Methods and compositions for the diagnosis and treatment of demyelinating inflammatory disorders

• US 20040001831A1
• Filed: 06/26/2002
• Published: 01/01/2004
• Est. Priority Date: 06/26/2002
• Status: Abandoned Application

• Current Assignee: Robert KOCH Institute, Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Robert KOCH Institute, Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Kroczek, Richard, Rottman, James B.
• Application Number:
  US10/186,381
• Publication Number:
  US 20040001831A1
• Time in Patent Office: Days
• US Class Current: 424/146.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/2026 IL-4
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: G01N 2333/70532 B7 molecules, e.g. CD80, CD86
• CPC Class Codes: G01N 2800/285 Demyelinating diseases; Multipel sclerosis
• CPC Class Codes: G01N 33/564 for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9

Abstract

The present invention provides methods of suppressing demyelinating inflammatory disorders in a patient by administering to the patient a compound that inhibits binding of B7RP-1 to ICOS or inhibits signaling through the B7RP-1 pathway. Various therapeutic regimens are provided. Methods of identifying such compounds are also provided. The present invention further provides kits and pharmaceutical compositions useful in the present methods.

Claims

1. A method of treating a multiple sclerosis in a patient, comprising administering to the patient in need of such treatment an ICOS-B7RP-1 inhibitor in an amount effective for treating the demyelinating inflammatory disorder, wherein the ICOS-B7RP-1 inhibitor is an anti-ICOS antibody.

2. The method of claim 1, wherein the ICOS-B7RP-1 inhibitor is administered during a period of relapse, during a period of remission, or during chronic progressive multiple sclerosis in said patient.

3. The method of claim 1, further comprising administering a second therapeutic agent selected from the group consisting of an immunosuppressive agent and a biological response modifier.

4. The method of claim 3, wherein the immunosuppressive agent is cyclosporine, FK506, rapamycin, or prednisone.

5. The method of claim 3, wherein the biological response modifier is an interleukin or an antibody.

6. The method of claim 5, wherein the interleukin is interleukin 4.

7. The method of claim 5, wherein the antibody is immunospecific to CCR1, RANTES, MCP-1, MIP-2, Interleukin-1α

, interleukin-1β

, interleukin-6, interleukin-12p35, CD28, CTLA-4 or IFN-γ

.

8. The method of claim 3, wherein the second therapeutic agent is administered concurrently with the ICOS-B7RP- l inhibitor.

9. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) contacting an ICOS polypeptide with a B7RP-1 polypeptide expressed on an endothelial cell surface and a test compound, under conditions that, in the absence of the test compound, allow the ICOS polypeptide to bind to the B7RP-1 polypeptide and thereby form an ICOS-B7RP-1 complex; and

(b) determining whether ICOS-B7RP-1 complex formation is inhibited by the test compound;

wherein inhibition of ICOS-B7RP-1 complex formation by the test compound identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

10. The method of claim 9, wherein the ICOS polypeptide is expressed on a T cell.

11. The method of claim 9, wherein the ICOS polypeptide is immobilized on a solid surface.

12. The method of claim 11, wherein the ICOS polypeptide is present in a cell membrane, which cell membrane is immobilized on the solid surface.

13. The method of claim 9, wherein determining whether ICOS-B7RP-1 complex formation is inhibited by the test compound comprises measuring the amount of binding between ICOS and B7RP-1 or measuring ICOS-B7RP-1 pathway activation.

14. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) identifying a test compound as a candidate ICOS-B7RP-1 inhibitor by the method of claim 9;

(b) contacting a T-cell, capable of being activated by B7RP-1, with B7RP-1 present on an endothelial cell surface, in the presence of the test compound; and

(c) determining whether a lower level of ICOS-B7RP-1 activity occurs in the T-cell after said contacting relative to a control T-cell contacted with B7RP-1 in the absence of the test compound;

wherein a lower level of activity identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

15. The method of claim 14, wherein determining whether a lower level of ICOS-B7RP-1 activity occurs in the T-cell comprises measuring ICOS pathway activation.

16. The method of claim 14, wherein determining whether a lower level of ICOS-B7RP-1 activity occurs in the T-cell comprises measuring T cell activation.

17. The method of claim 16, wherein T cell activation is evidenced by the ability of the T cell to traverse an in vitro model of the blood brain barrier.

18. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) identifying a test compound as a candidate ICOS-B7RP-1 inhibitor by the method of claim 9;

(b) administering to a model animal with experimental allergic encephalomyelitis the test compound during the efferent stage of said experimental allergic encephalomyelitis; and

(c) determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis,

wherein abrogation of a central nervous system phenotype of experimental allergic encephalomyelitis identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

19. The method of claim 18, wherein determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis comprises (i) determining whether ICOS positive T cells traverse the blood brain barrier of said model animal at a reduced rate relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

(ii) determining whether brain inflammation is reduced in said model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

or (iii) determining whether physical symptoms of experimental allergic encephalomyelitis are reduced in the model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered.

20. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) contacting a T-cell, capable of being activated by B7RP-1, with B7RP-1 present on an endothelial cell surface, in the presence of a test compound; and

(b) determining whether a lower level of ICOS-B7RP-1 activity occurs in the T-cell after said contacting relative to a control T-cell contacted with B7RP-1 in the absence of the test compound;

wherein a lower level of activity identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

21. The method of claim 20, wherein T cell activation is evidenced by the ability of the T cell to traverse an in vitro model of the blood brain barrier.

22. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) identifying a test compound as a candidate ICOS-B7RP-1 inhibitor by the method of claim 20;

(b) administering to a model animal with experimental allergic encephalomyelitis the test compound during the efferent stage of said experimental allergic encephalomyelitis; and

(c) determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis,

wherein abrogation of a central nervous system phenotype of experimental allergic encephalomyelitis identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

23. The method of claim 22, wherein determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis comprises (i) determining whether ICOS positive T cells traverse the blood brain barrier of said model animal at a reduced rate relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

(ii) determining whether brain inflammation is reduced in said model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

or (iii) determining whether physical symptoms of experimental allergic encephalomyelitis are reduced in the model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered.

24. A method of identifying a candidate ICOS-B7RP-1 inhibitor, comprising:

(a) administering to a model animal with experimental allergic encephalomyelitis a test compound during the efferent stage of said experimental allergic encephalomyelitis; and

(b) determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis,

wherein abrogation of a central nervous system phenotype of experimental allergic encephalomyelitis identifies the test compound as a candidate ICOS-B7RP-1 inhibitor.

25. The method of claim 24, wherein determining whether the test compound abrogates a central nervous system phenotype of experimental allergic encephalomyelitis comprises determining (i) determining whether ICOS positive T cells traverse the blood brain barrier of said model animal at a reduced rate relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

(ii) determining whether brain inflammation is reduced in said model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered;

or (iii) determining whether physical symptoms of experimental allergic encephalomyelitis are reduced in the model animal relative to a model animal with experimental allergic encephalomyelitis to whom the test compound is not administered.

26. The method of claim 24, further comprising, prior to step (a), identifying a suitable test compound by a method comprising:

(a) contacting an ICOS polypeptide with a B7RP-1 polypeptide and a molecule, under conditions that, in the absence of the molecule, allow the ICOS polypeptide to bind to the B7RP-1 polypeptide and thereby form an ICOS-B7RP-1 complex; and

(b) determining whether ICOS-B7RP-1 complex formation is inhibited by the molecule;

wherein inhibition of ICOS-B7RP-1 complex formation by the molecule identifies the molecule as a suitable test compound.