FcRn and its role as a therapeutic target

IgG was the only class of antibodies that were actively transported from mother to offspring for a long time, and this resulted in short-term passive immunity. The specific IgG transport was realized by FcRn.

In 1972, a receptor that transfers maternal IgG to newborns in the gut of neonatal rats was identified. It was later named as Neonatal Fc receptor (FcRn). FcRn expression at the time of pregnancy and lactation performs a role in transferring IgG across the placental barrier and the intestinal tract.

Various tissue cells can be identified throughout the life cycle. The major function is to retain the IgG level and albumin in the serum and control the distribution in the tissue.

Mechanism of FcRn to prolong the half-life

IgG has a half-life of up to 2 to 4 weeks in the human body. The effect of the half-life is major because of the FcRn-mediated recycling process. This process is achieved by the pH-dependent binding of IgG Fc fragment and serum albumin to FcRn.

FcRn and its role as a therapeutic target

Image Credit: ACROBiosystems

In acidic conditions (pH 6.0–6.5), FcRn binds IgG, and dissociation takes place under neutral and weakly alkaline conditions (pH 7.0–7.5). Endothelial cells form endocytosis vesicles by engulfing IgG to form an acidified endosome. IgG binds to FcRn to form an IgG-FcRn complex.

The IgG-FcRn complex is transferred to the cell surface through the recirculated endosome. Under physiological conditions like pH 7.4, the IgG-FcRn complex dissociates and the IgG gets released again into the blood circulation. By this receptor-mediated recycling process, FcRn efficiently safeguards IgG from lysosomal degradation, thus increasing the half-life of IgG.

Yet, IgG does not bind to FcRn to form an IgG-FcRn complex in the acidified body and degrades in the lysosome. Researches have demonstrated that the FcRn-mediated IgG recovery rate is 42% more than the IgG production rate. This indicates that IgG recycling is the major mechanism that retains IgG concentrations in the human body.

Structure of FcRn

FcRn is a heterodimer comprised of two subunits FCGRT and B2M. FCGRT has three extracellular functional regions, including a single transmembrane helix, three soluble domains (α1, α2, and α3) and a cytoplasmic tail (certain researches have demonstrated that the cytoplasmic tail region is made of 44 amino acid residues that may have signals that mediate intracellular pathways).

The molecular weight is 40 to 50 kDa, named the α chain and the molecular weight of B2M is 14 kDa, called the β chain. The two chains are combined with non-covalent bonds. FCGRT assembles with B2M to perform a transport role. Researches have demonstrated that the attaching site of FcRn with IgG and serum albumin is not the same, hence the binding of FcRn to IgG is not obstructed by serum protein.

FcRn has different binding sites with ligand IgG and albumin.

FcRn has different binding sites with ligand IgG and albumin. Image Credit: ACROBiosystems

FcRn to treat autoimmune diseases

The greater affinity of FcRn has adverse effects on IgG-mediated autoimmune diseases like rheumatoid arthritis, myasthenia gravis or pemphigus vulgaris. Targeting FcRn and inhibiting FcRn circulation can improve IgG catabolism, resulting in whole reduced IgG and pathogenic autoantibody levels, which is anticipated to decrease all autoimmune abnormalities induced by IgG.

Researches have substantiated that FcRn targeting therapy offers quick and more selective IgG reduction than therapeutic plasma exchange therapy for myasthenia gravis. Additionally, the pros of this treatment over numerous clinically used traditional therapies are also shown by the fact that IgA, IgD, IgE and IgM do not depend on FcRn-mediated circulation.

Hence, it does not lead to comprehensive immunosuppression, offering the basis for the safety and precision specificity of FcRn targeting.

Drugs that target FcRn antibodies are presently being evaluated in clinical trials and these include Efgartigimo, Orilanolimab (SYNT001), Nipocalimab (M281) and so on. Nipocalimab (M281) is a potential “best-in-class” anti-FcRn antibody produced by Momenta.

It is capable of treating various autoimmune diseases and was introduced by Johnson & Johnson. Batoclimab is a Hebo Pharmaceutical, from HanAll Biopharma introduced in 2018, and is a complete human antibody targeting the Fc receptor (FcRn) of newborns. They acquired the rights to develop, produce and commercialize it in the Greater China region.

Global Clinical Trials of FcRn Targeting for Autoimmune Diseases. Source: ACROBiosystems

Global Clinical Trials of FcRn Targeting for Autoimmune Diseases.

 

Summary

Drugs targeting FcRn do not use FcRn as a direct target for therapeutic intervention like traditional targets. Rather, it employs the advantages of cellular drug delivery, known as “revolutionary therapy”, that can erase all autoimmune diseases, with greater potential.

Concentrating on the potential of targeting FcRn in autoimmune diseases, principal pharmaceutical companies have come up with promises to treat all autoimmune diseases induced by autoantigens.

ACROBiosystems offers 19 high-quality FcRn protein products to encourage bispecific antibody, monoclonal antibody, ADC drug affinity research and targeted FcRn drug development for the treatment of autoimmune diseases.

Advantages of Fc receptor protein products

  • Expressed by HEK293 Cells: post-translational modification and proper protein folding
  • High purity: SDS-PAGE verification purity >95%, SEC-MALS verification purity > 90%
  • Multiple species: Human, Cynomolgus/Rhesus macaque, Mouse, Rat, Rabbit, Porcine, Feline, Bovine, can be applied wholly to various cross-species experiments
  • Low endotoxin: <1.0 EU/µg
  • Biotinylated FcRn proteins labeled with Avitag™ provided: The labeling efficacy is high, and the labeling site is specific and clear, which is suitable for ELISA/SPR/BLI detection depending on binding to streptavidin in the mechanism of drug development and optimization process
  • High stability: strict quality control to ensure high batch-to-batch consistency
  • Affinity verified by SPR and BLI: Activity guaranteed, and protocols offered free of charge

Product list

Source: ACROBiosystems

Molecule Cat.No. Host Product description Structure
FcRn (FCGRT & B2M) FCM-H5286 HEK293 Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (SPR & BLI & MALS verified)Hot
FCM-H8286 HEK293 Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag, ultra sensitivity (primary amine labeling) (SPR verified)
FCM-H82W4 HEK293 Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein, Avitag™, His Tag&Strep II Tag (SPR & BLI & MALS verified)Hot
FCM-H82W7 HEK293 Biotinylated Human FcRn / FCGRT&B2M Heterodimer Protein, His, Avitag™ (MALS & SPR verified)
FCN-H52W7 HEK293 Human FcRn / FCGRT&B2M Heterodimer Protein, His Tag (SPR & BLI & MALS verified)Hot
FCM-M52W2 HEK293 Mouse FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Twin-Strep Tag (MALS &
BLI verified)
FCM-M52W8 HEK293 Mouse FcRn / FCGRT&B2M Heterodimer Protein, His Tag (MALS & BLI verified)
FCM-M82W5 HEK293 Biotinylated Mouse FcRn / FCGRT&B2M Heterodimer Protein, His, Avitag™ (MALS & BLI verified)
FCM-M82W6 HEK293 Biotinylated Mouse FcRn / FCGRT&B2M Heterodimer Protein, Avitag™, His Tag&Twin-Strep Tag (MALS & BLI-verified)
FCM-R5287 HEK293 Rat FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & SPR verified)
FCM-R82W7 HEK293 Biotinylated Rat FcRn / FCGRT&B2M Heterodimer Protein, Avitag™, His Tag&Strep II Tag (MALS & SPR verified)
FCM-R52W5 HEK293 Rabbit FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Tag Free (MALS & SPR verified)
FCM-C5284 HEK293 Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & BLI verified)
FCM-C52W9 HEK293 Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His Tag (MALS & BLI verified)
FCM-C82W3 HEK293 Biotinylated Cynomolgus / Rhesus macaque FcRn / FCGRT&B2M Heterodimer Protein, His, Avitag™ (MALS & SPR verified)
FCM-C82W5 HEK293 Biotinylated Cynomolgus / Rhesus macaque FcRn Heterodimer Protein, His, Avitag™&Strep II Tag (SPR & BLI verified)
FCM-P5280 HEK293 Porcine FcRn / FCGRT&B2M Heterodimer Protein, His Tag&Strep II Tag (MALS & SPR verified)
FCN-F82W3 HEK293 Biotinylated Feline FcRn / FCGRT&B2M Heterodimer Protein, His, Avitag™ (MALS & SPR verified)
FCN-B82W3 HEK293 Biotinylated Bovine FcRn / FCGRT&B2M Heterodimer Protein, His, Avitag™ (SPR verified)

 

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Nov 11, 2021 at 8:12 AM

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