Compositions and methods for liver growth and liver protection

• US 20040170613A1
• Filed: 06/05/2003
• Published: 09/02/2004
• Est. Priority Date: 06/05/2002
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Ferrara, Napoleone, Hillan, Kenneth J., Le Couter, Jennifer
• Granted Patent: US 7,700,571 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2799/022 where the vector is derived from an adenovirus

Abstract

The present invention provides pharmaceutical compositions and methods for liver proliferation and protection. Specifically useful are VEGFR modulating agents capable of promoting liver growth. Disclosed compositions and methods may be useful for promoting proliferation or treating pathological conditions in other organs of significant biological functions.

Claims

1. A method for promoting liver growth in a subject, comprising administering to the subject an effective amount of a VEGFR modulating agent, whereby the liver mass of the subject is increased.

2. The method of claim 1, wherein the VEGFR modulating agent is a Flt-1 agonist.

3. The method of claim 2, wherein the Flt-1 agonist comprises a Flt-1 selective VEGF variant (Flt-sel) that selectively binds to Flt-1.

4. The method of claim 3, wherein the Flt-sel VEGF variant comprises the following amino acid substitutions to a wild type VEGF:

I43A, I46A, Q79A and I83A.

5. The method of claim 2, wherein the Flt-1 agonist comprises PIGF or VEGF-B.

6. The method of claim 2, wherein the Flt-1 agonist is a small molecule entity that selectively binds to and activates Flt-1.

7. The method of claim 2, further comprising administering an angiogenic agent in the amount effective to promote proliferation of nonparenchymal cells in the liver.

8. The method of claim 7, wherein the angiogenic agent is a KDR agonist.

9. The method of claim 8, wherein the KDR agonist is VEGF, a KDR selective VEGF variant (KDR-sel), an agonistic anti-KDR antibody, or a small molecule.

10. The method of claim 1, wherein the VEGFR modulating agent is administered to the subject through a systemic delivery system.

11. The method of claim 10, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant VEGFR modulating agent.

12. The method of claim 11, wherein the mammalian cells are CHO cells.

13. The method of claim 10, wherein the systemic delivery system comprises a slow release preparation comprising purified VEGFR modulating agent and a polymer matrix.

14. The method of claim 13, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

15. The method of claim 1, wherein the VEGFR modulating agent is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the VEGFR modulating agent.

16. The method of claim 15, wherein the liver-targeted gene delivery vector is a retroviral vector, adenoviral vector, adeno-associated viral vector or lentiviral vector.

17. The method of claim 15, wherein the liver-targeted gene delivery vector is a nonviral vector comprising a cationic liposome.

18. A method of treating a pathological liver condition in a subject, comprising administering to the subject a VEGFR modulating agent in a manner effective to alleviate the pathological liver condition.

19. The method of claim 18, wherein said pathological liver condition is liver failure, hepatitis, liver cirrhosis, toxic liver damage, medicamentary liver damage, hepatic encephalopathy, hepatic coma or hepatic necrosis.

20. The method of claim 18, wherein the VEGFR modulating agent is a Flt-1 agonist.

21. The method of claim 20, wherein the Flt-1 agonist comprises a Flt-1 selective VEGF variant (Flt-sel) that selectively binds to Flt-1.

22. The method of claim 21 wherein the Flt-sel VEGF variant comprises the following amino acid substitutions to a wild type VEGF:

I43A, I46A, Q79A and I83A.

23. The method of claim 20, wherein the Flt-1 agonist comprises PIGF or VEGF-B.

24. The method of claim 20, wherein the Flt-1 agonist is a small molecule entity that selectively binds to and activates Flt-1.

25. The method of claim 20, further comprising administering an angiogenic factor in the amount effective to promote proliferation of nonparenchymal cells in the liver.

26. The method of claim 25, wherein the angiogenic factor is a KDR agonist.

27. The method of claim 26, wherein the KDR agonist is VEGF, a KDR selective VEGF variant (KDR-sel), an agonistic anti-KDR antibody, or a small molecule.

28. The method of claim 18, wherein the VEGFR modulating agent is administered to the subject through a systemic delivery system.

29. The method of claim 28, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant VEGFR modulating agent.

30. The method of claim 29, wherein the mammalian cells are CHO cells.

31. The method of claim 28, wherein the systemic delivery system comprises a slow release preparation comprising purified VEGFR modulating agent and a polymer matrix.

32. The method of claim 31, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

33. The method of claim 18, wherein the VEGFR modulating agent is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the VEGFR modulating agent.

34. The method of claim 33, wherein the liver-targeted gene delivery vector is a retroviral vector, adenoviral vector, adeno-associated viral vector or lentiviral vector.

35. The method of claim 33, wherein the liver-targeted gene delivery vector is a nonviral vector comprising a cationic liposome.

36. A method for promoting hepatocyte proliferation in the liver of a subject, comprising administering to the subject a Flt-1 agonist, in a manner effective to promote hepatocyte proliferation.

37. The method of claim 36, wherein the Flt-1 agonist comprises a Flt-1 selective VEGF variant (Flt-sel) that selectively binds to Flt-1.

38. The method of claim 37, wherein the Flt-sel VEGF variant comprises the following amino acid substitutions to a wild type VEGF:

I43A, I46A, Q79A and I83A.

39. The method of claim 36, wherein the Flt-1 agonist comprises PIGF or VEGF-B.

40. The method of claim 36, wherein the Flt-1 agonist is a small molecule entity that selectively binds to and activates Flt-1.

41. The method of claim 36, wherein the Flt-1 agonist is delivered to the nonparenchymal cells of the liver.

42. The method of claim 41, wherein the nonparenchymal cells are sinusoidal endothelial cells.

43. The method of claim 36, wherein the Flt-1 agonist is administered to the subject through a systemic delivery system.

44. The method of claim 43, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant Flt-1 agonist.

45. The method of claim 44, wherein the mammalian cells are CHO cells.

46. The method of claim 43, wherein the systemic delivery system comprises a slow release preparation comprising purified Flt-1 agonist and a polymer matrix.

47. The method of claim 46, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

48. The method of claim 36, wherein the Flt-1 agonist is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the Flt-1 agonist.

49. The method of claim 48, wherein the liver-targeted gene delivery vector is a retroviral vector, adenoviral vector, adeno-associated viral vector or lentiviral vector.

50. The method of claim 48, wherein the liver-targeted gene delivery vector is a nonviral vector comprising a cationic liposome.

51. A method for protecting liver from damage in a subject duet to exposure to a hepatotoxic agent, said method comprising administering to the subject a VEGFR modulating agent, wherein said VEGFR modulating agent effectively protects liver from damage.

52. The method of claim 51, wherein the VEGFR modulating agent is a Flt-1 agonist.

53. The method of claim 52, wherein the Flt-1 agonist comprises a Flt-1 selective VEGF variant (Flt-sel) that selectively binds to Flt-1.

54. The method of claim 53, wherein the Flt-sel VEGF variant comprises the following amino acid substitutions to a wild type VEGF:

I43A, I46A, Q79A and I83A.

55. The method of claim 52, wherein the Flt-1 agonist comprises PIGF or VEGF-B.

56. The method of claim 52, wherein the Flt-I agonist is a small molecule entity that selectively binds to and activates FIt-1.

57. The method of claim 52, wherein the Flt-1 agonist is administered in combination with an angiogenic factor.

58. The method of claim 57, wherein the angiogenic factor is a KDR agonist.

59. The method of claim 58, wherein the KDR agonist is VEGF, a KDR selective VEGF variant (KDR-sel), an agonistic anti-KDR antibody, or a small molecule.

60. The method of claim 51, wherein the VEGFR modulating agent is administered prior to or concurrent with the exposure of said subject to the hepatotoxic agent.

61. The method of claim 60, wherein the hepatotoxic agent is a therapeutic agent effective for treating a disease.

62. The method of claim 61, wherein the therapeutic agent is a chemotherapeutic agent for treating cancer.

63. The method of claim 61, wherein the therapeutic agent is a radiation agent for treating cancer.

64. The method of claim 51, wherein the VEGFR modulating agent is administered after the exposure of said subject to said hepatotoxic agent but prior to any detectable liver damage in the subject.

65. The method of claim 64, wherein said subject is accidentally exposed to said hepatotoxic agent.

66. The method of claim 65, wherein the VEGFR modulating agent the Flt-1 agonist is administered within about 10 to about 20 hours after the accidental exposure.

67. The method of claim 52, further comprising administering an angiogenic agent in the amount effective to promote proliferation of nonparenchymal cells in the liver.

68. The method of claim 67, wherein the angiogenic agent is a KDR agonist.

69. The method of claim 68, wherein the KDR agonist is VEGF, a KDR selective VEGF variant (KDR-sel), an agonistic anti-KDR antibody, or a small molecule.

70. The method of claim 51, wherein the VEGFR modulating agent is administered to the subject through a systemic delivery system.

71. The method of claim 70, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant VEGFR modulating agent.

72. The method of claim 71, wherein the mammalian cells are CHO cells.

73. The method of claim 70, wherein the systemic delivery system comprises a slow release preparation comprising purified VEGFR modulating agent and a polymer matrix.

74. The method of claim 73, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

75. The method of claim 51, wherein the VEGFR modulating agent is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the VEGFR modulating agent.

76. The method of claim 75, wherein the liver-targeted gene delivery vector is a retroviral vector, adenoviral vector, adeno-associated viral vector or lentiviral vector.

77. The method of claim 75, wherein the liver-targeted gene delivery vector is a nonviral vector comprising a cationic liposome.

78. An article of manufacture comprising:

a) a container;

b) a composition contained within said container; and

c) a label on said container instructing uses of said composition for promoting liver growth;

wherein said composition comprises a VEGFR modulating agent in the amount effective to promote liver growth.

79. A kit comprising:

a) a first container, a label on said first container, and a composition contained within said first container;

wherein said composition comprises a VEGFR modulating agent in the amount effective to promote liver growth;

b) a second container comprising a pharmaceutically acceptable buffer; and

c) an instruction for using the kit for promoting liver growth.