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US 11,026,408 B2Granted
Genetically modified non-human animals and methods of use thereof
AssigneesRegeneron Pharmaceuticals, Inc., Yale University, Institute for Research in Biomedicine (IRB)
InventorsRichard Flavell, Markus Manz, Anthony Rongvaux, Till Strowig, Tim Willinger, Andrew J. Murphy, Sean Stevens, George Yancopoulos
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Abstract
The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.
Claims17
A method for in vivo evaluation of a vaccine, the method comprising:
- administering a vaccine to a genetically modified mouse, wherein the genetically modified mouse comprises in its genome:
- a recombination activating gene 2 (Rag-2) gene knock-out,
- an IL2 receptor gamma chain (IL2rg) gene knock-out,
- a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus,
- a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus,
- a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus,
- a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, and
- an insertion of a nucleic acid encoding a human SIRP polypeptide,
- wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRP polypeptide, and the human TPO polypeptide is operably linked to a promoter,
- wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide, and
- wherein the mouse is engrafted with human hematopoietic cells;
- and
- assessing an immune response to the vaccine in the genetically modified mouse.
10 more elements
A method for in vivo evaluation of a vaccine, the method comprising:
- administering a vaccine to a genetically modified mouse, wherein the genetically modified mouse comprises in its genome:
- a recombination activating gene 2 (Rag-2) gene knock-out,
- an IL2 receptor gamma chain (IL2rg) gene knock-out,
- a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus,
- a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus,
- a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus,
- a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, and
- an insertion of a nucleic acid encoding a human SIRP polypeptide,
- wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRP polypeptide, and the human TPO polypeptide is operably linked to a promoter,
- wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide, and
- wherein the mouse is engrafted with CD34+human hematopoietic cells and wherein the mouse exhibits a significantly higher proportion of human CD33+myeloid cells in blood and bone marrow relative to a genetically modified mouse engrafted with human CD34+cells which does not express the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide;
- and
- assessing an immune response to the vaccine in the genetically modified mouse.
10 more elements
A method for testing the effect of an agent that modulates cancer cell growth or survival, or for the in vivo evaluation of a cancer treatment involving the agent, the method comprising:
- administering the agent to a genetically modified mouse, wherein the genetically modified mouse comprises in its genome:
- a recombination activating gene 2 (Rag-2) gene knock-out,
- an IL2 receptor gamma chain (IL2rg) gene knock-out,
- a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus,
- a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus,
- a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus,
- a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, and
- an insertion of a nucleic acid encoding a human SIRP polypeptide,
- wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRP polypeptide, and the human TPO polypeptide is operably linked to a promoter,
- wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide, and
- wherein the mouse is engrafted with human hematopoietic cells and wherein the mouse is engrafted with human cancer cells;
- and
- assessing effect of the agent on cancer cell growth or survival in the genetically modified mouse.
10 more elements
Dependencies are inferred from the claim text.