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1. WO2016115092 - PROCÉDÉS DE CIBLAGE DE MÉCANISME VASCULAIRE HÔTE À DES FINS DE PROTECTION THÉRAPEUTIQUE CONTRE LA FIÈVRE HÉMORRAGIQUE

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WHAT IS CLAIMED IS:

1 . A method for treating hemorrhagic fever in a subject, comprising modulating an activity or expression of an adherens junction protein.

2. A method for treating hemorrhagic fever in a subject, comprising administering to the subject, an agonist or antagonist of an adherens junction protein in an amount sufficient to treat the hemorrhagic fever.

3. The method of claim 1 or claim 2 wherein the adherens junction protein is a cadherin, VE-cadherin, p120, gamma-catenin, or alpha-catenin.

4. A method for treating hemorrhagic fever in a subject, comprising modulating an activity or expression of a tight junction protein in the subject.

5. A method for treating hemorrhagic fever in a subject comprising administering an agonist or antagonist of a tight junction protein in an amount sufficient to treat the hemorrhagic fever.

6. The method of claim 4 or claim 5 wherein the tight junction protein is ZO-1 , ZO-2, ZO-3, an occluden, a claudin, or JAM-1 .

7. A method for treating hemorrhagic fever in a subject, comprising modulating a VEGF pathway in the subject.

8. A method for treating hemorrhagic fever in a subject, comprising modulating an Ang-1/Ang-2 pathway in the subject.

9. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an agonist or antagonist of the VEGF pathway in an amount sufficient to treat the hemorrhagic fever.

10. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an agonist or antagonist of the Ang-1 /Ang-2 pathway in an amount sufficient to treat the hemorrhagic fever.

1 1 . A method for treating hemorrhagic fever in a subject, comprising modulating two or more of a VEGF pathway, an Ang-1 /Ang-2 pathway and a TNF pathway in combination.

12. A method for treating hemorrhagic fever in a subject, comprising administering an agonist or antagonist of VE-PTP in an amount sufficient to treat the hemorrhagic fever.

13. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an amount of a Tie-2 agonist or antagonist sufficient to treat the hemorrhagic fever.

14. A method for treating hemorrhagic fever in a subject, comprising administering to the subject, a TNFa agonist or antagonist and a Tie-2 agonist or antagonist in amounts sufficient to treat the hemorrhagic fever.

15. A method for treating hemorrhagic fever in a subject, comprising administering to the subject, a VEGF agonist or antagonist and a Tie-2 agonist or antagonist in amounts sufficient to treat the hemorrhagic fever.

16. A method for treating hemorrhagic fever in a subject, comprising administering to the subject, a TNFa agonist or antagonist and a VEGF agonist or antagonist in amounts sufficient to treat the hemorrhagic fever.

17. A method for treating hemorrhagic fever in subject, comprising administering to the subject, a TNFa agonist or antagonist and an Ang-1 agonist or antagonist in amounts sufficient treat the hemorrhagic fever.

18. A method for treating hemorrhagic fever in a subject, comprising administering to the subject, a TNFa agonist or antagonist and an Ang-2 agonist or antagonist in amounts sufficient to treat the hemorrhagic fever.

19. The method of claim 17 or claim 18, wherein the method further comprises administration of an amount of a VEGF agonist or antagonist sufficient to treat the hemorrhagic fever.

20. A method for treating hemorrhagic fever in subject, comprising administering to the subject, a VEGF agonist or antagonist and an Ang-1 agonist or antagonist in amounts sufficient treat the hemorrhagic fever.

21 . A method for treating hemorrhagic fever in a subject, comprising administering to the subject, a VEGF agonist or antagonist and an Ang-2 agonist or antagonist in amounts sufficient to treat the hemorrhagic fever.

22. The method of any one of claims 16 to 21 , wherein the method further comprises administration of an effective amount of a Tie-2 agonist or antagonist in order to treat the hemorrhagic fever.

23. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an effective amount of a Tie-2 antagonist sufficient to treat the hemorrhagic fever.

24. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an effective amount of a VEGF antagonist sufficient to treat the hemorrhagic fever.

25. A method for treating hemorrhagic fever in a subject, comprising administering to the subject an effective amount of a TNFa antagonist sufficient to treat the hemorrhagic fever.

26. The method of any one of claims 1 to 25, wherein the hemorrhagic fever comprises a viral hemorrhagic fever caused by one or more of Arenaviridae (Lassa virus, Lujo virus, Junin virus, Machupo virus, Sabia virus or Guanarito virus), Bunyaviridae (Hantavirus, Nairovirus, Garissa virus, llesha virus, Orthobunyavirus or Phlebovirus), Filoviradae (Ebola virus, Marburg virus), Flaviviridae (Dengue virus, Yellow fever virus, Omsk hemorrhagic fever virus or Kyasanur Forest disease virus) or Rhabdoviridae.

27. The method of any one of claims 1 to 26, wherein the hemorrhagic fever comprises Lassa fever, South American hemorrhagic fevers including Argentine hemorrhagic fever, Bolivian hemorrhagic fever, Venezuelan hemorrhagic fever or Brazilian hemorrhagic fever, Whitwater Arroyo virus fever, Flexal virus fever, Ebola hemorrhagic fever, Marburg hemorrhagic fever, Crimean-Congo hemorrhagic fever, Rift Valley fever, hemorrhagic fevers with renal syndrome including Hantaan virus hemorrhagic fever, Seoul virus hemorrhagic fever, Dobrava virus hemorrhagic fever, Puumala virus hemorrhagic fever, hantavirus pulmonary syndrome-associated hemorrhagic fevers, including Bayou virus hemorrhagic fever, Black Creek Canal virus hemorrhagic fever, New York virus hemorrhagic fever, Sin Nombre virus hemorrhagic fever, Andes virus hemorrhagic fever, Oran virus hemorrhagic fever, Juquitiba virus hemorrhagic fever, Laguna Negra virus hemorrhagic fever,

Lechiguanas virus hemorrhagic fever, dengue hemorrhagic fever, dengue shock syndrome, Kyasanur Forest disease, Omsk hemorrhagic fever or yellow fever.

28. The method of any one of claims 1 to 27, wherein the hemorrhagic fever comprises Dengue fever.

29. The method of any one of claims 1 to 28, wherein the hemorrhagic fever is caused by antibody dependent enhancement of Dengue fever.

30. The method of any one of claims 1 to 29, wherein the treatment reduces, decreases, inhibits, delays, eliminates or prevents the probability, severity, frequency, or duration of one or more symptoms associated with or caused by the hemorrhagic fever.

31 . The method of claim 30, wherein the symptoms comprise one or more of pain, disseminated intravascular coagulation, bone marrow dysfunction, bleeding, headache, muscle or joint pain, nausea, vomiting, rash, vascular leakage, plasma leakage, fluid accumulation, respiratory distress, organ impairment or damage, fatigue or restlessness.

32. The method of any one of claims 14 to 22, wherein the agonists and/or antagonists are combined into a single molecule.

33. The method of claim 32, wherein the single molecule comprises a bi-specific or tri-specific antibody or aptamer.

34. The method of any one of 14,16, 17, 18, 19 and 25 wherein the TNFa antagonist comprises one of Etanercept, Infliximab, Adalimumab or Golimumab.

35. The method of any one of claims 13, 14, 15, 22 and 23, wherein the Tie-2 antagonist comprises one of SB-203580, 4-(6-Methoxy-2-naphthyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1 H-imidazole; Disodium succinate; 5-[4-[[[2-[[(1 S)-1 -Cyclohexylethyl]amino]-2-oxoethyl][(4-methylphenoxy)carbonyl]amino]methyl]phenyl]-3-pyridinecarboxylic acid, MGCD-265, 4-(4-pyrrolidinylphenyl)-1 ,3-thiazole-2-ylamine; or 2-Aimino-4-(4-pyrrolidin-1 -ylphenyl)-1 ,3-thiazole.

36. The method of any one of claims 15, 16, 19, 20, 21 , 22 and 24 wherein the VEGF antagonist comprises one of apatinib, bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, vandetanib, cabozantinib, ramucirumab, ponatinib, regorafenib or ziv-af libercept, ZM 323881 HCI.

37. The method of any one of claims 17, 19, 20 and 22 wherein the Ang-1 antagonist comprises ml_4-3.

38. The method of any one of claims 18, 19, 21 and 22 wherein the Ang-2 antagonist comprises L1 -7(N) or Angy-2-1 .

39. A method for treating hemorrhagic fever in a subject, comprising modulating the inflammatory response in the subject in combination with reducing, decreasing, inhibiting, delaying, eliminating or preventing vascular leakage in the subject.

40. A method for treating hemorrhagic fever in a subject, comprising modulating the inflammatory response in the subject in combination with modulating angiogenesis in the subject.

41 . The method of any one of claims 1 to 40 wherein the method comprises treating antibody-dependent-enhancement of infection in the subject.

42. The method of any one of claims 1 to 41 wherein the subject has vascular leakage resulting from antibody-dependent-enhancement of infection.

43. The method of any one of claims 1 to 42 wherein the subject has cytokine storm.

44. The method of any one of claim 1 to 143 wherein the subject has secondary viral infection.

45. A composition comprising one or more of a TNFa agonist or antagonist, an Ang-1 agonist or antagonist, an Ang-2 agonist or antagonist, a VEGF agonist or antagonist and a Tie-2 agonist or antagonist.

46. A composition comprising a TNFa agonist or antagonist and an Ang-1 agonist or antagonist.

47. A composition comprising a TNFa agonist or antagonist and an Ang-2 agonist or antagonist.

48. The composition of claim 46 or claim 47, further comprising a VEGF agonist or antagonist.

49. A composition comprising a VEGF agonist or antagonist and an Ang-1 agonist or antagonist.

50. A composition comprising a VEGF agonist or antagonist and an Ang-2 agonist or antagonist.

51 . The composition of any one of claims 46 to 50, further comprising a Tie-2 agonist or antagonist.

52. A composition comprising a TNFa agonist or antagonist and a Tie-2 agonist or antagonist.

53. A composition comprising a VEGF agonist or antagonist and a Tie-2 agonist or antagonist.

54. A composition comprising a VEGF agonist or antagonist and a TNFa agonist or antagonist.

55. The composition of any one of claims 45, 46, 47, 48, 52 and 54, wherein the TNFa antagonist comprises one of Etanercept, Infliximab, Adalimumab or Golimumab.

56. The composition of any one of claims 45, 51 ,52 and 53, wherein the Tie-2 antagonist comprises one of SB-203580, 4-(6-Methoxy-2-naphthyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1 H-imidazole; Disodium succinate; 5-[4-[[[2-[[(1 S)-1 -Cyclohexylethyl]amino]-2-oxoethyl][(4-methylphenoxy)carbonyl]amino]methyl]phenyl]-3-pyridinecarboxylic acid, MGCD-265, 4-(4-pyrrolidinylphenyl)-1 ,3-thiazole-2-ylamine; or 2-Aimino-4-(4-pyrrolidin-1 -ylphenyl)-1 ,3-thiazole.

57. The composition of any one of claims 45, 48, 49, 50, 51 , 53 and 54 wherein the VEGF antagonist comprises one of apatinib, bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, vandetanib, cabozantinib, ramucirumab, ponatinib, regorafenib or ziv-aflibercept, ZM 323881 HCI.

58. The composition of any one of claims 45, 46, 48, 49 and 51 wherein the Ang-1 antagonist comprises ml_4-3.

59. The composition of any one of claims 45, 47, 48, 50, 51 , wherein the Ang-2 antagonist comprises L1 -7[N] or Angy-2-1 .

60. A pharmaceutical composition comprising any one of the compositions of claims 45 to 59.

61 . A method of treating, preventing, or slowing one or more adverse symptoms and/or complications associated with a hemorrhagic fever pathology comprising administering to a subject having hemorrhagic fever, or at risk of having hemorrhagic fever, one or more Tie-2 antagonists in an amount sufficient to treat, prevent or slow the one or more adverse symptoms and/or complications.

62. The method of claim 61 , wherein the hemorrhagic fever is caused by a virus of the family Flaviviridae.

63. The method of claim 62, wherein the hemorrhagic fever is caused by a virus of the genus Flavivirus.

64. The method of claim 63, wherein the hemorrhagic fever is caused by DENV.

65. The method of any one of claims 61 to 64, wherein the Tie-2 antagonist comprises an Ang-1 antagonist or an Ang-2 agonist.

66. The method of any one of claims 61 to 64, wherein the Tie-2 antagonist comprises a tyrosine kinase inhibitor.

67. The method of claim 66, wherein the Tie-2 antagonist comprises a small compound tyrosine kinase inhibitor that blocks tyrosine kinase activity of a Tie-2 receptor stimulated by a Tie-2 agonist.

68. The method of claim 61 , further comprising administering a TNF antagonist.

69. A method of treating, preventing, or slowing a DENV infection comprising administering to a subject having a DENV infection, or at risk of having a DENV infection, one or more Tie-2 antagonists in an amount sufficient to treat, prevent or slow the DENV infection.

70. The method of claim 69, further comprising administering an effective amount of a TNF antagonist to the subject.

71 . A composition comprising a Tie-2 antagonist for use in treating, preventing or slowing one or more adverse symptoms and/or complications associated with a hemorrhagic fever pathology or for treating or preventing a virus infection.