Fc-gamma receptors: Attractive targets for autoimmune drug discovery searching for intelligent therapeutic designs

Bosques, Carlos J.; Manning, Anthony M.

doi:10.1016/j.autrev.2016.07.035

Cited by 16 publications

(13 citation statements)

References 68 publications

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“…Although these were believed to be secondary to unwanted engagement of the therapeutic Fc region with FcγRs, these were not abrogated when a humanized anti-FcγR with an aglycosylated Fc was used, suggesting that alternative approaches may be required (reviewed in ref. 22). Blockade of the critical proximal signaling molecule spleen tyrosine kinase (SYK) downstream of several FcγRs initially showed promising efficacy in rheumatoid arthritis (23), chronic lymphocytic leukemia, and non-Hodgkin's lymphoma (24), providing clinical support for therapeutic FcγR blockade in human disease.…”

Section: Significancementioning

confidence: 99%

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action

Robinson

Baxter

Owen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcγRIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate FcγRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically.

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Section: Significancementioning

confidence: 99%

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action

Robinson

Baxter

Owen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…An increasing number of studies have shown that the immune inflammatory mechanism is important in the occurrence and development of DN. FcγR belongs to the Ig superfamily, which is widely expressed in the hematopoietic system and can regulate the inflammatory and immune response and ensure the dynamic balance of DN ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

AMPKα, hs-CRP and FcγR in diabetic nephropathy and drug intervention

et al. 2018

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The aim of this study was to investigate the roles of AMP-activated protein kinase α subunit (AMPKα), hypersensitive C-reactive protein (hs-CRP) and Fcγ receptor (FcγR) in diabetic nephropathy and drug intervention effects. Sixty Sprague Dawley male rats were randomly divided into the control (n=30) and observation (n=30) groups. The model of type 2 diabetic nephropathy was established by high-fat and high-glucose diet and streptozotocin injection. The rats in the observation group were treated with baicalein and the rats in control group did not receive any drug intervention. The pathological changes of kidneys were observed by hematoxylin and eosin (H&E) staining. The expression of AMPKα mRNA in renal tissue was detected by reverse transcription-polymerase chain reaction (RT-PCR). The levels of hs-CRP and FcγR were measured by enzyme-linked immunosorbent assay (ELISA) at 1, 4, 6 and 8 weeks after drug intervention and blood urea nitrogen (BUN) and the 24 h urinary micro-albumin (U-ALB) levels were compared at 1, 4, 6 and 8 weeks after intervention. After 8 weeks of drug intervention, the pathological changes of kidneys in the observation group were significantly lower than those in the control group (p<0.05), while the relative expression levels of AMPKα mRNA and protein in the control group were higher than those in the observation group (p<0.05). The levels of hs-CRP, BUN and 24 h U-ALB in the control group were significantly higher than those in the observation group at different time-points after drug intervention and the level of FcγR in the control group was significantly lower than that in the observation group (p<0.05). Baicalein may protect renal function by inhibiting the expression of AMPKα and inflammatory reaction, and can also decrease BUN and 24 h U-ALB levels and improve the pathological changes of the kidney.

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“…In spite of these advantages, in the follow-up study, we found that the binding to unrelated proteins was generally observed for such monomeric Fcs, raising potential risks for their clinical application due to the immunogenicity and pharmacokinetics-related issues. For instance, the unwanted formation of antigen–antibody immune complexes can elicit a variety of downstream effects and further immunogenic responses ( 28 ). Their levels, kinetics of interaction, size, polyclonal diversity, distribution, elimination, and antibody-mediated physiological effects can be potentially translated to clinically observable adverse effects ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

Engineered Soluble Monomeric IgG1 Fc with Significantly Decreased Non-Specific Binding

Wang

et al. 2017

Front. Immunol.

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Due to the long serum half-life provided by the neonatal Fc receptor (FcRn) recycling, the IgG1 Fc has been pursued as the fusion partner to develop therapeutic Fc-fusion proteins, or as the antibody-derived scaffold that could be engineered with antigen-binding capabilities. In previous studies, we engineered the monomeric Fc by mutating critical residues located on the IgG1 Fc dimerization interface. Comparing with the wild-type dimeric Fc, monomeric Fc might possess substantial advantages conferred by its smaller size, but also suffers the disadvantage of non-specific binding to some unrelated antigens, raising considerable concerns over its potential clinical development. Here, we describe a phage display-based strategy to examine the effects of multiple mutations of IgG1 monomeric Fc and, simultaneously, to identify new Fc monomers with desired properties. Consequently, we identified a novel monomeric Fc that displayed significantly decreased non-specificity. In addition, it exhibited higher thermal stability and comparable pH-dependent FcRn binding to the previous reported monomeric Fc. These results provide baseline to understand the mechanism underlying the generation of soluble IgG1 Fc monomers and warrant the further clinical development of monomeric Fc-based fusion proteins as well as antigen binders.

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Fc-gamma receptors: Attractive targets for autoimmune drug discovery searching for intelligent therapeutic designs

Cited by 16 publications

References 68 publications

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action

AMPKα, hs-CRP and FcγR in diabetic nephropathy and drug intervention

Engineered Soluble Monomeric IgG1 Fc with Significantly Decreased Non-Specific Binding

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