Some content of this application is unavailable at the moment.
If this situation persist, please contact us atFeedback&Contact
1. (WO2018037103) PROCAINAMIDE FOR TREATING IMMUNE DISORDERS AND FOR MODULATING IDO EXPRESSION
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

CLAIMS

1 . Procainamide or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of an immune related disease, disorder or condition.

2. Use of procainamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of an immune related disease, disorder or condition.

3. A method of treating an immune related disease, disorder or condition comprising administering to a subject in need thereof a therapeutically effective amount of procainamide or a pharmaceutically acceptable salt thereof.

4. Procainamide, use or method according to any one of claims 1 to 3 wherein

procainamide induces indolamine 2,3-dioxygenase (IDO).

5. Procainamide, use or method according to any one of claims 1 to 4 wherein the immune related disease, disorder or condition is selected from the group consisting of autoimmune diseases and disorders; immune rejection of transplants; and immune reactions to an

exogenous therapeutic agent.

6. Procainamide, use or method according to claim 5 wherein the immune related disease, disorder or condition is an autoimmune disease or disorder e.g. Achlorhydria, Acute haemorrhagic leukoencephalitis, Addison's Disease, Alopecia Areata, Anemia, Ankylosing Spondylitis, Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome, Aplastic Anemia, Atopic Allergy, Autoimmune Atrophic Gastritis, Autoimmune Hearing Loss, Autoimmune hemolytic anemia, Autoimmune Hepatitis, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune Lymphoproliferative, Autoimmune Myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy, Autoimmune Polyendocrinopathy, Autoimmune Syndrome Type II, Behcet Syndrome, Celiac Disease, Chagas Disease, Chronic Active Hepatitis, Chronic Inflammatory Demyelinating Polyneuropathy, Chronic lymphocytic thyroiditis, Churg-Strauss Syndrome, Crohn's disease, Cryoglobulinemia, Cushing Syndrome, Dermatitis Herpetiformis, Dermatomyositis, Diabetes Mellitus type 1 , Diffuse Cerebral Sclerosis of Schilder, Experimental Autoimmune Encephalomyelitis (EAE), Epidermolysis Bullosa Acquisita, Erythematosis, Experimental Autoimmune Neuritis, Felty's Syndrome, Glomerulonephritis, Glomerulonephritis Membranous, Goodpasture Syndrome, Graves' Disease, Guillain-Barre Syndrome, Hamman-Rich syndrome, Idiopathic Thrombocytopenic Purpura, Inflammatory Bowel Diseases, Insulin resistance-type B, Lambert-Eaton Myasthenic Syndrome, Lens-induced uveitis, Lichen Sclerosus et Atrophicus, Lymphopenia, Meniere's Disease, Mixed Connective Tissue Disease, Mooren's ulcer, Mucocutaneous Lymph Node Syndrome, Multiple Sclerosis, Myasthenia Gravis, Myelitis

Transverse, Myocarditis, Narcolepsy, Neuromyelitis Optica, Oculovestibular auditory syndrome, Ophthalmia Sympathetic, Opsoclonus-Myoclonus Syndrome, Pancreatitis, Pemphigoid Bullous, Pemphigus foliaceous, Pemphigus Vulgaris, Polyarteritis Nodosa, Polymyalgia Rheumatica, Polyradiculoneuropathy, Primary biliary cirrhosis, Psoriasis, Raynauds, Reiter Disease, Relapsing Polychondritis, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sclerosing Cholangitis, Sjogren's Syndrome, Stiff-Person Syndrome, Adult-Onset Still's Disease, Takayasu's Arteritis, Temporal Arteritis, Thyrotoxicosis, Type B Insulin Resistance, Ulcerative Colitis, Uveomeningoencephalitic Syndrome, Vitiligo and Wegener's Granulomatosis.

7. Procainamide, use or method according to claim 5 wherein the immune related disease, disorder or condition is immune rejection of a transplant e.g. transplant of an organ, tissue or cells (including normal cells or genetically modified cells)

8. Procainamide, use or method according to claim 5 wherein the immune related disease, disorder or condition is immune reaction to exogenous therapeutic agent e.g. a biological drug such as FVIII, Factor IX or an antibody and the immune reaction is the raising of antibodies thereto.

9. Procainamide, use or method according to any one of claims 1 to 8 wherein

procainamide is administered as the sole active ingredient.

10. Procainamide, use or method according to any one of claims 1 to 8 wherein

procainamide is administered in combination with one or more additional active ingredients.

1 1 . Procainamide, use or method according to claim 10 wherein the one or more additional active ingredients are selected from metabolites of tryptophan; immunosuppressive reagents; aldehyde oxidase inhibitors; methotrexate; rapamycin; cyclophosphamide; antimetabolites; immunophilin-binding drugs; inhibitors of nucleotide synthesis; FTY720; lymphocyte depleting antibodies; non-depleting antibodies; anti-TNF antibodies; natalizumab; anti-CD154 antibodies; soluble cytokine receptors; soluble TNF receptors; and anakinra.

12. Procainamide, use or method according to claim 10 wherein the one or more additional active ingredients are selected from other compounds which induce I DO such as cytidine analogues (e.g. zebularine or a pharmaceutically acceptable salt thereof); histone deacetylase inhibitors; vitamin D3 analogues; interferons (e.g. interferon gamma or interferon alpha or a pharmaceutically acceptable salt thereof); toll-like receptor ligands; gonadotropine receptor signalling hormones; prostaglandine E2 analogues; IDO stabilizers; soluble CTLA4 conjugates; and glycocorticoids.

13. Procainamide, use or method according to claim 10 wherein the one or more additional active ingredients which induce IDO are selected from the group consisting of psammaplin A, decitabine, guadecitabine and azacytidine and pharmaceutically acceptable salts thereof.

14. Procainamide, use or method according to claim 12 or 13 wherein an additional active ingredient which induces IDO is azacytidine or a pharmaceutically acceptable salt thereof.

15. Procainamide, use or method according to claim 12 or 13 wherein an additional active ingredient which induces IDO is decitabine or a pharmaceutically acceptable salt thereof.

16. Procainamide, use or method according to claim 10 wherein the one or more additional active ingredients are other than psammaplin A, decitabine, guadecitabine or azacytidine, or pharmaceutically acceptable salts thereof.

17. Procainamide, use or method according to any one of claims 1 to 16 wherein procainamide is administered by injection.

18. A method of inducing IDO expression in a culture of antigen presenting cells obtained or derived from a subject who is suffering from or susceptible to an immune related disease, disorder or condition comprising the steps of:

(a) isolating antigen presenting cells or other cells which are capable of being matured or differentiated into antigen presenting cells, said antigen presenting cells being capable of IDO expression, from blood or bone marrow of the subject;

(b) culturing in vitro said antigen presenting cells or antigen presenting cells obtained by maturation or differentiation of said other cells in the presence of procainamide or a

pharmaceutically acceptable salt thereof, and optionally one or more antigens associated with the immune related disease, disorder or condition, whereby IDO expression is induced in said antigen presenting cells.

19. A method according to claim 18 comprising the steps of:

(a) isolating antigen presenting cells or other cells which are capable of being matured or differentiated into antigen presenting cells, said antigen presenting cells being capable of IDO expression, and CD4+ T-cells which are capable of being differentiated into Treg cells, from the blood or bone marrow of the subject;

(b) co-culturing in vitro said antigen presenting cells or antigen presenting cells obtained by maturation or differentiation of said other cells and CD4+ T-cells in the presence of

procainamide or a pharmaceutically acceptable salt thereof, and optionally one or more antigens associated with the immune related disease, disorder or condition, whereby IDO expression is induced in said antigen presenting cells and whereby said CD4+ T-cells are differentiated into Treg cells.

20. A method of inducing tolerance in a subject who is suffering from or susceptible to an immune related disease, disorder or condition comprising the steps of:

(a) isolating antigen presenting cells or other cells which are capable of being matured or differentiated into antigen presenting cells, said antigen presenting cells being capable of IDO expression, from blood or bone marrow of the subject;

(b) culturing in vitro said antigen presenting cells or antigen presenting cells obtained by maturation or differentiation of said other cells in the presence of procainamide or a

pharmaceutically acceptable salt thereof, and optionally one or more antigens associated with the immune related disease, disorder or condition, whereby IDO expression is induced in said antigen presenting cells;

(c) after IDO expression has been induced in said antigen presenting cells, transferring said cells back to the subject thereby to establish immune tolerance to the one or more antigens associated with the immune related disease, disorder or condition.

21 . A method of inducing tolerance in a subject who is suffering from or susceptible to an immune related disease, disorder or condition comprising the steps of:

(a) isolating antigen presenting cells or other cells which are capable of being matured or differentiated into antigen presenting cells, said antigen presenting cells being capable of IDO expression, and CD4+ T-cells which are capable of being differentiated into Treg cells, from the blood or bone marrow of the subject;

(b) co-culturing in vitro said antigen presenting cells or antigen presenting cells obtained by maturation or differentiation of said other cells and CD4+ T-cells in the presence of

procainamide or a pharmaceutically acceptable salt thereof, and optionally one or more antigens associated with the immune related disease, disorder or condition, whereby IDO expression is induced in said antigen presenting cells and whereby said CD4+ T-cells are differentiated into Treg cells;

(c) after IDO expression has been induced in said antigen presenting cells and CD4+ T-cells have been differentiated into Treg cells, transferring either the antigen presenting cells in which

IDO expression has been induced or the Treg cells or both the antigen presenting cells in which IDO expression has been induced and the Treg cells back to the subject thereby to establish immune tolerance to the one or more antigens associated with the immune related disease, disorder or condition.

22. A method according to claim 21 wherein in step (c), either the antigen presenting cells in which IDO expression has been induced or the Treg cells are transferred back to the subject.

23. A method according to claim 21 wherein in step (c), both the antigen presenting cells in which IDO expression has been induced and the Treg cells are transferred back to the subject.

24. A method according to any one of claims 18 to 23 wherein the immune related disease, disorder or condition is selected from the group consisting of autoimmune diseases and disorders; immune rejection of transplants; and immune reactions to an exogenous therapeutic agent.

25. A method according to claim 24 wherein the subject is suffering from or susceptible to an autoimmune disease or disorder and the one or more antigens comprise self-antigens e.g. antigens derived from collagen, cartilage or other tissues of the subject.

26. A method according to claim 24 wherein the subject is suffering from or susceptible to immune rejection of a transplant and the one or more antigens comprise antigens derived from the transplant.

27. A method according to claim 26 wherein the transplant is transplant of an organ, tissue or cells (including normal cells or genetically modified cells).

28. A method according to claim 24 wherein the subject is suffering from or susceptible to immune reaction to an exogenous therapeutic agent and the one or more antigens comprise antigens from the exogenous therapeutic agent.

29. A method according to claim 28 wherein the exogenous therapeutic agent is a biological drug such as FVIII, Factor IX or an antibody and the immune reaction comprises the raising of antibodies thereto.

30. A method according to any one of claims 20 to 29 wherein the subject receives treatment with one or more other pharmaceutically active agents e.g. with rapamycin concurrently with the treatment with cells

31 . A method according to any one of claims 18 to 30 wherein the antigen presenting cells are dendritic cells.

32. A method according to any one of claims 18 to 31 wherein the blood is peripheral blood.

33. A method according to any one of claims 18 to 32 wherein procainamide is employed in step (b) as the sole active ingredient.

34. A method according to any one of claims 18 to 32 wherein one or more additional active ingredients are employed in step (b) and are selected from metabolites of tryptophan;

immunosuppressive reagents; aldehyde oxidase inhibitors; methotrexate; rapamycin;

cyclophosphamide; antimetabolites; immunophilin-binding drugs; inhibitors of nucleotide synthesis; FTY720; lymphocyte depleting antibodies; non-depleting antibodies; anti-TNF antibodies; natalizumab; anti-CD154 antibodies; soluble cytokine receptors; soluble TNF receptors; and anakinra.

35. A method according to any one of claims 18 to 32 wherein one or more additional active ingredients which induce IDO are employed in step (b) and are selected from compounds such as cytidine analogues (e.g. zebularine or a pharmaceutically acceptable salt thereof); histone deacetylase inhibitors; vitamin D3 analogues; interferons (e.g. interferon gamma or interferon alpha or a pharmaceutically acceptable salt thereof); toll-like receptor ligands; gonadotropine receptor signalling hormones; prostaglandine E2 analogues; IDO stabilizers; soluble CTLA4 conjugates; and glycocorticoids.

36. A method according to any one of claims 18 to 32 wherein one or more additional active ingredients which induce IDO are employed in step (b) and are selected from the group consisting of psammaplin A, decitabine, guadecitabine and azacytidine and pharmaceutically acceptable salts thereof.

37. A method according to claim 35 or 36 wherein the additional active ingredient which induces IDO is azacytidine or a pharmaceutically acceptable salt thereof.

38. A method according to claim 35 or 36 wherein the additional active ingredient which induces IDO is decitabine or a pharmaceutically acceptable salt thereof.

39. A method according to any one of claims 18 to 32 wherein procainamide is employed in step (b) in combination with one or more additional active ingredients wherein the one or more additional active ingredients are other than psammaplin A, decitabine, guadecitabine or azacytidine, or pharmaceutically acceptable salts thereof.

40. A method according to any one of claims 18 to 39 wherein step (b) further comprises stimulating the cultured antigen presenting cells with oligonucleotides.

41 . A cell culture in which IDO expression has been induced, obtained or obtainable by the method of any one of claims 18 to 40.

42. A cell culture in which IDO expression has been induced comprising:

(a) isolated antigen presenting cells or antigen presenting cells obtained by maturation or differentiation of other isolated cells which are capable of being matured or differentiated into antigen presenting cells from blood or bone marrow of a subject; and

(b) procainamide or a pharmaceutically acceptable salt thereof.

43. A cell culture according to claim 42 further comprising Treg cells obtained by differentiation in the cell culture of CD4+ T-cells isolated from blood or bone marrow of the subject.

44. A cell culture according to claim 42 or claim 43 further comprising one or more antigens associated with the immune related disease, disorder or condition.

45. Antigen presenting cells in which I DO expression has been induced obtained or obtainable by the method of any one of claims 18, 19 or 24 to 40.

46. Antigen presenting cells isolated from the cell culture of claim 42 to 44.

47. Treg cells isolated from the cell culture of claim 43 or 44.

48. Antigen presenting cells according to claim 45 or 46 for use in a method of treating a subject suffering from or susceptible to an immune related disease, disorder or condition whereby according to said method said cells are transferred back to said subject thereby to establish immune tolerance to the immune related disease, disorder or condition.

49. Treg cells according to claim 47 for use in a method of treating a subject suffering from or susceptible to an immune related disease, disorder or condition whereby according to said method said cells are transferred back to said subject thereby to establish immune tolerance to the immune related disease, disorder or condition.

50. Antigen presenting cells or Treg cells for use according to claim 48 or 49 wherein the immune related disease, disorder or condition is selected from the group consisting of autoimmune diseases and disorders; immune rejection of transplants; and immune reactions to an exogenous therapeutic agent.

51 . A method of inducing I DO in a transplant comprising the steps of:

(a) obtaining a transplant (for example, organ, tissue or cells) from a donor;

(b) administering ex vivo to said transplant an effective amount of procainamide or a pharmaceutically acceptable salt thereof such that I DO is induced in cells of the transplant.

52. A method of inducing immune tolerance to a transplant in a subject who is to receive said transplant comprising the steps of:

(a) obtaining a transplant (for example, organ, tissue or cells) from a donor;

(b) administering ex vivo to said transplant an effective amount of procainamide or a pharmaceutically acceptable salt thereof such that I DO is induced in cells of the transplant;

(c) after I DO expression has been induced in said transplant, implanting the transplant in the subject in need thereof such that immune tolerance to the transplant in the subject is established.

53. A method according to claim 51 or 52 wherein procainamide is employed in step (b) as the sole active ingredient.

54. A method according to claim 51 or 52 wherein one or more additional active ingredients are employed in step (b) and are selected from metabolites of tryptophan; immunosuppressive reagents; aldehyde oxidase inhibitors; methotrexate; rapamycin; cyclophosphamide;

antimetabolites; immunophilin-binding drugs; inhibitors of nucleotide synthesis; FTY720;

lymphocyte depleting antibodies; non-depleting antibodies; anti-TNF antibodies; natalizumab; anti-CD154 antibodies; soluble cytokine receptors; soluble TNF receptors; and anakinra.

55. A method according to claim 51 or 52 wherein one or more additional active ingredients which induce IDO are employed in step (b) and are selected from compounds such as cytidine analogues (e.g. zebularine or a pharmaceutically acceptable salt thereof); histone deacetylase inhibitors; vitamin D3 analogues; interferons (e.g. interferon gamma or interferon alpha or a pharmaceutically acceptable salt thereof); toll-like receptor ligands; gonadotropine receptor signalling hormones; prostaglandine E2 analogues; IDO stabilizers; soluble CTLA4 conjugates; and glycocorticoids.

56. A method according to claim 51 or 52 wherein one or more additional active ingredients which induce IDO are employed in step (b) and are selected from the group consisting of psammaplin A, decitabine, guadecitabine and azacytidine and pharmaceutically acceptable salts thereof.

57. A method according to claim 55 or 56 wherein the additional active ingredient which induces IDO is azacytidine or a pharmaceutically acceptable salt thereof.

58. A method according to claim 55 or 56 wherein the additional active ingredient which induces IDO is decitabine or a pharmaceutically acceptable salt thereof.

59. A method according to claim 51 or 52 wherein procainamide is employed in step (b) in combination with one or more additional active ingredients wherein the one or more additional active ingredients is other than psammaplin A, decitabine, guadecitabine or azacytidine, or pharmaceutically acceptable salts thereof.