically meaningful when antibodies are bound in the form of antigen–antibody immune complexes.

  • One of the three most extensively characterized families of leukocyte FcRs are the FcγRs: the receptors that bind immunoglobulin G. This family of receptors includes activating-type receptors (FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa and FcγRIIIb) and inhibitory receptors (FcγRIIb). All have distinct affinities and specificities for IgG.

  • The development of therapeutics for the treatment of inflammation includes strategies to prevent immune complex-mediated activation of cells with FcγR-based 'decoy' receptors, FcR-blocking antibodies and designer anti-FcR small chemical entities, as well the modulation of signalling by kinase inhibitors or by the enhancement of inhibitory FcγR function.

  • The development of therapeutic monoclonal antibodies has seen growing interest in targeting FcRs by modifying the Fc region to selectively improve the specificity and affinity of binding to different FcγRs and thereby enhance or select for effector function — notably, pro-inflammatory or killing functions. In destructive inflammation there is interest in selective harnessing of inhibitory FcγR functions. Such strategies also complement attempts to manipulate antibody half-life by modifying Fc interactions with the neonatal FcR.

  • Future developments include the harnessing of effector function of other FcR families, including the IgE and IgA FcRs, for the targeting of destructive forces to treat cancer or infection.

  • Paradoxically, inhibition of inflammation in the future may also exploit the inhibitory ITAM (immunoreceptor tyrosine-based activation motif) function of the usually activating FcγRs.

Abstract

The direct or indirect targeting of antibody Fc receptors (FcRs) presents unique opportunities and interesting challenges for the treatment of inflammatory diseases, cancer and infection. Biological responses induced via the Fc portions of antibodies are powerful, complex and unusual, and comprise both activating and inhibitory effects. These properties can be exploited in the engineering of therapeutic monoclonal antibodies to improve their activity in vivo. FcRs have also emerged as key participants in the pathogenesis of several important autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Therapeutic approaches based on antagonizing FcR function with small molecules or biological drugs such as monoclonal antibodies and recombinant soluble FcR ectodomains have gained momentum. This Review addresses various strategies to manipulate FcR function to overcome immune complex-mediated inflammatory diseases, and considers approaches to improve antibody-based anticancer therapies.

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Figure 1: Diagrammatic representation of the human leukocyte Fc receptors.
Figure 2: The role of Fc receptors in normal antibody-based activation of cell responses.
Figure 3: Graphical representation of the relative differences in affinity among IgG subclasses for human Fcγ receptors.
Figure 4: Generalized view of the interaction between IgG and an FcγR.
Figure 5: Three views of the IgG binding site of FcγR, which is significantly conserved in other FcγRs.
Figure 6: Comparison of the ectodomains of the immunoglobulin superfamily leukocyte Fc receptors.
Figure 7: Potential scenarios for the use of soluble Fc receptors in the blockade of immune complex-induced activation of inflammatory cells and tissue destruction.
Figure 8: The 'scorpion effect'.

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Acknowledgements

The authors thank J. Stubbs, A. Gavin and J. Cambier for their editorial assistance and scientific advice, and B. Wines and M. Powell for helpful suggestions. P.M.H. is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship, project grants and the Victorian Operational Infrastructure Grant Scheme.

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Glossary

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism of killing antibody-coated cells by effector cells (for example, natural killer cells, neutrophils or eosinophils).

Small chemical entities

Chemical compounds that are less than 500 Da in size.

Immunoreceptor tyrosine-based activation motif

(ITAM). An amino acid sequence (12–14 amino acids long) containing two precisely spaced tyrosine residues that, upon phosphorylation by the SRC family of tyrosine kinases and following receptor aggregation, initiate an intracellular signalling cascade that leads to cell activation. This motif is typically found in small, often dimeric membrane proteins that are non-covalently associated with major immunoreceptors such as Fc receptors and antigen receptors.

Immunoreceptor tyrosine-based inhibition motif

(ITIM). An amino acid sequence, distinct from an immunoreceptor tyrosine-based activation motif, that is present within the cytoplasmic tail of some membrane receptors and functions solely in the transduction of inhibitory signals. ITIMs are normally composed of a six-amino-acid sequence containing a tyrosine residue, a hydrophobic residue two amino acids upstream of the tyrosine residue and a leucine residue three amino acids downstream of the tyrosine residue. The inhibitory function of the ITIM is activated by phosphorylation of the tyrosine residue, which is mediated by the SRC family of kinases. This leads to the recruitment and activation of tyrosine and/or lipid phosphatases including SHP (SH2 domain-containing protein tyrosine phosphatase) and SHIP (SH2 domain-containing inositol-5-phosphatase), respectively. The ITIM of the Fc receptor FcγRIIb is the archetypal ITIM.

Arthus reaction

A type III hypersensitivity reaction of classical antibody (immune complex)-based hypersensitivity, as described by Maurice Arthus.

Protein A

An immunoglobulin G binding protein of Staphylococcus aureus that is useful in the purification of immunoglobulin.

Phage display

The expression of recombinant proteins by a bacteriophage typically displayed on the phage coat. The technology is usually used for the discovery and generation of antigen-combining sites of antibodies but also used for the display of peptide- and/or protein-based ligands.

IVIg

Intravenous immunoglobulin. A therapeutic modality involving treatment with pooled immunoglobulins derived from thousands of ostensibly healthy donors.

Inhibitory ITAM

(ITAMi). Tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) activates negative feedback as well as stimulatory signalling pathways. Under certain circumstances, especially when receptors are stimulated by low-avidity ligands, signalling is biased towards inhibition. This inhibitory bias is associated with monotyrosyl phosphorylation of the ITAM and the recruitment of phosphotyrosine and phosphoinositide phosphatases, which act as effectors.

Orthologues

Genes of different species that originated from a common ancestor.

C1q

The q fragment of the first component of serum complement activated by interaction with immune complexes.

Allelomorphs

The related protein products encoded by different alleles.

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Hogarth, P., Pietersz, G. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat Rev Drug Discov 11, 311–331 (2012). https://doi.org/10.1038/nrd2909

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