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Your Position: Home > Insights > Increase or Decrease: The Two Therapeutic Strategies via FcRn-Mediated Mechanism
Increase or Decrease: The Two Therapeutic Strategies via FcRn-Mediated Mechanism
Release time: 2022-01-25 Source: ACROBiosystems Read: 6882

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On December 17, 2021, Argenx, a global immunology company, announced that the FDA had approved VYVGART™ (EFgartigimod AlFA-FCAB), the world's first antibody-drug targeting FcRn. This drug treats general Myasthenia gravis (gMG) in adults with positive anti-acetylcholine receptor (AChR) antibodies. As early as January 2021, Zai Lab Pharmaceutical has entered into an agreement with Argenx for the exclusive right to develop and commercialize EFgartigimod in Greater China.

Antibodies are components of the humoral immune response, which is part of the adaptive branch of the immune system. Antibodies are also known as immunoglobulins (Ig), and there are five different types (IgA, IgD, IgE, IgG, and IgM) with varying:

- Molecular weights range from ~150 kDa (IgG) to ~900 kDa (IgM).  

- Half-life, ranging from 3 days for IgA and IgD to 23 days for IgG (except for IgG3).

- Immune functions include complement binding ability, immune cell binding affinity, and action sites.

The constant region of the antibody heavy chain determines that IgG has a γ heavy chain, IgM has a μ heavy chain, IgA has an α heavy chain, IgD has a δ heavy chain, IgE has an ε heavy chain. The Fab region is flexible and responsible for antigen binding, while the Fc region is responsible for the binding of cellular receptors located on the surface of cells, conferring its effector function.

Distribution and function of different immunoglobulins

FcRn is a receptor that binds exclusively to IgG and mediates a recycling mechanism for IgG transport in a pH-dependent manner.  (Click here to find out more about the structure of FcRn and its mediated recycling mechanism) Two therapeutic strategies rely on FcRn-mediated mechanisms:

(1)Decrease in the half-life of pathological IgG antibody to treat autoimmune diseases.

(2)Increase in the half-life of therapeutic antibody drugs to extend the therapeutic benefits.

Decrease in the half-life of pathological IgG antibody to treat autoimmune diseases

Various autoimmune diseases such as myasthenia gravis (MG), chronic inflammatory demyelinating multiple radiculopathy (CIDP), pemphigus, and primary immune thrombocytopenia are mediated by IgG autoantibodies. For instance, these antibodies play a pathogenic role in MG, leading to the failure of neuromuscular signal transduction by receptors and proteins at neuromuscular junctions. To address this mechanism of autoimmunity, leaders in the field have explored FcRn inhibitors to decrease the pathogenesis of IgG and develop targeted therapies. This approach can potentially decrease endogenous pathogenic IgG concentrations by leveraging the discrepancy in FcRn affinity, resulting in competitive binding with endogenous IgG causing autoimmune disease.

Structure of FcRn targeted drugs

- Efgartigimod is the first and the only FcRn antagonist approved by FDA. Efgartigimod is a modified fragment of human IgG1 Fc that binds to FcRn with high affinity. It is also the first approved therapy specifically targeted at reducing pathogenic IgG, providing a new therapeutic approach for treating gMG. In a Phase I trial, IgG levels were decreased by 50-75% with no effect on albumin levels. This study progressed into a Phase II trial which resulted in 75% of patients showing improvement in a timely manner with minimal to no relapse. Finally, phase III trial studies showed improvement in daily activities in MG patients.

- Rozanolixizuma is a humanized monoclonal antibody derived from UCB Biopharma, a biotechnology company based in Brussels. Rozanolixizuma can specifically bind human FcRn, block the interaction between FcRn and IgG, inhibit the IgG cycle, and induce the clearance of pathogenic IgG autoantibodies. Rozanolixizuma is currently in phase III trials.

- Nipocalimab is an IgG1 anti-FcRn monoclonal antibody developed by Johnson  Johnson. This therapeutic decreases IgG levels by up to 90%, showing a slight decrease in total protein and serum albumin levels. However, adverse reactions such as headaches and fever indicated that the tolerability of Nipocalimab needs to be improved.

- Batoclimab (RVT-1401) is a complete human monoclonal antibody derived from Harbour BioMed. Batoclimab binds to FcRn and blocks FcRn-IgG interaction to accelerate the degradation of autoantibodies and treat a variety of pathogenic IgG-mediated autoimmune diseases. This product has been included as a breakthrough therapy in China and is currently undergoing clinical trials for various indications.

Increase in the half-life of therapeutic antibody drugs to extend the therapeutic benefits.

Structure of IgG antibody and FcRn-mediated recycling mechanism

The FcRn pathway has been used to prolong the half-life of therapeutic antibodies. Antibody binding to FcRn can be enhanced using biomolecular engineering technology, fusing Fc fragments, or exchanging amino acids in specific binding bags.

- Etanercept is a treatment consisting of a TNF receptor and an IgG1 Fc fragment approved for rheumatoid arthritis (RA) and other autoimmune diseases. Etanercept can be combined to freely utilize TNFα and β, thereby reducing the levels of these inflammatory factors. During degradation, TNF can be broken down upon release, while Fc fragments can pass through the FcRn pathway, resulting in decreased levels of pro-inflammatory cytokines and a prolonged half-life of therapeutic drugs.

- VRC01 is a neutralizing monoclonal antibody (bnMAb) IgG1 broadly used for HIV-1 prevention. VRC01LS performs two amino acid mutations (M428L and N434S) in the Fc region of VRC01 to extend the serum half-life. LS mutations enhance IgG-FcRn binding, with no effect on FcγRs binding. Hence, VRC01 does not impair Fc-mediated effector functions like antibody-dependent cytotoxicity (ADCC).

- Eculizumab, a monoclonal antibody that inhibits complement protein, C5, is the first drug therapy approved to treat life-threatening thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome (aHUS), improving outcomes in patients with aHUS and TMA. However, Eculizumab requires intravenous infusion every 2-3 weeks, increasing the infusion burden and associated adverse events. To overcome this problem, a long-effective anti-C5 monoclonal antibody (Ravulizumab, Ultomiris®) engineered based on Eculizumab offers an important treatment option. Ravulizumab is a combination of Eculizumab with two structural changes designed to extend its terminal elimination half-life. First, two histidine substitutions in the complementary determinate region increased the dissociation rate of the monoclonal antibody C5 complex at pH 6.0, eliminating targeted mediated antibody clearance. Secondly, the affinity of the antibody to human FcRn was enhanced by two amino acid substitutions in the Fc region. Ravulizumab addresses TMA and is well tolerated in adult and pediatric aHUS patients. The mechanism of action is similar to Eculizumab except with a 4-fold increase in action time; hence, minimizing the maintenance dose frequency.

- Satralizumab is a humanized monoclonal antibody targeting IL-6R, and it utilizes a new "antibody recycling technique." Tocilizumab is injected subcutaneously at 162mg per week, while Satralizumab alters the amino acid sequence in the Fc region: mutating a tyrosine residue to a histidine residue, allowing longer antibody cycle time, and thus reducing the frequency of administration, at 120mg per month subcutaneously.(Click here to view previous highlights: 【Inspiring Target】Therapeutic potential of IL-6 immunization in multiple fields continues to burst)

To support affinity validation of antibody drugs and the development of FcRn-targeted antibody drugs for the treatment of autoimmune diseases, ACROBiosystems provides you with a range of high-quality FcRn proteins.

FcRn: Product Features

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

Variousspecies: Human, Mouse, Cynomolgus/Rhesus macaque, Rat, Porcine, Rabbit, Feline, Bovine, canbe fully applied to different cross-species experiments

High purity:

more than 95% as verified by SDS-PAGE

more than 90% as verified by SEC-MALS

Low endotoxin:<1.0 EU/µg

Biotinylated FcRnproteins labeled with AvitagTMoffered. High labeling efficiency, specificity, and clarity. Suitable for ELISA/SPR/BLIdetection based on binding to streptavidin for drug development and optimization process

Affinity verified by SPR  BLI:bioactivity is tested and guaranteed, and protocols are offered freeof charge.

Product List
MoleculeCat. No.HostProduct DescriptionStructure
FcRn (FCGRT  B2M)FCM-H5286HEK293Human FcRn / FCGRTB2M Heterodimer Protein, His TagStrep II Tag (SPR MALS verified)Hot
FCM-H8286HEK293Biotinylated Human FcRn / FCGRTB2M Heterodimer Protein, His TagStrep II Tag, ultra sensitivity (primary amine labeling) (SPR verified)
FCM-H82W4HEK293Biotinylated Human FcRn / FCGRTB2M Heterodimer Protein,,His TagStrep II Tag (SPR  BLI  MALS verified)Hot
FCM-H82W7HEK293Biotinylated Human FcRn / FCGRTB2M Heterodimer Protein, His,(MALS  SPR verified)
FCN-H52W7HEK293Human FcRn / FCGRTB2M Heterodimer Protein, His Tag (SPR  BLI MALS verified)Hot
FCM-M52W2HEK293Mouse FcRn / FCGRTB2M Heterodimer Protein, His TagTwin-Strep Tag (MALS  BLI verified)
FCM-M52W8HEK293Mouse FcRn / FCGRTB2M Heterodimer Protein, His Tag (MALS  BLI verified)
FCM-M82W5HEK293Biotinylated Mouse FcRn / FCGRTB2M Heterodimer Protein, His,(MALS  BLI verified)
FCM-M82W6HEK293Biotinylated Mouse FcRn / FCGRTB2M Heterodimer Protein,,His TagTwin-Strep Tag (MALS  BLI-verified)
FCM-R5287HEK293Rat FcRn / FCGRTB2M Heterodimer Protein, His TagStrep II Tag (MALS SPR verified)
FCM-R82W7HEK293Biotinylated Rat FcRn / FCGRTB2M Heterodimer Protein,,His TagStrep II Tag (MALS  SPR verified)
FCM-R52W5HEK293Rabbit FcRn / FCGRTB2M Heterodimer Protein, His TagTag Free (MALS SPR verified)
FCM-C5284HEK293Cynomolgus / Rhesus macaque FcRn / FCGRTB2M Heterodimer Protein, His TagStrep II Tag (MALS  BLI verified)
FCM-C52W9HEK293Cynomolgus / Rhesus macaque FcRn / FCGRTB2M Heterodimer Protein, His Tag (MALS  BLI verified)
FCM-C82W3HEK293Biotinylated Cynomolgus / Rhesus macaque FcRn / FCGRTB2M Heterodimer Protein, His,(MALS  SPR verified)
FCM-C82W5HEK293Biotinylated Cynomolgus / Rhesus macaque FcRn Heterodimer Protein, His,Strep II Tag (SPR  BLI verified)
FCM-P5280HEK293Porcine FcRn / FCGRTB2M Heterodimer Protein, His TagStrep II Tag (MALS  SPR verified)
FCN-F82W3HEK293Biotinylated Feline FcRn / FCGRTB2M Heterodimer Protein, His,(MALS  SPR verified)
FCN-B82W3HEK293Biotinylated Bovine FcRn / FCGRTB2M Heterodimer Protein, His,(MALS  SPR verified)

>>>    Click here to find out more high-quality FcRn proteins and verification data with free protocols
 

FcRn(Neonatal Fc Receptor)

Parallel to the previous work, ACROBiosystems has also been developing a series of IgG Fc proteins, containing only the hinge region, CH2 and CH3 sequences, without the Fab sequences. These IgG Fc proteins can be used as ideal isotype controls for monoclonal antibodies, IgG-like bispecific antibodies, ADC, and IgG Fc- fusion drugs. Applications of this product include drug screening, functional verification, etc. In addition, our IgG Fc proteins are used as endogenous IgG for competitive validation of FcRn binding to FcRn targeted antibody drugs.

IgG Fc: Product Features

Expressed by HEK293 cells: for post-translational glycosylation, modifications, and correct protein folding

Various species and subclasses:

Human IgG1 Fc,IgG2 Fc,IgG3 Fc,IgG4 Fc

Mouse IgG1 Fc,IgG2a Fc,IgG2b Fc

Llama IgG2b Fc,Rabbit IgG Fc

Various tags: Tag Free,AvitagTM,His Tag,gDTag,Flag Tag,AvitagTM His tag

Low endotoxin: Less than 1.0 EU/μg by the LAL method

High purity:

more than 95% as verified by SDS-PAGE

more than 90% as verified by SEC-MALS

Highbioactivity: verified by ELISA  SPR with free protocols

IgG Fc:Product List
MoleculeCat. No.SpeciesProduct descriptionPreorder/Order
IgG1 FcFCC-H5214HumanHuman IgG1 Fc Protein, Tag Free (MALS verified)

Order

IgG1 FcIG1-H5225HumanHuman IgG1 Fc Protein, His Tag (MALS verified)

Order

IgG1 FcIG1-H52C9HumanHuman IgG1 Fc (C103S) Protein, Flag Tag (MALS verified)

Order

IgG1 FcIG1-H52G6HumanHuman IgG1 Fc (C103S) Protein, gD Tag (MALS verified)

Order

IgG1 FcIG1-H8213HumanBiotinylated Human IgG1 Fc protein,(MALS verified)

Order

IgG1 FcIG1-H82E9HumanBiotinylated Human IgG1 Fc (C103S) Protein,,His Tag

Preorder

IgG1 FcIG1-M5208MouseMouse IgG1 Fc Protein, Tag Free (MALS verified)

Order

IgG1 FcIG1-M8211MouseBiotinylated Mouse IgG1 Fc protein,(MALS verified)

Order

IgG2 FcIG2-H5206HumanHuman IgG2 Fc Protein, Tag Free (MALS & SPR verified)

Order

IgG2a FcIGA-M5207MouseMouse IgG2a Fc Protein, Tag Free (MALS verified)

Order

IgG2a FcIGA-M8210MouseBiotinylated Mouse IgG2a Fc Protein,(MALS verified)

Order

IgG2b FcIGB-M5203MouseMouse IgG2b Fc Protein, Tag Free (MALS verified)

Order

IgG2b FcIGB-L5204LlamaLlama IgG2b Fc Protein, Tag Free (MALS verified)

Order

IgG3 FcIG3-H5200HumanHuman IgG3 Fc Protein, Tag Free (MALS & SPR verified)

Order

IgG3 FcIG3-M5214MouseMouse IgG3 Fc Protein, Tag Free (MALS verified)

Order

IgG4 FcIG4-H5205HumanHuman IgG4 Fc Protein, Tag Free (MALS & SPR verified)

Order

IgG FcIGG-R5203RabbitRabbit IgG Fc Protein, Tag Free (MALS verified)

Order

>>> Click here to find out more IgG Fc proteins and verification data with free    protocols

IgG Fc Proteins——Ideal Isotype Control for IgG Structured Drug Development

References:

1. Hans-Hartmut    Peter, Hans D. Ochs, Charlotte Cunningham-Rundles, et al. Targeting FcRn for immunomodulation: Benefits, risks, and    practical considerations. Journal of Allergy and Clinical Immunology. 2020, 146(3): 479-491.    https://doi.org/10.1016/j.jaci.2020.07.016.

2. Adrian W. Zuercher, Rolf Spirig, Adriana    Baz Morelli et al. Next-generation Fc receptor–targeting biologics for autoimmune diseases, Autoimmunity Reviews,    2019,18(10). https://doi.org/10.1016/j.autrev.2019.102366

3. Yahiya Y. Syed. Ravulizumab: A Review in    Atypical Haemolytic Uraemic SyndromeDrugs. 2021, 81: 587–594. https://doi.org/10.1007/s40265-021-01481-6

4. Gil I. Wolfe, E. Sally Ward, Hans de    Haard et al. IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis, Journal    of the Neurological Sciences, 2021, 430. https://doi.org/10.1016/j.jns.2021.118074

5. Johann Sellner, Harald H. Sitte, Paulus    S. Rommer. Targeting interleukin-6 to treat neuromyelitis optica spectrum disorders: Implications from immunology,    the FcRn pathway and clinical experience, Drug Discovery Today, 2021, 26(7):1591-1601,    https://doi.org/10.1016/j.drudis.2021.03.018

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