Granted Patent
B2
US 12,672,643 · App. 18/152,086 · Granted Jul 7, 2026
Genetically modified non-human animals and methods of use thereof
Inventors:
Dietmar Herndler-Brandstetter (New Haven, CT); Richard A. Flavell (Guilford, CT); Davor Frleta (Tarrytown, NY); Cagan Gurer (Tarrytown, NY); Markus Gabriel Manz (Zurich, CH); Andrew J. Murphy (Tarrytown, NY); Noah W. Palm (New Haven, CT); Liang Shan (New Haven, CT); Sean Stevens (Del Mar, CA); Till Strowig (Braunschweig, DE); George D. Yancopoulos (Yorktown Heights, NY); Marcel de Zoete (Amersfoort, NL)
Assignees:
Regeneron Pharmaceuticals, Inc.; Yale University; Institute for Research in Biomedicine (IRB)
A01K67/0278A01K67/0271A61K49/0008A01K2207/12A01K2217/072A01K2217/15A01K2227/105A01K2267/0331A01K2267/0337
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Abstract
Genetically modified non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome are provided. Also provided are methods for making non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome, and methods for using non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome. These animals and methods find many uses in the art, including, for example, in modeling human T cell and/or natural killer (NK) cell development and function, in modeling human pathogen infection of human T cells and/or NK cells, and in various in vivo screens.
Claims (24)
1 . A genetically modified mouse comprising in its genome:
a humanized SIRPα gene comprising exon 1 of a mouse SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the mouse SIRPα gene, wherein the humanized SIRPα gene is operably linked to a mouse SIRPα promoter at the endogenous mouse SIRPα locus, and expresses in the mouse a humanized SIRPα protein comprising an extracellular portion of the human SIRPα protein encoded by the human SIRPα gene and an intracellular portion of the mouse SIRPα protein encoded by the mouse SIRPα gene; and
a humanized IL-15 gene comprising exons 3 and 4 of a mouse IL-15 gene and exons 5, 6, 7 and 8 of a human IL-15 gene, wherein the humanized IL-15 gene is operably linked to a mouse IL-15 promoter at the endogenous mouse IL-15 locus, and expresses in the mouse a humanized IL-15 protein.
2 . The genetically modified mouse of claim 1 , wherein the genetically modified mouse is heterozygous for the humanized SIRPα gene.
3 . The genetically modified mouse of claim 1 , wherein the genetically modified mouse is homozygous for the humanized SIRPα gene.
4 . The genetically modified mouse of claim 1 , wherein the genetically modified mouse is heterozygous for the humanized IL-15 gene.
5 . The genetically modified mouse of claim 1 , wherein the genetically modified mouse is homozygous for the humanized IL-15 gene.
6 . The genetically modified mouse of claim 1 , wherein the genetically modified mouse is immunodeficient.
7 . The genetically modified mouse of claim 6 , wherein the genetically modified mouse comprises a Rag2 gene knock-out.
8 . The genetically modified mouse of claim 6 , wherein the genetically modified mouse comprises an IL2rg gene knock-out.
9 . The genetically modified mouse of claim 6 , wherein the genetically modified mouse comprises a Rag2 gene knock-out and an IL2rg gene knock-out.
10 . The genetically modified mouse of claim 6 , wherein the genetically modified mouse comprises an engraftment of human hematopoietic cells.
11 . The genetically modified mouse of claim 10 , wherein the genetically modified mouse comprises an infection with a human pathogen.
12 . The genetically modified mouse of claim 11 , wherein the human pathogen activates, induces and/or targets T cells.
13 . The genetically modified mouse of claim 11 , wherein the human pathogen activates, induces and/or targets natural killer (NK) cells.
14 . The genetically modified mouse of claim 11 , wherein the human pathogen is a pathogen that infects human intestine.
15 . The genetically modified mouse of claim 14 , wherein the human pathogen is a human rotavirus.
16 . The genetically modified mouse of claim 11 , wherein the human pathogen is a pathogen that infects human lung.
17 . The genetically modified mouse of claim 16 , wherein the human pathogen is an influenza virus.
18 . The genetically modified mouse of claim 6 , wherein the genetically modified mouse comprises a transplanted tumor.
19 . The genetically modified mouse of claim 1 , wherein:
the humanized SIRPα gene comprises a replacement of exons 2, 3 and 4 of the mouse SIRPα gene at the endogenous mouse SIRPα locus with exons 2, 3 and 4 of the human SIRPα gene;
the humanized IL-15 gene comprises a replacement of exons 5, 6, 7 and 8 of the mouse IL-15 gene at the endogenous mouse IL-15 locus with exons 5, 6, 7 and 8 of the human IL-15 gene; and
the genetically modified mouse is homozygous for the humanized SIRPα gene.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 2, 2023
From: HERNDLER-BRANDSTETTER, DIETMAR; SHAN, LIANG; DE ZOETE, MARCEL; PALM, NOAH W.; FLAVELL, RICHARD A.; STROWIG, TILL
To: YALE UNIVERSITY
Reel/Frame 063512/0354 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 2, 2023
From: FRLETA, DAVOR; GURER, CAGAN; MURPHY, ANDREW J.; STEVENS, SEAN; YANCOPOULOS, GEORGE D.
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 063512/0315 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 2, 2023
From: MANZ, MARKUS GABRIEL
To: INSTITUTE FOR RESEARCH IN BIOMEDICINE (IRB)
Reel/Frame 063512/0378 →
Continuity (7)
Provisional Application
62287842
· Jan 27, 2016
Provisional Application
62148667
· Apr 16, 2015
Provisional Application
62146938
· Apr 13, 2015
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