Compositions and methods for liver growth and liver protection

• US 7,700,571 B2
• Filed: 06/05/2003
• Issued: 04/20/2010
• 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
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US10/455,470
• Publication Number:
  US 20040170613A1
• Time in Patent Office: 2,511 Days
• Field of Search: 435/6, 435/91.1, 435/455, 435/458, 435/69.1, 514/1, 514/2, 514/44, 536/23.1, 536/23.5, 530/350
• US Class Current: 514/44.00R
• 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, wherein the liver mass of the subject is increased, wherein the VEGFR modulating agent is a Flt-1 agonist comprising a Flt-1 selective VEGF-variant (Flt-sel) that selectively binds to Flt-1, wherein the Flt-sel VEGF variant comprises one or more amino acid sequence substitutions selected from the group consisting of I43A, I46A, Q79A and I83A, wherein the numbers refer to the amino acid residue positions along the amino acid sequence of a native VEGF₁₆₅.

2. The method of claim 1, wherein the Flt-sel VEGF variant comprises the following amino acid substitutions:

I43A, I46A, Q79A and I83A.

3. The method of claim 1, further comprising administering an angiogenic agent in the amount effective to promote proliferation of nonparenchymal cells in the liver, and wherein the angiogenic agent is VEGF.

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

5. The method of claim 4, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant VEGFR modulating agent.

6. The method of claim 5, wherein the mammalian cells are CHO cells.

7. The method of claim 4, wherein the systemic delivery system comprises a slow release preparation comprising purified VEGFR modulating agent and a polymer matrix.

8. The method of claim 7, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

9. 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.

10. The method of claim 9, wherein the liver-targeted gene delivery vector is an adenoviral vector.

11. 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, wherein the liver condition is liver failure, hepatitis, liver cirrhosis, toxic liver damage, medicamentary liver damage, hepatic encephalopathy, hepatic coma or hepatic necrosis, wherein the VEGFR modulating agent is a Flt-1 agonist comprising a Flt-1 selective VEGF-variant (Flt-sel) that selectively binds to Flt-1, wherein the Flt-sel VEGF variant comprises one or more amino acid sequence substitutions selected from the group consisting of I43A, I46A, Q79A and I83A, wherein the numbers refer to the amino acid residue positions along the amino acid sequence of a native VEGF₁₆₅.

12. The method of claim 11 wherein the Flt-sel VEGF variant comprises the following amino acid substitutions:

I43A, I46A, Q79A and I83A.

13. The method of claim 11, further comprising administering an angiogenic factor in the amount effective to promote proliferation of nonparenchymal cells in the liver, and wherein the angiogenic factor is VEGF.

14. The method of claim 11, wherein the VEGFR modulating agent is administered to the subject through a systemic delivery system.

15. The method of claim 14, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant VEGFR modulating agent.

16. The method of claim 15, wherein the mammalian cells are CHO cells.

17. The method of claim 14, wherein the systemic delivery system comprises a slow release preparation comprising purified VEGFR modulating agent and a polymer matrix.

18. The method of claim 17, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

19. The method of claim 11, wherein the VEGFR modulating agent is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the VEGFR modulating agent.

20. The method of claim 19, wherein the liver-targeted gene delivery vector is an adenoviral vector.

21. 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, wherein the Flt-1 agonist comprises a Flt-1 selective VEGF variant (Flt-sel) that selectively binds to Flt-1, wherein the Flt-sel VEGF variant comprises one or more amino acid sequence substitutions selected from the group consisting of I43A, I46A, Q79A and I83A, wherein the numbers refer to the amino acid residue positions along the amino acid sequence of a native VEGF₁₆₅.

22. The method of claim 21, wherein the Fit-sel VEGF variant comprises the following amino acid substitutions:

I43A, I46A, Q79A and I83A.

23. The method of claim 21, wherein the Flt-1 agonist is delivered to the nonparenchymal cells of the liver.

24. The method of claim 23, wherein the nonparenchymal cells are sinusoidal endothelial cells.

25. The method of claim 21, wherein the Flt-1 agonist is administered to the subject through a systemic delivery system.

26. The method of claim 25, wherein the systemic delivery system comprises a cell preparation comprising mammalian cells expressing a recombinant Flt-1 agonist.

27. The method of claim 26, wherein the mammalian cells are CHO cells.

28. The method of claim 25, wherein the systemic delivery system comprises a slow release preparation comprising purified Flt-1 agonist and a polymer matrix.

29. The method of claim 28, wherein the polymer matrix is a microcapsule selected from the group consisting of liposome, microsphere, microemulsion, nanoparticle and nanocapsule.

30. The method of claim 21, wherein the Flt-1 agonist is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the Flt-1 agonist.

31. The method of claim 30, wherein the liver-targeted gene delivery vector is an adenoviral vector.

32. 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, wherein said VEGFR modulating agent is a Flt-1 agonist comprising a Flt-1 selective VEGF variant (Fit-sel) that selectively binds Flt-1, wherein the Flt-sel VEGF variant comprises one or more amino acid sequence substitutions selected from the group consisting of I43A, I46A, Q79A and I83A, wherein the numbers refer to the amino acid residue positions along the amino acid sequence of a native VEGF₁₆₅.

33. The method of claim 32, wherein the Fit-sel VEGF variant comprises the following amino acid substitutions:

I43A, 146A, Q79A and I83 A.

34. The method of claim 32, wherein the Flt-1 agonist is administered in combination with an angiogenic factor, and wherein the angiogenic factor is VEGF.

35. The method of claim 32, wherein the VEGFR modulating agent is administered prior to or concurrent with the exposure of said subject to the hepatotoxic agent.

36. The method of claim 35, wherein the hepatotoxic agent is a therapeutic agent effective for treating a disease.

37. The method of claim 36, wherein the therapeutic agent is a chemotherapeutic agent for treating cancer.

38. The method of claim 36, wherein the therapeutic agent is a radiation agent for treating cancer.

39. The method of claim 32, 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.

40. The method of claim 39, wherein said subject is accidentally exposed to said hepatotoxic agent.

41. The method of claim 40, wherein the VEGFR modulating agent is administered within about 10 to about 20 hours after the accidental exposure.

42. The method of claim 34, further comprising administering the angiogenic agent in the amount effective to promote proliferation of nonparenchymal cells in the liver.

43. The method of claim 32, wherein the VEGFR modulating agent 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 VEGFR modulating agent.

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 VEGFR modulating agent 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 32, wherein the VEGFR modulating agent is administered via a liver-targeted gene delivery vector comprising a nucleic acid encoding the VEGFR modulating agent.

49. The method of claim 48, wherein the liver-targeted gene delivery vector is an adenoviral vector.