Tim-3 ligands and methods thereof

• US 20050191721A1
• Filed: 10/04/2004
• Published: 09/01/2005
• Est. Priority Date: 10/03/2003
• Status: Active Grant

• Current Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.), Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated, BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Inventors: Zhu, Chen, Sanchez-Fueyo, Alberto, Sabatos, Catherine, Cha, Eugene K., Zheng, Xin Xiao, Strom, Terry, Chakravarti, Sumone, Kuchroo, Vijay K.
• Granted Patent: US 8,329,660 B2
• Time in Patent Office: Days
• US Class Current: 435/69.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 14/4713 : Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
• CPC Class Codes: C07K 14/70503 : Immunoglobulin superfamily
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• 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
• CPC Class Codes: G01N 33/505 : involving T-cells

Abstract

The invention relates to isolated polypeptides and nucleic acids encoding polypeptides which comprise a tim-3 IgV domain and a tim-3 intracellular domain, wherein the polypeptides do not comprise a tim-3 mucin domain or a tim-3 transmembrane domain. In addition, the invention relates to methods of modulating immune responses in a subject, comprising administering to the subject a therapeutically effective amount of an agent that modulates tim-3 activity. Immune responses include, but are not limited to, immune tolerance, transplantation tolerance, Th1 responses and Th2 responses.

Claims

1. An isolated polypeptide comprising a tim-3 IgV domain and a tim-3 intracellular domain, wherein the polypeptide does not comprise a tim-3 mucin domain or a tim-3 transmembrane domain.

13. A composition comprising the isolated polypeptide of claim 1 and a pharmaceutically acceptable carrier.

14. An isolated nucleic acid encoding the polypeptide of claim 1.

2-12. -12. (canceled)

15-16. -16. (canceled)

17. An isolated nucleic acid which hybridizes under high stringency conditions to a nucleic acid encoding soluble tim-3 but which does not hydridize under high stringency conditions to a nucleic acid encoding full-length tim-3.

25. An isolated polypeptide encoded by the isolated nucleic acid of claim 17.

18-24. -24. (canceled)

26. A pharmaceutical package comprising (i) a polypeptide which comprises the IgV domain of tim-3;

and (ii) instructions for administering the composition to a subject for treating a hyperplastic condition or for treating a Th2-mediated condition.

27. (canceled)

28. A pharmaceutical package comprising (i) a polypeptide which comprises a galectin-9 polypeptide;

and (ii) instructions for administering the composition to a subject for treating an autoimmune disorder.

29. An isolated antibody or fragment thereof which binds to a polypeptide having an amino acid sequence set forth in SEQ ID NO:

2 but which does not bind to a polypeptide having the amino acid sequence set forth in SEQ ID NO;

13.

30-32. -32. (canceled)

33. An isolated antibody or fragment thereof which binds to a polypeptide having an amino acid sequence set forth in SEQ ID NO:

4 but which does not bind to a polypeptide having the amino acid sequence set forth in SEQ ID NO;

14.

34-36. -36. (canceled)

37. A method of modulating an immune response in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent that modulates tim-3 activity.

38. The method of claim 37, wherein modulating an immune response comprises increasing a Th1 response or decreasing a Th2 response and wherein the agent decreases tim-3 activity.

49. The method of claim 38, wherein the agent comprises a polypeptide comprising

(i) amino acids 30-128 of SEQ ID NO:

13;

or

(iii) an amino acid sequence that is at least 90% identical to amino acids 30-128 of SEQ ID NO;

13.

55. The method of claim 38, wherein the agent inhibits binding of full-length tim-3 to galectin-9.

63. The method of claim 37, wherein modulating an immune response comprises decreasing a Th1 response or increasing a Th2 response, and wherein the agent increases tim-3 activity.

71. The method of claim 63, wherein the agent is a tim-3 ligand.

39-48. -48. (canceled)

50-54. -54. (canceled)

56-62. -62. (canceled)

64-70. -70. (canceled)

72-78. -78. (canceled)

79. A method of identifying an agent that modulates the binding between a tim-3 polypeptide and a galectin-9 polypeptide, the method comprising:

(a) contacting the tim-3 polypeptide and the galectin-9 polypeptide in the presence of a test agent; and

(b) determining the effect of the test agent on the binding of the tim-3 polypeptide and the galectin-9 polypeptide;

thereby identifying a agent that modulates the binding between a tim-3 polypeptide and a galectin-9 polypeptide.

80. A method of identifying an agent that modulates an immune response, the method comprising

(a) contacting the tim-3 polypeptide and the galectin-9 polypeptide in the presence of a test agent;

and

(b) determining the effect of the test agent on the binding of the tim-3 polypeptide and the galectin-9 polypeptide;

thereby identifying an agent that modulates an immune response.

81-95. -95. (canceled)

96. A method of increasing tim-3 activity, comprising contacting a cell which expresses soluble tim-3 with an amount of a double stranded RNA sufficient to decrease the expression of soluble tim-3, wherein the double stranded RNA does not inhibit the expression of full-length tim-3 in the cell, thereby increasing tim-3 activity.

97-100. -100. (canceled)

101. A method of detecting soluble tim-3 gene expression comprising detecting the presence of a nucleic acid encoding soluble tim-3, wherein the detection of a nucleic acid encoding the soluble tim-3 indicates soluble tim-3 gene expression.