Human antibodies derived from immunized xenomice

• US 6,150,584 A
• Filed: 10/02/1996
• Issued: 11/21/2000
• Est. Priority Date: 01/12/1990
• Status: Expired due to Fees

• Current Assignee: Amgen Fremont Inc. (Amgen Inc.)
• Original Assignee: Abgenix Inc (Amgen Inc.)
• Inventors: Jakobovits, Aya, Capon, Daniel J., Kucherlapati, Raju, Brenner, Daniel G., Klapholz, Sue
• Primary Examiner(s): HAUDA, KAREN MARIE
• Application Number:
  US08/724,752
• Time in Patent Office: 1,511 Days
• Field of Search: 800/2, 800/6, 800/25, 800/18, 424/93.21
• US Class Current: 800/18
• 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: C07K 16/1282 from Clostridium (G)
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 16/2812 against CD4
• CPC Class Codes: C07K 16/2854 against selectins, e.g. CD62
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

Fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Claims

1. A transgenic mouse wherein all of the somatic and germ cells comprise a DNA fragment of human chromosome 14 from the five most proximal V_H gene segments, continuing through the D segment genes, the J segment genes and the constant region genes through Cδ

of the human immunoglobulin heavy chain locus, wherein said fragment does not contain a Cγ

gene, and wherein said fragment is operably linked to a human Cγ

2 region gene;

said transgenic mouse producing fully human IgG2 heavy chains specific for a desired antigen when immunized with said desired antigen.

2. The transgenic mouse according to claim 1, wherein all of the somatic and germ cells of said transgenic mouse further comprise a fragment of human chromosome 2 comprising V.sub.κ

, J.sub.κ and

C.sub.κ

gene segments of an immunoglobulin kappa light chain locus, said transgenic mouse producing fully human IgG2 antibodies specific for a desired antigen when immunized with said desired antigen.

3. The transgenic mouse according to claim 1, wherein all of the somatic and germ cells comprise the human DNA contained in the yH1C YAC having ATCC accession no. 74367.

4. The transgenic mouse according to claim 2, wherein all of the somatic and germ cells comprise the human DNA contained in the yH1C YAC having ATCC accession no. 74367.

5. The transgenic mouse according to claim 3, wherein said fragment of human chromosome 2 extends from the three most proximal V.sub.κ

gene segments, continuing through the J.sub.κ and

C.sub.κ

gene segments, through the human kappa deleting element.

6. The transgenic mouse according to claim 4, wherein said fragment of human chromosome 2 extends from the three most proximal V.sub.κ

gene segments, continuing through the J.sub.κ and

C.sub.κ

gene segments, through the human kappa deleting element.

7. The transgenic mouse and progeny according to any one of claims 1-6, wherein all of the somatic and germ cells further comprise:

a) inactivated endogenous immunoglobulin heavy chain loci in which all of the J segment genes are deleted to prevent rearrangement and to prevent formation of a transcript of a rearranged locus and the expression of an endogenous immunoglobulin heavy chain; and

b) inactivated endogenous immunoglobulin light chain loci in which the C.sub.κ

gene is deleted to prevent expression of an endogenous immunoglobulin light chain;

wherein said transgenic mouse and progeny lack expression of endogenous immunoglobulin heavy chains.

8. A method for producing a fully human IgG antibody specific for a desired antigen, comprising:

(a) immunizing a transgenic mouse according to any one of claims 1-7 with said desired antigen; and

(b) recovering the antibody.

9. The method according to claim 8, wherein the desired antigen is selected from the group consisting of:

leukocyte markers;

histocompatibility antigens;

integrins;

adhesion molecules;

interleukins;

interleukin receptors;

chemokines;

growth factors;

growth factor receptors;

interferon receptors;

immunoglobulins and their receptors;

tumor antigens;

allergens;

viral proteins;

toxins;

blood factors;

enzymes;

ganglioside GD3, ganglioside GM2;

LMP1, LMP2;

eosinophil major basic protein, eosinophil cationic protein;

pANCA;

Amadori protein;

Type IV collagen;

glycated lipids;

γ

-interferon;

A7;

P-glycoprotein;

Fas (AFO-1) and oxidized-LDL.

10. The method according to claim 8, wherein the desired antigen is human IL-8.

11. The method according to claim 8, wherein the desired antigen is PTHrp.

12. The yHlC YAC having ATCC accession number 74367.