B6N-hFCRN(Extra) Mice

Catalog Number: I001007

Strain Name: C57BL/6NCya-Fcgrttm2(hFCGRT)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Neonatal Fc receptor (FcRn) is a cell surface receptor protein that binds to the Fc region of IgG antibodies. It is structurally similar to MHC class I molecules and is composed of an α-chain and β2-microglobulin (β2M). The α-chain of the FcRn receptor is encoded by the Fcγ receptor and transporter (FCGRT) gene, while β2-microglobulin is encoded by the β-2-microglobulin (B2M) gene. FcRn is expressed widely on epithelial cells, endothelial cells, and hematopoietic cells, and is found in a variety of tissues and organs, including the intestine, placenta, kidney, and liver [1-2].

IgG antibodies are the most abundant immunoglobulins in human serum (about 75%), and play an important role in the immune response by defending against pathogens and toxins. Compared to other immunoglobulins, IgG has a high circulating level, a longer half-life, and the ability to be transferred from mother to offspring. These properties are closely related to its interaction with FcRn. FcRn binds to the Fc region of IgG, preventing IgG molecules from being degraded by lysosomes. This prolongs the in vivo half-life of IgG and is involved in the transport, maintenance, and distribution metabolism of IgG. In addition, the specific transport process of IgG from the mother to the fetus to provide the fetus with short-term passive immunity is also mediated by FcRn [1-2]. In addition to its protective role, IgG autoantibodies are also associated with many pathological conditions. Therefore, novel FcRn blocking therapies are an effective strategy to reduce the circulating levels of pathogenic IgG autoantibodies and to reduce IgG-mediated diseases. In addition, many drugs also utilize FcRn's protective mechanism for IgG by fusing or conjugating with the Fc portion of IgG to prolong its serum half-life and improve its pharmacokinetics. The FCGRT gene encodes the α-chain of the FcRn protein, and its homologous genes are present in most mammals.

This model is a humanized FcRn mouse, in which the sequence encoding the extracellular domain of the endogenous protein in the mouse Fcgrt gene has been replaced by the corresponding sequence in the human FCGRT gene. B6N-hFCRN(Extra) mice are therefore useful for in vivo studies of IgG, screening of IgG antibody drug candidates, and evaluating the pharmacology, efficacy, and pharmacokinetics of drugs. The homozygous mice are viable and fertile.

Strain Strategy

The sequence encoding the extracellular domain of the mouse FCGRT protein in the mouse Fcgrt gene has been replaced by the corresponding sequence in the human FCGRT gene using gene editing technology.


Applications

  • In vivo transport, maintenance, and metabolism studies of IgG;
  • Development and screening of IgG antibody drug candidates;
  • Pharmacology, efficacy, and pharmacokinetics of IgG antibody drugs;
  • Evaluation of Fc-based immunotherapy.

 

Validation Data

1. Expression detection of human FCGRT gene


Figure 1. Expression of the human FCGRT gene (hFCGRT) in the kidneys and livers of wild-type (WT) mice and B6N-hFCRN (Extra) mice. RT-qPCR was used to detect the expression of the human FCGRT gene using species-specific primers. The results showed that B6N-hFCRN (Extra) mice successfully expressed the human FCGRT gene.

2. Expression detection of human FcRn protein


Figure 2. Human FcRn protein expression in the liver and kidney of wild-type mice (WT) and B6N-hFCRN(Extra) mice. The expression of human FcRn protein was detected by Western Blotting using a species-specific FcRn antibody. The results showed that B6N-hFCRN(Extra) mice successfully expressed human FcRn protein.

3. In vivo pharmacokinetics (PK) of FcRn-specific antibody (Ab1)


Figure 3. Pharmacokinetics of FcRn-specific antibody (Ab1) in B6N-hFCRN(Extra) and wild-type (WT) mice*. The pharmacokinetics (PK) curves show that the drug half-life of Ab1 antibodies in B6N-hFCRN(Extra) mice is significantly extended than that in wild-type mice.

*The data was provided by a collaborating client of Cyagen.

 

References
[1]Challa DK, Velmurugan R, Ober RJ, Sally Ward E. FcRn: from molecular interactions to regulation of IgG pharmacokinetics and functions. Curr Top Microbiol Immunol. 2014;382:249-72.
[2]Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. J Allergy Clin Immunol. 2020 Sep;146(3):467-478.