Mice expressing humanized Fc α receptors
Provided herein are methods and compositions related to mice that express human or humanized Foot receptors (FcaR) from an FcaR locus positioned in the mouse leukocyte receptor complex (LRC). In certain embodiments, such mice are useful for in vivo testing of therapeutic agents comprising a human IgA Fc (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such therapeutic agents and dosing regimens). Also provided herein are methods of using such mice, cells from such mice, methods of making such mice, and ES cells comprising the same genetic modifications as such mice. Provided herein are methods and compositions related to mice that express human or humanized Foot receptors (FcaR) from an FcaR locus positioned in the mouse leukocyte receptor complex (LRC). In certain embodiments, such mice are useful for in vivo testing of therapeutic agents comprising a human IgA Fc (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such therapeutic agents and dosing regimens). Also provided herein are methods of using such mice, cells from such mice, methods of making such mice, and ES cells comprising the same genetic modifications as such mice.
1 . A mouse comprising in its genome an Fc alpha receptor (FcαR) locus positioned in the mouse leukocyte receptor complex (LRC), wherein the FcαR locus comprises a nucleic acid sequence encoding a FcαR polypeptide comprising a human extracellular domain and a human or rodent cytoplasmic domain, and further comprising in its genome a human or humanized Fc gamma receptor (FcγR) locus, a human or humanized IgH locus, a human or humanized Igκ locus, a human or humanized Igλ locus, a human or humanized FcRn locus, a human or humanized β2M locus, and/or a human or humanized FcεR1α locus.
2 . The mouse of claim 1 , wherein the FcαR locus is positioned in an intergenic region between the gene loci for the Pira6 protein and the Ncr1 protein.
3 . The mouse of claim 1 , wherein the FcαR locus is positioned between coordinates 4,303,905-4,312,280 on mouse chromosome 7 (+strand, GRCm38 assembly).
4 . The mouse of claim 1 , wherein the nucleic acid sequence encodes a fully human FcαR polypeptide.
5 . The mouse of claim 1 , wherein the FcαR locus comprises human exons 1-5 of the human Fc alpha receptor gene.
6 . The mouse of claim 5 , wherein the FcαR receptor locus comprises a genomic sequence found between coordinates 54,862,297 and 54,906,185 on human chromosome 19 (+strand, GRCh38 assembly).
7 . The mouse of claim 5 , wherein the FcαR locus further comprises a nucleic acid sequence present in a human KIR3DL2 gene and/or a nucleic acid sequence present in the 5′UTR of the human NCR1 gene.
8 . The mouse of claim 1 , wherein the FcαR locus comprises a non-coding portion of non-mouse rodent FcαR exon 1, a coding portion of human FcαR exons 1 and 2, human FcαR exons 3 and 4, and non-mouse rodent FcαR exon 5.
9 . The mouse of claim 1 , wherein the mouse expresses the FcαR polypeptide on mouse neutrophils, monocytes, macrophages, eosinophils, and dendritic cells.
10 . The mouse of claim 1 , wherein the mouse is homozygous for the FcαR locus.
11 . The mouse of claim 1 , wherein the FcαR polypeptide comprises a human or rodent transmembrane domain.
12 . A mouse comprising in its genome an Fc alpha receptor (FcαR) locus positioned in the mouse leukocyte receptor complex (LRC), wherein the FcαR locus comprises a nucleic acid sequence encoding a FcαR polypeptide comprising a human extracellular domain, a human transmembrane domain, and a human cytoplasmic domain, wherein the FcαR locus comprises human exons 1-5 of the human Fc alpha receptor gene, and wherein the FcαR locus further comprises a nucleic acid sequence present in the 5′UTR of the human NCR1 gene.
13 . The mouse of claim 12 , wherein the FcαR locus further comprises a nucleic acid sequence present in a human KIR3DL2 gene.
14 . The mouse of claim 12 , wherein the FcαR locus is positioned in an intergenic region between the gene loci for the Pira6 protein and the Ncr1 protein.
15 . The mouse of claim 12 , wherein the FcαR locus is positioned between coordinates 4 , 303 , 905 - 4 , 312 , 280 on mouse chromosome 7 (+strand, GRCm38 assembly).
16 . The mouse of claim 12 , wherein the FcαR receptor locus comprises a genomic sequence found between coordinates 54,862,297 and 54,906,185 on human chromosome 19 (+strand, GRCh38 assembly).
17 . The mouse of claim 12 , wherein the mouse expresses the FcαR polypeptide on mouse neutrophils, monocytes, macrophages, eosinophils, and dendritic cells.
18 . The mouse of claim 12 , wherein the mouse is homozygous for the FcαR locus.
19 . The mouse of claim 12 , further comprising in its genome a human or humanized Fc gamma receptor (FcγR) locus, a human or humanized IgH locus, a human or humanized Igκ locus, a human or humanized Igλ locus, a human or humanized FcRn locus, a human or humanized β2M locus, and/or a human or humanized FcεR1α locus.
20 . A mouse comprising in its genome an Fc alpha receptor (FcαR) locus positioned in the mouse leukocyte receptor complex (LRC), wherein the FcαR locus comprises a nucleic acid sequence encoding a FcαR polypeptide comprising a human extracellular domain, a rodent transmembrane domain, and a rodent cytoplasmic domain, wherein the FcαR locus comprises a non-coding portion of non-mouse rodent FcαR exon 1, a coding portion of human FcαR exons 1 and 2, human FcαR exons 3 and 4, and non-mouse rodent FcαR exon 5.
21 . The mouse of claim 20 , wherein the FcαR locus is positioned in an intergenic region between the gene loci for the Pira6 protein and the Ncr1 protein.
22 . The mouse of claim 20 , wherein the FcαR locus is positioned between coordinates 4,303,905-4,312,280 on mouse chromosome 7 (+strand, GRCm38 assembly).
23 . The mouse of claim 20 , wherein the mouse expresses the FcαR polypeptide on mouse neutrophils, monocytes, macrophages, eosinophils, and dendritic cells.
24 . The mouse of claim 20 , wherein the mouse is homozygous for the FcαR locus.
25 . The mouse of claim 20 , further comprising in its genome a human or humanized Fc gamma receptor (FcγR) locus, a human or humanized IgH locus, a human or humanized Igκ locus, a human or humanized Igλ locus, a human or humanized FcRn locus, a human or humanized β2M locus, and/or a human or humanized FcεR1α locus.