IP Library › Granted Patent US 12672643
Granted Patent B2
US 12672643 · 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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Quick Facts
Patent No.
US 12672643
App. No.
18/152,086
Granted
Jul 7, 2026
Kind
B2
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.