Methods of blocking tissue destruction by autoreactive T cells

• US 20030106084A1
• Filed: 04/10/2002
• Published: 06/05/2003
• Est. Priority Date: 03/29/2000
• Status: Abandoned Application

• Current Assignee: The Ohio State University Research Foundation
• Original Assignee: The Ohio State University Research Foundation
• Inventors: Zheng, Pan, Liu, Yang, Bai, Xuefeng, Liu, Xingluo
• Application Number:
  US10/119,637
• Publication Number:
  US 20030106084A1
• Time in Patent Office: Days
• US Class Current: 800/18
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Methods for blocking autoreactive T cell-initiated destruction of tissues in a mammal are provided. In one embodiment, the method comprises administering a purified CD24 polypeptide, a fusion protein comprising such polypeptide, or a biologically active fragment of such polypeptide to a mammalian subject who is suspected of having or predisposed to having an autoimmune disease. In another embodiment, anti-CD24 antibody or anti-CD24 Fab fragments are administered to the subject. In another embodiment, the method comprises administering a CD24 antisense molecule, an expression vector encoding a CD24 antisense molecule, CD24 dsRNAi, or an expression vector encoding CD24 dsRNAi to the subject. The present invention also relates to isolated and purified CD24 fusion proteins employed in the present methods and to transgenic mice that express the human CD24 protein on their T cells and/or their vascular endothelial cells but do not express murine heat shock antigen on any cells.

Claims

1. A method for inhibiting autoreactive T cell-initiated destruction of tissues in a mammal comprising:

administering a pharmaceutical composition to the mammal, said pharmaceutical composition comprising an agent selected from the group consisting of;

an isolated HSA/CD24 polypeptide, an isolated biologically active fragment of an HSA/CD24 polypeptide, a fusion protein comprising an HSA/CD24 polypeptide, a fusion protein comprising a biologically active fragment of an HSA/CD24 polypeptide, and an anti-HSA/CD24 antibody;

wherein said pharmaceutical composition is administered in an amount sufficient to reduce autoreactive T cell-initiated tissue destruction in said mammal.

2. The method of claim 1 wherein the HSA/CD24 polypeptide or fragment thereof is glycosylated.

7. The method of claim 2 wherein the agent is a fusion protein comprising a peptide tag linked by a peptide bond to the core region of the HSA/CD24 polypeptide.

8. The method of claim 7 wherein the HSA/CD24 polypeptide or fragment thereof is glycosylated.

9. The method of claim 8 wherein the peptide tag is human IgG 1 Fc and the polypeptide is the human CD24 polypeptide.

14. The transgenic mouse of claim 8 wherein said mouse further expresses human CD24 polypeptide on its endothelial cells.

3. A method for treating a patient suspected of having, known to have, or predisposed to having an autoimmune disease, said method comprising.

administering to said patient a pharmaceutical composition comprising an agent selected from the group consisting of an HAS/CD24 polypeptide, an isolated biologically active fragment of an HSA/CD24 polypeptide, a fusion protein comprising an HSA/CD24 polypeptide, a fusion protein comprising a biologically active fragment of an HSA/CD24 polypeptide, and an anti-HSA/CD24 antibody.

4. The method of claim 3 wherein the HSA/CD24 polypeptide or fragment thereof is glycosylated.

5. The method of claim 3 wherein the antibody is a monoclonal antibody.

6. The method of claim 3 wherein the antibody is a humanized monoclonal antibody.

10. A fusion protein comprising human IgG 1 Fc and human CD24 polypeptide or the core fragment thereof.

11. The fusion protein of claim 10 wherein the human CD24 polypeptide or fragment thereof is glycosylated.

12. The fusion protein of claim 11 wherein the fragment is the core region of the human CD24 polypeptide.

13. A transgenic mouse whose genome comprises a polynucleotide encoding human CD24 polypeptide, wherein said polynucleotide is operably linked to a promoter;

and wherein said transgenic mouse expresses human CD24 on the surface of its T cells.

15. The transgenic mouse of claim 13 wherein the transgenic mouse lacks endogenous mouse HSA.

16. A method of blocking binding of autoreactive T cells to vascular endothelial cells, comprising:

contacting said vascular endothelial cells with an agent selected from the group consisting of an isolated HSA/CD24 polypeptide, an isolated biologically active fragment of an HSA/CD24 polypeptide, a fusion protein comprising an HSA/CD24 polypeptide, a fusion protein comprising an biologically fragment of an HSA/CD24 polypeptide, and an anti-HSA/CD24 antibody, wherein said cells are contacted with a sufficient amount of said agent to inhibit interaction of the autoreactive T cells with the vascular endothelial cells.

17. The method of claim 16 wherein the HSA/CD24 polypeptide or fragment thereof is glycosylated.

18. A method of reducing autoreactive T cell-initiated destruction of tissues in a mammal, comprising:

administering to the mammal an agent that reduces interaction of the CD24 polypeptide that is present on the autoreactive T cells with a functional ligand of the CD24 polypeptide.

19. The method of claim 18 wherein the agent disrupts the function of the CD24 gene at the genomic, transcriptional, post-transcriptional, translational or ligand binding level.

20. The method of claim 18 wherein the agent is an agent that reduces expression of the CD24 polypeptide in the mammal'"'"'s T cells.

21. The method of claim 19 wherein the agent is a CD24 antisense molecule, and wherein the CD24 antisense molecule is administered to the mammal by an ex vivo or in vivo procedure.

22. The method of claim 19 wherein the agent is a polynucleotide that encodes a CD24 antisense molecule, and wherein said polynucleotide is administered to the mammal by an ex vivo or in vivo procedure.

23. The method of claim 19 wherein the agent is a CD24 dsRNAi molecule, and wherein said CD24 dsRNAi molecule is administered to the mammal by an ex vivo or in vivo procedure.

24. The method of claim 19 wherein the agent is a polynucleotide that encodes a CD24 dsRNAi molecule, and wherein said polynucleotide is administered to the mammal by an ex vivo or in vivo procedure.

25. The method of claim 18 wherein the agent is selected from the group consisting of an HSA/CD24 polypeptide, a biologically active variant of an HSA/CD24 polypeptide, the core region of an HSA/CD24 polypeptide, and a biologically active variant the core region of an HSA/CD24 polypeptide, or combinations thereof.

26. The method of claim 18 wherein the agent is an anti-HSA/CD24 antibody.

27. The method of claim 26 wherein the mammal is a human and the antibody is a humanized antibody.

28. A method for inhibiting autoreactive T cell-initiated destruction in a mammal by targeting CD24 molecules at genomic, transcription, post-transcriptional, translational and ligand binding levels, the method comprising:

administering a pharmaceutical composition to the mammal, said pharmaceutical composition comprising an agent selected from the group consisting of an isolated HSA/CD24 polypeptide, an isolated biologically active fragment of an HSA/CD24 polypeptide, a fusion protein comprising an HSA/CD24 polypeptide, a fusion protein comprising a biologically active fragment of an HSA/CD24 polypeptide, an anti-HSA/CD24 antibody, a CD24 antisense molecule, a polynucleotide encoding a CD24 antisense molecule, a CD24 dsRNAi molecule and a polynucleotide encoding a CD24 dsRNAi molecule;

wherein said pharmaceutical composition is administered in an amount sufficient to reduce autoreactive T cell-initiated tissue destruction in said mammal.