Non-human animals having a humanized signal-regulatory protein gene

Patent metadata

Field	Value
Publication number	US-10426146-B2
Application number	US-201916238589-A
Country	US
Kind code	B2
Filing date	Jan 3, 2019
Priority date	Sep 23, 2013
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus.

First claim

We claim:

1. A rodent whose genome comprises a humanized SIRPα gene at an endogenous rodent SIRPα locus, wherein the humanized SIRPα gene
(i) comprises exon 1 of a rodent SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rodent SIRPα gene,
(ii) is operably linked to a rodent SIRPα promoter at the endogenous rodent SIRPα locus, and
(iii) expresses in the rodent 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 rodent SIRPα protein encoded by the rodent SIRPα gene; and
wherein the rodent is a rat and is homozygous for the humanized SIRPα gene.

2. The rodent of claim 1 , wherein the extracellular portion of the human SIRPα protein comprises amino acid residues 28-362 of the human SIRPα protein.

3. The rodent of claim 1 , wherein the human SIRPα protein comprises the amino acid sequence as set forth in SEQ ID NO: 4.

4. The rodent of claim 1 , wherein the rodent does not express an endogenous rodent SIRPα protein.

5. A rodent embryonic stem (ES) cell, comprising a humanized SIRPα gene at an endogenous rodent SIRPα locus, wherein the humanized SIRPα gene
(i) comprises exon 1 of a rodent SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rodent SIRPα gene,
(ii) is operably linked to a rodent SIRPα promoter at the endogenous rodent SIRPα locus, and
(iii) encodes 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 rodent SIRPα protein encoded by the rodent SIRPα gene; and
wherein the rodent ES cell is a rat ES cell.

6. The rodent ES cell of claim 5 , wherein the extracellular portion of the human SIRPα protein comprises amino acid residues 28-362 of the human SIRPα protein.

7. The rodent ES cell of claim 5 , wherein the human SIRPα protein comprises the amino acid sequence as set forth in SEQ ID NO: 4.

8. The rodent ES cell of claim 5 , wherein the rodent ES cell is homozygous for the humanized SIRPα gene.

9. A rodent embryo comprising the rodent ES cell of claim 5 , wherein the rodent embryo is a rat embryo.

Assignees

• Regeneron Pharma

Inventors

• Murphy Andrew J
• Thurston O Gavin
• Varghese Bindu
• Gurer Cagan

Classifications

• C07K14/70503

  Immunoglobulin superfamily · CPC title

• C12N9/16

  acting on ester bonds (3.1) · CPC title

• A01K2227/105

  Murine · CPC title

• G01N2500/10

  involving cells · CPC title

• A01K2267/0387

  Animal model for diseases of the immune system · CPC title