US2015342163A1PendingUtilityA1

Genetically modified major histocompatibility complex mice

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Assignee: REGENERON PHARMAPriority: Feb 22, 2013Filed: Aug 19, 2015Published: Dec 3, 2015
Est. expiryFeb 22, 2033(~6.6 yrs left)· nominal 20-yr term from priority
Inventors:Vera VoroninaCagan GurerAndrew J. MurphyLynn MacdonaldYingze Xue
A01K 2267/03A01K 2227/105C12N 15/8509A01K 2217/072C07K 14/70539A01K 67/0271A01K 2207/15C07K 14/70514C07K 14/70517A01K 67/0278
56
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Claims

Abstract

The invention provides genetically modified non-human animals that express chimeric human/non-human MHC I and MHC II polypeptides and/or human or humanized β2 microglobulin polypeptide, as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same. Methods of using the genetically modified animals to study various aspects of human immune system are provided.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A non-human animal comprising at an endogenous MHC locus:
 a first nucleotide sequence encoding a chimeric human/non-human animal MHC I polypeptide, wherein a human portion of the chimeric MHC I polypeptide comprises an extracellular domain of a human MHC I polypeptide,   a second nucleotide sequence encoding a chimeric human/non-human animal MHC II α polypeptide, wherein a human portion of the chimeric human/non-human MHC II α polypeptide comprises an extracellular domain of a human MHC II α polypeptide, and   a third nucleotide sequence encoding a chimeric human/non-human animal MHC II β polypeptide, wherein a human portion of the chimeric human/non-human MHC II β polypeptide comprises an extracellular domain of a human MHC II β polypeptide,   wherein the non-human animal expresses chimeric human/non-human MHC I and MHC II proteins from the endogenous MHC locus, and   wherein all genes encoding endogenous non-human animal MHC I and MHC II proteins that are expressed on a cell surface are functionally inactivated.   
     
     
         2 . The non-human animal of  claim 1 , wherein the first nucleotide sequence is located at an endogenous non-human animal MHC I locus, the second nucleotide sequence is located at an endogenous non-human animal MHC II α locus, and the third nucleotide sequence is located at an endogenous non-human animal MHC II β locus. 
     
     
         3 . The non-human animal of  claim 1 , wherein the first, second and/or third nucleotide sequence(s) are operably linked to endogenous non-human animal regulatory elements. 
     
     
         4 . The non-human animal of  claim 1 , wherein the human portion of the chimeric MHC I polypeptide comprises α1, α2, and α3 domains of the human MHC I polypeptide. 
     
     
         5 . The non-human animal of  claim 1 , wherein the non-human animal portion of the chimeric MHC I polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human MHC I polypeptide. 
     
     
         6 . The non-human animal of  claim 1 , wherein the human MHC I polypeptide is selected from the group consisting of HLA-A, HLA-B, and HLA-C. 
     
     
         7 . The non-human animal of  claim 1 , further comprising at an endogenous non-human animal β2 microglobulin locus a nucleotide sequence encoding a human or humanized β2 microglobulin polypeptide, wherein the non-human animal expresses the human or humanized β2 microglobulin polypeptide. 
     
     
         8 . The non-human animal of  claim 1 , wherein the human MHC II α extracellular domain comprises human MHC II α1 and α2 domains. 
     
     
         9 . The non-human animal of  claim 1 , wherein the human MHC II β extracellular domain comprises human MHC II β1 and β2 domains. 
     
     
         10 . The non-human animal of  claim 1 , wherein the first nucleotide sequence is operably linked to endogenous non-human animal MHC I promoter and regulatory elements, the second nucleotide sequence is operably linked to endogenous non-human animal MHC II α promoter and regulatory elements, and the third nucleotide sequence is operably linked to endogenous non-human animal MHC II β promoter and regulatory elements. 
     
     
         11 . The non-human animal of  claim 1 , wherein the non-human animal portion of the chimeric human/non-human animal MHC II α polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human animal MHC II α polypeptide. 
     
     
         12 . The r non-human animal of  claim 1 , wherein the non-human animal portion of the chimeric human/non-human animal MHC II β polypeptide comprises transmembrane and cytoplasmic domains of an endogenous non-human animal MHC II β polypeptide. 
     
     
         13 . The non-human animal of  claim 1 , wherein the human portions of the chimeric human/non-human animal MHC II α and β polypeptides are derived from a human HLA class II protein selected from the group consisting of HLA-DR, HLA-DQ, and HLA-DP. 
     
     
         14 . The non-human animal of  claim 13 , wherein the human portions of the chimeric human/non-human animal MHC II α and β polypeptides are derived from a human HLA-DR protein. 
     
     
         15 . The non-human animal of  claim 1 , wherein the non-human animal is a mouse, wherein the first nucleotide sequence encodes a chimeric human/mouse MHC I polypeptide, and wherein a mouse portion of the chimeric MHC I polypeptide is derived from H-2K, H-2D, or H-2L. 
     
     
         16 . The mouse of  claim 15 , wherein the mouse portion of the chimeric MHC I polypeptide is derived from H-2K. 
     
     
         17 . The non-human animal of  claim 13 , wherein the non-human animal is a mouse, wherein the second nucleotide sequence encodes a chimeric human/mouse MHC II α polypeptide, the third nucleotide sequence encodes a chimeric human/mouse MHC II β polypeptide, and wherein mouse portions of the chimeric MHC II α and β polypeptides are derived from H-2E or H-2A. 
     
     
         18 . The mouse of  claim 17 , wherein the mouse portions of the chimeric MHC II polypeptides are derived from H-2E. 
     
     
         19 . The mouse of  claim 18 , wherein the mouse endogenous gene encoding a H-2A polypeptide is functionally inactivated. 
     
     
         20 . The non-human animal of  claim 1 , wherein the non-human animal is a mouse, wherein the first nucleotide sequence encodes a chimeric HLA-A/H-2K polypeptide, the second nucleotide sequence encodes an α chain of a chimeric HLA-DR/H-2E polypeptide, and the third nucleotide sequence encodes a β chain of a chimeric HLA-DR/H-2E polypeptide, and wherein the mouse expresses HLA-A/H-2K and HLA-DR/H-2E proteins. 
     
     
         21 . The mouse of  claim 20 , wherein the first nucleotide sequence is located at an endogenous mouse H-2K locus and wherein the mouse lacks all or part of an endogenous H-2D gene and/or all or part of an endogenous mouse H-2L gene. 
     
     
         22 . The mouse of  claim 20 , wherein the second nucleotide sequence is located at an endogenous H-2E α locus and the third nucleotide sequence is located at an endogenous H-2E β gene, and wherein the mouse lacks all or part of an endogenous mouse H-2A gene. 
     
     
         23 . The mouse of  claim 21 , wherein the second nucleotide sequence is located at an endogenous H-2E α locus and the third nucleotide sequence is located at an endogenous H-2E β locus, and wherein the mouse lacks all or part of an endogenous mouse H-2A gene. 
     
     
         24 . The non-human animal of  claim 1 , wherein the non-human animal is a rodent. 
     
     
         25 . The non-human animal of  claim 23 , wherein the rodent is a mouse or a rat.

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