Transgenic bovine comprising human immunoglobulin loci and producing human immunoglobulin

• US 7,074,983 B2
• Filed: 11/16/2001
• Issued: 07/11/2006
• Est. Priority Date: 11/19/1999
• Status: Expired due to Term

• Current Assignee: SAB LLC (W.P. Carey, Inc. (Real Estate))
• Original Assignee: Kirin Beer Kabushiki Kaisha, Hematech, LLC (MeritCare Health System)
• Inventors: Kuroiwa, Yoshimi, Goldsby, Richard A., Tomizuka, Kazuma, Ferguson, Stacy E., Osborne, Barbara A., Ishida, Isao, Robl, James M.
• Primary Examiner(s): Crouch, Deborah
• Application Number:
  US09/988,115
• Publication Number:
  US 20030037347A1
• Time in Patent Office: 1,698 Days
• Field of Search: 800 14- 18, 800/24, 800 4- 7, 435/325, 435/326, 514/12
• US Class Current: 800/15
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/101 Bovine
• CPC Class Codes: A01K 2267/01 Animal expressing industrially exogenous proteins
• CPC Class Codes: A01K 67/0273 Cloned vertebrates
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2800/30 Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
• CPC Class Codes: C12N 9/1051 Hexosyltransferases (2.4.1)

Abstract

The present invention relates to the production of a transgenic bovine which comprises a genetic modification that results in inactivation and loss of expression of its endogenous antibodies, and the expression of xenogenous antibodies, preferably human antibodies. This is effected by inactivation of the IgM heavy chain expression and, optionally, by inactivation of the Ig light chain expression, and by the further introduction of an artificial chromosome which results in the expression of non-bovine antibodies, preferably human antibodies.

Claims

1. A transgenic bovine whose cells comprise one or more artificial chromosomes, each artificial chromosome comprising one or more human immunoglobulin heavy or light chain loci that undergo rearrangement and are expressed in B-cells to produce a human immunoglobulin in response to exposure to one or more antigens.

2. The transgenic bovine of claim 1, wherein said one or more artificial chromosomes comprise a human artificial chromosome.

3. The transgenic bovine of claim 2, wherein said human artificial chromosome is Δ

HAC or Δ

Δ

HAC.

4. The transgenic bovine of claim 2, wherein said human artificial chromosome is derived from one or more of human chromosome 14, human chromosome 2, and human chromosome 22.

5. The transgenic bovine of claim 1, wherein said immunoglobulin loci comprise both a human immunoglobulin light chain locus and human immunoglobulin heavy chain locus.

6. An isolated B-cell obtained from a transgenic bovine of claim 1, wherein the B-cell comprises one or more artificial chromosomes, each artificial chromosome comprising one or more human immunoglobulin loci that undergo rearrangement and are expressed to produce a human immunoglobulin in response to exposure to one or more antigens.

7. An isolated transgenic bovine B-cell comprising one or more artificial chromosomes, each artificial chromosome comprising one or more human immunoglobulin heavy or light chain loci that undergo rearrangement and are expressed to produce a human immunoglobulin in response to exposure to one or more antigens.

8. The cell of claim 7, wherein said one or more artificial chromosomes comprise a human artificial chromosome.

9. The cell of claim 8, wherein said human artificial chromosome is derived from one or more of human chromosome 14, human chromosome 2, and human chromosome 22.

10. The cell of claim 8, wherein said human artificial chromosome is Δ

HAC or Δ

Δ

HAC.

11. The cell of claim 7, wherein said immunoglobulin loci comprise both a human immunoglobulin light chain locus and human immunoglobulin heavy chain locus.

12. A method of producing human antibodies, said method comprising the steps of:

(a) administering one or more antigens of interest to a transgenic bovine whose cells comprise one or more artificial chromosomes, each artificial chromosome comprising one or more human immunoglobulin heavy or light chain loci that undergo rearrangement and are expressed in B-cells, resulting in production of human antibodies against said one or more antigens; and

(b) recovering said human antibodies from said bovine.

13. The method of claim 12, wherein said one or more artificial chromosomes comprise a human artificial chromosome.

14. The method of claim 13, wherein said human artificial chromosome is derived from one or more of human chromosome 14, human chromosome 2, and human chromosome 22.

15. The method of claim 13, wherein said human artificial chromosome is Δ

HAC or Δ

Δ

HAC.

16. A method of producing human antibodies to one or more antigens, said method comprising recovering human antibodies from a transgenic bovine whose cells comprise one or more artificial chromosomes, each artificial chromosome comprising one or more human immunoglobulin heavy or light chain loci that undergo rearrangement and are expressed in B-cells, resulting in production of human antibodies against said one or more antigens.

17. The method of claim 16, wherein said one or more artificial chromosomes comprise a human artificial chromosome.

18. The method of claim 17, wherein said human artificial chromosome is derived from one or more of human chromosome 14, human chromosome 2, and human chromosome 22.

19. The method of claim 17, wherein said human artificial chromosome is Δ

HAC or Δ

Δ

HAC.