FcRn-/- hFcRn (line 276) Tg mice are useful in evaluating the pharmacokinetics and pharmacodynamics of human immunoglobulin G (hIgG), such as therapeutic IgG. These mice carry a null mutation for the mouse gene and a transgene expressing the human FcRn α-chain under the control of the ubiquitous CAG promoter.
Dr. Derry Roopenian, The Jackson Laboratory
FcRn-/- hFcRn (276) Tg mice harbor a knockout allele of the FcRn α-chain (Fcgrttm1Dcr) and express the human FcRn α-chain cDNA (FCGRT) under the control the human cytomegalovirus immediate early promoter/enhancer with chicken beta-actin/rabbit beta-globin hybrid promoter (CAG). FcRn-/- mice (see Stock No. 003982) lack murine FcRn α-chain expression and fail to transport IgG across the neonatal gut; they do not recycle IgG and albumin and therefore show low plasma levels of both. In FcRn-/- hFcRn (276) Tg mice, plasma albumin levels are similar to wild-type mice, however the serum IgG levels remain low due to the species-specific behavior of human FcRn. A number of studies have shown this model's usefulness for pharmacokinetic and pharmacodynamic studies of human IgG and to screen hIgGs, with regard to their serum half-life. For example, human antibodies engineered to have enhanced binding to human FcRn (Hu4D5-IgG1, directed against human EGFR2) exhibit a significant increase in their serum half-life (2-2.5 fold) in these mice. Specifically, longer half-lives are observed in this strain with mice homozygous for the hFcRn transgene (hFcRn Tg/Tg) when compared to mice hemizygous for the hFcRn transgene (hFcRn Tg/0), indicating that higher copy number correlates with higher expression of FCGRT and provides greater protection of IgG from clearance. This mouse model is useful for studying human FcRn biology and the behavior of IgG antibodies and Fc-domain proteins, including Fc-engineered molecules.
FcRn α-chain knockout mice expressing a human FcRn transgene (line 276) are also called FcRn-/- hFcRn (276) Tg mice, cDNA transgenic line 276, mFcRn-/- hFcRn (276) Tg [carrying one allele of the transgene], or mFcRn-/- hFcRn (276) Tg/Tg [carrying two alleles of the transgene]. These FcRn-/- hFcRn (276) Tg mice were generated in the laboratory of Derry Roopenian (The Jackson Laboratory) by crossing Fcgrttm1Dcr targeted mutant mice (backcrossed five generations to C57BL/6J) with Tg(CAG-FCGRT)276Dcr transgenic mice (coisogenic on a C57BL/6J genetic background). These double mutant mice were backcrossed for several additional generations to C57BL/6J (~N11) prior to transfer to The Jackson Laboratory Repository.
To generate the FcRn α-chain knockout mice (Fcgrttm1Dcr; see also Stock No. 003982), a targeting vector was designed to replace 1588 nucleotide fragments (encoding promoter sequence 5' of the transcriptional start site, exon1, intron 2, and most of exon2) with a PGK-Neor cassette. The vector was electroporated into 129X1/SvJ-derived ESV/J-1182 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice. These FcRn α-chain mutant mice were backcrossed to C57BL/6J for five generations prior to breeding with hFcRn line 276 transgenic mice.
To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn α-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. The donating investigator reports that this transgene was injected into C57BL/6J embryos. The resulting transgenic offspring were bred to C57BL/6J mice to establish founder line 276. These hFcRn line 276 transgenic mice were maintained on a C57BL/6J genetic background.
|Expressed Gene||FCGRT, Fc fragment of IgG receptor and transporter, human|
|Site of Expression|
|Allele Name||targeted mutation 1, Derry C Roopenian|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Fcgrt, Fc receptor, IgG, alpha chain transporter|
|Gene Synonym(s)||FCRN; FcRn; alpha-chain; neonatal Fc receptor|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product.|
|Allele Name||transgene insertion 276, Derry C Roopenian|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||Tg276; hFcRn (276) Tg|
|Gene Symbol and Name||Tg(CAG-FCGRT)276Dcr, transgene insertion 276, Derry C Roopenian|
|Gene Synonym(s)||hFcRn (276) Tg|
|Promoter||ACTB, actin, beta, chicken|
|Expressed Gene||FCGRT, Fc fragment of IgG receptor and transporter, human|
|Strain of Origin||C57BL/6J|
|Molecular Note||To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn alpha-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. Line 276 was established.|
When using the FcRn KO hFcRn Tg mouse strain in a publication, please cite the originating article(s) and include JAX stock #004919 in your Materials and Methods section.
|Heterozygous for Fcgrt<tm1Dcr>, Hemizygous for Tg(CAG-FCGRT)276Dcr|
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