Name: huFcRn(FCGRT) Mouse
Brand: 싸이아젠(Cyagen)
SKU: C001701

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huFcRn(FCGRT) Mouse

제품명

huFcRn(FCGRT) Mouse

제품 ID

C001701

품종 계통

C57BL/6NCya-Fcgrt^tm2(hFCGRT)/Cya

Backgroud

C57BL/6NCya

상태

이 마우스 계통을 논문에서 사용할 경우, “huFcRn(FCGRT) Mouse (카탈로그 번호 C001701)은 Cyagen에서 구입하였습니다.”라고 명시해 주시기 바랍니다.

HUGO-GT Humanized Models

Immune Target Humanized Mouse Models

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Genotype

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가격 문의

HUGO-GT Humanized Models

Immune Target Humanized Mouse Models

기본 정보

검증 데이터

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mouse, in which the sequence encoding the extracellular domain of the endogenous protein in the mouse Fcgrt gene has been replaced by the corresponding sequence in the human FCGRT gene. huFcRn(FCGRT) 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.

Reference

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.

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.

Ilie M, Hofman P. Atezolizumab in advanced non-small cell lung cancer. J Thorac Dis. 2017 Oct;9(10):3603-3606.

Amgen Inc. (2024). REPATHA (evolocumab) injection, for subcutaneous use [PDF document]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125522s043lbl.pdf

Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020 Jun;86:102017.

변형 전략

The mouse Fcgrt endogenous extracellular domain was replaced with the human FCGRT extracellular domain. The murine signal peptide was remained.

Figure 1. Gene editing strategy of huFcRn(FCGRT) mice.

응용 분야

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.

검증 데이터

1. Expression detection of human FCGRT gene

RT-qPCR was used to detect the expression of the human FCGRT gene using species-specific primers. The results showed that huFcRn(FCGRT) mice successfully expressed the human FCGRT gene.

Figure 2. Expression of the human FCGRT gene (hFCGRT) in the kidneys and livers of wild-type (WT) mice and huFcRn(FCGRT) mice.

2. Expression detection of human FcRn protein

The expression of human FcRn protein was detected by Western Blotting using a species-specific FcRn antibody. The results showed that huFcRn(FCGRT) mice successfully expressed human FcRn protein.

Figure 3. Human FcRn protein expression in the liver and kidney of wild-type mice (WT) and huFcRn(FCGRT) mice.

3. Mouse IgG Expression Assay

The serum of the mice was collected, and the expression level of mouse IgG was detected by enzyme-linked immunosorbent assay (ELISA) using a mouse IgG-specific ELISA kit. The results showed that the content of mIgG in the serum of huFcRn(FCGRT) mice was lower than that in WT mice.

Figure 4. Expression of mouse IgG in the serum of huFcRn(FCGRT) mice and wild-type (WT) mice (7-week-old, homozygous, female, n=6).

4. In vivo pharmacokinetics (PK) of monoclonal antibody drugs

（1）Atezolizumab

The human IgG1 subtype antibody Atezolizumab at a concentration of 10 mg/kg was injected into the tail veins of huFcRn(FCGRT) mice and WT mice, respectively. The serum of the mice was collected at different time points, and the concentration of the hIgG1 subtype antibody was analyzed by enzyme-linked immunosorbent assay (ELISA) using a human IgG1-specific ELISA kit. The results showed that the pharmacokinetic profile of Atezolizumab differed between huFcRn(FCGRT) mice and wild-type mice. Specifically, the half-life of Atezolizumab was longer in wild-type mice (with murine FcRn), which is consistent with previous reports. This indicates that the antibody has a higher affinity for murine FcRn.

*Atezolizumab is a humanized monoclonal IgG1 antibody. It activates the tumor-specific immune response by blocking the interaction between PD-L1 and PD-1/B7.1 receptors, and can directly inhibit the proliferation of tumor cells, and induce mitochondrial-related apoptosis and autophagy ^[3].

Figure 5. In vivo pharmacokinetics (PK) of Atezolizumab in huFcRn(FCGRT) mice and wild-type (WT) mice (8-week-old, homozygous, female, n=3).

（2）Evolocumab

The human IgG2 subtype antibody Evolocumab at a concentration of 10 mg/kg was injected into the tail veins of huFcRn(FCGRT) mice and WT mice, respectively. The serum of the mice was collected at different time points, and the concentration of the hIgG2 subtype antibody was analyzed by enzyme-linked immunosorbent assay (ELISA) using a human IgG2-specific ELISA kit. The results showed that the pharmacokinetic profile of Evolocumab differed between huFcRn(FCGRT) mice and wild-type mice. Specifically, Evolocumab exhibited a longer half-life in wild-type mice (which express murine FcRn), a finding consistent with previous reports. This indicates that the antibody has a higher affinity for murine FcRn.

*Evolocumab is a fully human monoclonal antibody. By specifically binding to and inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), it increases the number of low-density lipoprotein (LDL) receptors on the surface of hepatocytes, thereby significantly reducing the level of low-density lipoprotein cholesterol (LDL-C) in the blood. It is suitable for the treatment of primary hypercholesterolemia, familial hypercholesterolemia (including homozygous and heterozygous types), and the control of cardiovascular risks in patients with atherosclerotic cardiovascular diseases ^[4].

Figure 6. In vivo pharmacokinetics (PK) of Evolocumab in huFcRn(FCGRT) mice and wild-type (WT) mice (8-week-old, homozygous, female, n=3).

（3）Bevacizumab

The human IgG1-subtype antibody Bevacizumab was administered to huFcRn(FCGRT) mice and WT mice via tail vein injection, respectively. Antibody concentrations were analyzed using enzyme-linked immunosorbent assay (ELISA). The results showed that:

① The drug half-life in WT mice was longer than that in huFcRn(FCGRT) mice, which was consistent with reported data. This is attributed to the higher affinity between wild-type human antibodies and murine FcRn.

② After undergoing different modifications, the antibody exhibited a prolonged drug half-life in huFcRn(FCGRT) mice.

*Bevacizumab is a recombinant humanized IgG1 monoclonal antibody that specifically inhibits vascular endothelial growth factor (VEGF) to block tumor angiogenesis. It is indicated for the treatment of various solid tumors, including advanced colorectal cancer, non-small cell lung cancer, ovarian cancer, and cervical cancer^[5].

Figure 7. In vivo pharmacokinetics (PK) of Bevacizumab in huFcRn(FCGRT) Mice and Wild-Type (WT) Mice (6–8 weeks old, female)*.

5. Half-Life Comparison of IgG1-Type Antibody Before and After Modification*

（1）YTE mutation modification extends the antibody half-life (female mice).

Female huFcRn(FCGRT) mice were intravenously injected with the IgG1-type antibody at a dose of 10 mg/kg. The antibody concentration in mice was detected by ELISA at different time points. The results showed that the half-life of the Ab antibody was prolonged after YTE mutation modification.

*This data was provided by Cyagen's partner.

Figure 8. Pharmacokinetic Analysis of IgG1-Type Antibody in huFcRn(FCGRT) Mice*.

（2）After YTE mutation modification, there is no significant gender difference in the antibody half-life between female and male mice.

When the same modified antibody was injected into huFcRn(FCGRT) mice of different genders, there was no significant gender difference in its half-life.

*This data was provided by Cyagen's partner.

Figure 9. Pharmacokinetic Analysis of IgG1-Type Antibody in huFcRn(FCGRT) Mice*.

6. Other Pharmacokinetic (PK) Evaluation Cases

A single subcutaneous dose of 1mg/kg IgG1-type antibody was administered to 7-week-old male mice. Antibody concentrations in the mice were detected at different time points. The results showed that:

① The unmodified Ab antibody exhibited a longer half-life in WT mice (murine FcRn), which was consistent with reported data, indicating a higher affinity of this antibody for murine FcRn.

② After undergoing different modifications, the Ab antibody showed prolonged half-life in huFcRn(FCGRT) mice.

*The data and test antibodies were provided by Cyagen's partner.

Figure 10. Pharmacokinetic Analysis of IgG1-Type Antibodies in huFcRn(FCGRT) Mice and Wild-Type (WT) Mice*.

huFcRn(FCGRT) Mouse

기본 정보

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관련 자료

유전자명

유전자 별칭

NCBI ID

염색체

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Datasheet

품종 계통 설명

Reference

변형 전략

응용 분야

1. Expression detection of human FCGRT gene

2. Expression detection of human FcRn protein

3. Mouse IgG Expression Assay

4. In vivo pharmacokinetics (PK) of monoclonal antibody drugs

5. Half-Life Comparison of IgG1-Type Antibody Before and After Modification*

6. Other Pharmacokinetic (PK) Evaluation Cases

관련 제품

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