Methods of therapy

• US 20050159425A1
• Filed: 05/09/2003
• Published: 07/21/2005
• Est. Priority Date: 05/10/2002
• Status: Abandoned Application

• Current Assignee: Medical Research Council (Government of United Kingdom)
• Original Assignee: Medical Research Council (Government of United Kingdom)
• Inventors: Kelly, Rodney William
• Application Number:
  US10/513,998
• Publication Number:
  US 20050159425A1
• Time in Patent Office: Days
• US Class Current: 514/252.160
• CPC Class Codes: A61K 2039/55511 Organic adjuvants
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 39/001 Preparations to induce tolerance to non-self, e.g. prior to transplantation
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method of inducing tolerance to an antigen in a patient, the method comprising administering to the patient a prostaglandin or agonist thereof, a phosphodiesterase inhibitor and the antigen or a derivative thereof.

Claims

1. A method of inducing tolerance to an antigen in a patient, the method comprising administering to the patient a prostaglandin or agonist thereof, a phosphodiesterase (PDE) inhibitor, and the antigen or derivative thereof.

2. A method according to claim 1 wherein the prostaglandin or agonist thereof and/or the PDE inhibitor and/or the antigen or derivative thereof is administered locally at a site where tolerance is required.

3. A method according to claim 1 or wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is administered systemically.

4. A method according to claim 3 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is administered orally.

5. A method according to claim 3 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is administered as a suppository or capsule.

6. A method according to claim 5 wherein the suppository or capsule has an enteric coating for release of the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof in the bowel of the patient.

7. A method according to claim 1 wherein any two of the prostaglandin or agonist thereof, the PDE inhibitor, and the antigen or derivative thereof are administered simultaneously.

8. A method according to claim 1 wherein the prostaglandin or agonist thereof, the PDE inhibitor, and the antigen or derivative thereof are administered simultaneously.

9. A method according to claim 1 wherein the prostaglandin or agonist thereof is any one of a prostaglandin E, prostaglandin E₂ or an analogue thereof, dinoprostone, gemeprost, misoprostol, alprostadil, limaprost, butaprost, 11-deoxy PGE1, AH23848, AH13205, 19-hydroxy PGE1 or 19-hydroxy PGE2.

10. A method according to claim 1 wherein the prostaglandin is a 19-hydroxy PGE.

11. A method according to claim 1 wherein the PDE inhibitor is selective for any of type IV, VII or VIII PDE.

12. A method according to claim 1 wherein the PDE inhibitor is any one of 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline (3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione), rolipram (4-[3-cyclopentyloxy-4-methoxyphenyl]-2-pyrrolidinone), CP80 633, CP102 995, CP76 593, Ro-20-1724 (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone), theophylline, or denbufylline (1,3-di-n-butyl-7-(2-oxopropyl)-xanthine).

13. A method according to claim 1 wherein the PDE inhibitor is selective for type IV PDE.

14. A method according to claim 13 wherein the PDE inhibitor selective for type IV PDE is any one of rolipram (4-[3-cyclopentyloxy-4-methoxyphenyl]-2-pyrrolidinone), CP80 633, CP102 995, CP76 593, Ro-20-1724 (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone), denbufylline (1,3-di-n-butyl-7-(2-oxopropyl)-xanthine), or CDP840, RP73401 or RS33793.

15. A method of combating a disease or condition associated with transplant rejection comprising:

performing the method according to claim 1 wherein said administering is effective to combat a disease or condition associated with transplant rejection.

16. A method according to claim 15 wherein the disease or condition associated with transplant rejection comprises graft versus host disease or host versus graft disease.

17. A method according to claim 15 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or antigen or derivative thereof are administered prior to the transplant.

18. A method according to claim 15 wherein the antigen is HLA-A2.

19. A method for treating an autoimmune disease or condition comprising:

performing the method according to claim 1, wherein said administering is effective to treat an autoimmune disease or condition.

20. A method according to claim 19 wherein the antigen is a self-antigen.

21. A method according to claim 19, wherein the autoimmune disease is pernicious anaemia, and the antigen is vitamin B₁₂;

the disease is Addison'"'"'s disease, and the antigen is adrenal antigen;

if the disease is IDDM, and the antigen is glutamic acid decarboxylase (GAD), insulin, or IA-2;

the disease is Goodpasture'"'"'s syndrome or renal vasculitis, and the antigen is renal antigen or endothelial antigen;

the disease is myasthenia gravis, and the antigen is the acetyl choline receptor;

the disease is sympathetic ophthalmia, and the antigen is ocular antigen;

the disease is multiple sclerosis (MS), and the antigen is myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG);

the disease is autoimmune haemolytic anaemia, and the antigen is red cell antigen;

the disease is idiopathic leucopenia, and the antigen is leukocyte antigen;

the disease is ulcerative colitis, and the antigen is a food antigen or a viral antigen;

the disease is dermatomyositis, and the antigen is smooth muscle antigen;

the disease is scleroderma, and the antigen is a connective tissue antigen;

the disease is mixed connective tissue disease, and the antigen is a connective tissue antigen;

the disease is irritable bowel syndrome, and the antigen is a food antigen;

the disease is systemic lupus erythmatosus (SLE), and the antigen is a histone protein or immunoglobulin heavy chain;

the disease is Hashimoto'"'"'s disease, primary myxoedema or thyrotoxicosis, and the antigen is thyroid antigen;

the disease is rheumatoid arthritis, and the antigen is type II collagen or a heat shock protein (HSP);

the disease is thyroiditis, and the antigen is thyroglobulin;

the disease is Behcet'"'"'s disease, and the antigen is Sag, HLA-B44, B51, or HSP65;

the disease is Coeliac disease/Dermatitis herpetiformis, and the antigen is gliadin or the α

fraction thereof;

or the disease is demyelinating disease, and the antigen is myelin.

22. A method for treating an allergic disease or condition in the patient comprising:

performing the method according to claim 1, wherein said administering is effective to treat an allergic disease or condition in the patient.

23. A method according to claim 22 wherein the allergic disease or condition is allergic asthma.

24. A method according to claim 22, wherein the antigen is a mite allergen, a dust allergen, a cat allergen, a dog allergen or a horse allergen.

25. A method according to claim 1, wherein the induced tolerance to the antigen is effective to treat an aberrant or undesired immune or inflammatory response to the antigen in the patient.

26. A method according to claim 25 wherein the aberrant or undesired immune or inflammatory response involves a deficiency in IL-10 production and/or an increase in IL-12 production.

27. Use of one or more of (i) a prostaglandin or agonist thereof, (ii) a PDE inhibitor, and (iii) an antigen or a derivative thereof in the manufacture of a medicament for inducing tolerance to the an antigen in a patient wherein the patient is administered any of (i), (ii), and (iii) that are not present in the medicament.

34. Use according to claim 27 wherein the PDE inhibitor is selective for any of type IV, VII or VIII PDE.

35. Use according to claim 27 wherein the PDE inhibitor is any one of IBMX, pentoxifylline, CP80 633, CP102 995, CP76 593, rolipram, Ro-20-1724, theophylline, caffeine or denbufylline.

36. Use according to claim 27 wherein the PDE inhibitor is selective for type IV PDE.

37. Use according to claim 36 wherein the PDE inhibitor selective for type IV PDE is any one of rolipram, CP80 633, CP102 995, CP76 593, Ro-20-1724, denbufylline, CDP840, RP73401, or 7S33793.

38. Use according to claim 27 wherein the prostaglandin or agonist thereof is any one of a prostaglandin E, prostaglandin E₂ or an analogue thereof, carboprost, dinoprostone, gemeprost, misoprostol, alprostadil, lamaprost, butaprost, 11-deoxy PGE1, AH23848, AH13205, 19-hydroxy PGE1 or 19-hydroxy PGE2 or agonist thereof.

39. Use according to claim 27 wherein the prostaglandin is a 19-hydroxy PGE.

40. Use according to claim 27 wherein the medicament is administered locally at a site where tolerance is required.

41. Use according to claim 27 wherein the medicament is formulated to be administered systemically.

42. Use according to claim 41 wherein the medicament is formulated to be administered orally.

43. Use according to claim 41 wherein the medicament is formulated to be administered as a suppository or capsule.

44. Use according to claim 43 wherein the suppository or capsule has an enteric coating for release of the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof in the bowel of the patient.

45. Use according to claim 27 for combating a disease or condition associated with transplant rejection.

46. Use according to claim 45 wherein the disease or condition associated with transplant rejection comprises graft versus host disease or host versus graft disease.

47. Use according to claim 45 wherein the medicament is administered prior to the transplant.

48. Use according to claim 45 wherein the antigen is HLA-A2.

49. Use according to claim 27 for treating an autoimmune disease or condition.

50. Use according to claim 49 wherein the antigen is a self-antigen.

51. Use according to claim 49, wherein the autoimmune disease is pernicious anaemia, and the antigen is vitamin B₁₂;

the disease is Addison'"'"'s disease, and the antigen is adrenal antigen;

the disease is IDDM, and the antigen is GAD, insulin, or IA-2;

the disease is Goodpasture'"'"'s syndrome or renal vasculitis, and the antigen is renal antigen or endothelial antigen;

the disease is myasthenia gravis, and the antigen is the acetyl choline receptor;

the disease is sympathetic ophthalmia, and the antigen is ocular antigen;

the disease is MS, and the antigen is MBP, PLP, or MOG;

the disease is autoimmune haemolytic anaemia, and the antigen is red cell antigen;

the disease is idiopathic leucopenia, and the antigen is leukocyte antigen;

the disease is ulcerative colitis, and the antigen is a food antigen or a viral antigen;

the disease is dermatomyositis, and the antigen is smooth muscle antigen;

the disease is scleroderma, and the antigen is a connective tissue antigen;

the disease is mixed connective tissue disease, and the antigen is a connective tissue antigen;

the disease is irritable bowel syndrome, and the antigen is a food antigen;

the disease is SLE, and the antigen is a histone protein or immunoglobulin heavy chain;

the disease is Hashimoto'"'"'s disease, primary myxoedema or thyrotoxicosis, and the antigen is thyroid antigen;

the disease is rheumatoid arthritis, and the antigen is type II collagen or an HSP;

the disease is thyroiditis, and the antigen is thyroglobulin;

the disease is Behcet'"'"'s disease, and the antigen is Sag, HLA-B44, B51, or HSP65;

the disease is Coeliac disease/Dermatitis herpetiformis, and the antigen is gliadin or the α

fraction thereof;

or the disease is demyelinating disease, and the antigen is myelin.

52. Use according to claim 27 for treating an allergic disease or condition in the patient.

53. Use according to claim 52 wherein the allergic disease or condition is allergic asthma.

54. Use according to claim 52, wherein antigen is a mite allergen, a dust allergen, a cat allergen, a dog allergen or a horse allergen.

55. Use according to claim 27 wherein the tolerance to the antigen is to treat an aberrant or undesired immune or inflammatory response to the antigen in the patient.

56. Use according to claim 55 wherein the aberrant or undesired immune or inflammatory response involves a deficiency in IL-10 production and/or an increase in IL-12 production.

87. The use according to claim 27, wherein the prostaglandin or agonist thereof is present in the medicament.

88. The use according to claim 27, wherein the PDE inhibitor is present in the medicament.

89. The use according to claim 27, wherein the antigen or the derivative thereof is present in the medicament.

90. The use according to claim 27, wherein a combination of the prostaglandin or agonist thereof and the PDE inhibitor is present in the medicament.

91. The use according to claim 27, wherein a combination of the prostaglandin or agonist thereof and the antigen is present in the medicament.

92. The use according to claim 27, wherein a combination of the PDE inhibitor and the antigen or derivative thereof is present in the medicament.

93. The use according to claim 27, wherein a combination of the prostaglandin or agonist thereof, the PDE inhibitor, and the antigen or derivative thereof is present in the medicament.

28-33. -33. (canceled)

57. A therapeutic system for inducing tolerance to an antigen in a patient, the system comprising a prostaglandin or agonist thereof, a PDE inhibitor, and the antigen or a derivative thereof.

58. A therapeutic system according to claim 57 wherein the prostaglandin or agonist thereof and/or the PDE inhibitor and/or the antigen or derivative thereof is in a preparation for administration locally at a site where tolerance is required.

59. A therapeutic system according to claim 57 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is in a preparation for systemic administration.

60. A therapeutic system according to claim 59 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is in a preparation for oral administration.

61. A therapeutic system according to claim 59 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof is formulated as a suppository or capsule.

62. A therapeutic system according to claim 61 wherein the suppository or capsule has an enteric coating for release of the prostaglandin or agonist thereof and/or PDE inhibitor and/or the antigen or derivative thereof in the bowel of the patient

63. A therapeutic system according to claim 57 wherein the prostaglandin or agonist thereof is any one of a prostaglandin E, prostaglandin E₂ or an analogue thereof, dinoprostone, gemeprost, misoprostol, alprostadil, limaprost, butaprost, 11-deoxy PGE1, AH23848, AH13205, 19-hydroxy PGE1 or 19-hydroxy PGE2.

64. A therapeutic system according to claim 57 wherein the prostaglandin is a 19-hydroxy PGE.

65. A therapeutic system according to claims 57 wherein the PDE inhibitor is selective for any of type IV, VII or VIII PDE.

66. A therapeutic system according to claim 57 wherein the PDE inhibitor is any one of IBMX, pentoxifylline, rolipram, CP80 633, CP102 995, CP76 593, Ro-20-1724, theophylline or denbufylline.

67. A therapeutic system according to claim 57 wherein the PDE inhibitor is selective for type IV PDE.

68. A therapeutic system according to claim 67 wherein the PDE inhibitor selective for type IV PDE is any one of rolipram, CP80 633, CP102 995, CP76 593, Ro-20-1724, denbufylline, CDP840, RP73401, or RS33793.

69. A therapeutic system according to claim 57 for combating a disease or condition associated with transplant rejection.

70. A therapeutic system according to claim 69 wherein the disease or condition associated with transplant rejection comprises graft versus host disease or host versus graft disease.

71. A therapeutic system according to claim 69 wherein the prostaglandin or agonist thereof and/or PDE inhibitor and/or antigen or derivative thereof are for administration prior to the transplant.

72. A therapeutic system according to claim 69 wherein the antigen is HLA-A2.

73. A therapeutic system according to claim 57 for treating an autoimmune disease or condition.

74. A therapeutic system according to claim 73 wherein the antigen is a self-antigen.

75. A therapeutic system according to claim 73 wherein the autoimmune disease is pernicious anaemia, and the antigen is vitamin B₁₂;

the disease is Addison'"'"'s disease, and the antigen is adrenal antigen;

the disease is IDDM, and the antigen is GAD, insulin, or IA-2;

the disease is Goodpasture'"'"'s syndrome or renal vasculitis, and the antigen is renal antigen or endothelial antigen;

the disease is myasthenia gravis, and the antigen is the acetyl choline receptor;

the disease is sympathetic ophthalmia, and the antigen is ocular antigen;

the disease is MS, and the antigen is MBP, PLP, or MOG;

the disease is autoimmune haemolytic anaemia, and the antigen is red cell antigen;

the disease is idiopathic leucopenia, and the antigen is leukocyte antigen;

the disease is ulcerative colitis, and the antigen is a food antigen or a viral antigen;

the disease is dermatomyositis, and the antigen is smooth muscle antigen;

the disease is scleroderma, and the antigen is a connective tissue antigen;

the disease is mixed connective tissue disease, and the antigen is a connective tissue antigen;

the disease is irritable bowel syndrome, and the antigen is a food antigen;

the disease is SLE, and the antigen is a histone protein or immunoglobulin heavy chain;

the disease is Hashimoto'"'"'s disease, primary myxoedema or thyrotoxicosis, and the antigen is thyroid antigen;

the disease is rheumatoid arthritis, and the antigen is type II collagen or an HSP;

the disease is thyroiditis, and the antigen is thyroglobulin;

the disease is Behcet'"'"'s disease, and the antigen is Sag, HLA-B44, B51, or HSP65;

the disease is Coeliac disease/Dermatitis herpetiformis, and the antigen is gliadin or the α

fraction thereof;

or the disease is demyelinating disease, and the antigen is myelin.

76. A therapeutic system according to claim 57 for treating an allergic disease or condition in the patient.

77. A therapeutic system according to claim 76 wherein the allergic disease or condition is allergic asthma.

78. A therapeutic system according to claim 76 wherein the antigen is a mite allergen, a dust allergen, a cat allergen, a dog allergen or a horse allergen.

79. A therapeutic system according to claim 57, wherein the tolerance to the antigen is to treat an aberrant or undesired immune or inflammatory response to the antigen in the patient.

80. A therapeutic system according to claim 79 wherein the aberrant or undesired immune or inflammatory response involves a deficiency in IL-10 production and/or an increase in IL-12 production.

81. A composition for inducing tolerance to an antigen in a patient comprising a prostaglandin or agonist thereof, a PDE inhibitor, and the antigen or a derivative thereof.

82. A composition according to claim 81 wherein the PDE inhibitor is a type IV selective PDE inhibitor.

83. A composition according to claim 81 wherein the prostaglandin is a 19 hydroxy PGE.

84. A composition according to claim 81 for use in medicine.

85. A pharmaceutical composition comprising the composition of claim 81 and a pharmaceutically acceptable carrier.

86. (canceled)