Methods and Compositions for Increasing Iduronate 2-Sulfatase Activity in the CNS

• US 20110110935A1
• Filed: 10/08/2010
• Published: 05/12/2011
• Est. Priority Date: 10/09/2009
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Boado, Ruben J., Pardridge, William M.
• Granted Patent: US 8,834,874 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C12N 9/16 acting on ester bonds (3.1)
• CPC Class Codes: C12Y 301/06013 Iduronate-2-sulfatase (3.1.6.13)

Abstract

Provided herein are methods and compositions for treating a subject suffering from a deficiency in iduronate 2-sulfatase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody that crosses the blood brain barrier (BBB) and an iduronate 2-sulfatase.

Claims

1. A method for treating an iduronate-2-sulfatase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase activity, wherein the fusion antibody comprises:

(a) a fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain; and

(b) an immunoglobulin light chain;

wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin.

2. The method of claim 1, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

3. The method of claim 2, wherein the fusion antibody comprises formylglycine.

4. The method of claim 1, wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity.

5. The method of claim 1, wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity.

6. The method of claim 1, wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to the brain, normalized per 50 kg body weight.

7. The method of claim 1, wherein the therapeutically effective dose comprises at least about 250,000 units of iduronate-2-sulfatase activity or at least about 25,000 units/Kg of body weight.

8. The method of claim 1, wherein the iduronate-2-sulfatase specific activity of the fusion antibody is at least 10,000 units/mg.

9. The method of claim 1, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

10. The method of claim 1, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of kappa class.

11. The method of claim 1, wherein the immunoglobulin heavy chain comprises a CDR1 corresponding to the amino acid sequence of SEQ iD NO:

1, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

2, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

3.

12. The method of claim 1, wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG.

13. The method of claim 1, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

14. The method of claim 1, wherein the immunoglobulin light chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:

4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

6.

15. The method of claim 1, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

16. The method of claim 1, wherein the fusion antibody crosses the BBB vie an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.

17. The method of claim 1, wherein the fusion antibody crosses the BBB by binding an insulin receptor.

24. The method of claim 1, wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity.

18. A method for treating an iduronate-2-sulfatase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase activity, wherein the fusion antibody comprises:

(a) a fusion protein comprising the amino acid sequence that is at least 95% identical to SEQ ID NO;

10, and

(b) an immunoglobulin light chain;

wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin.

19. The method of claim 18, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

20. The method of claim 18, wherein the fusion antibody comprises formylglycine.

21. The method of claim 18, wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to the brain, normalized per 50 kg body weight.

22. The method of claim 18, wherein the therapeutically effective dose comprises at least about 250,000 units of iduronate-2-sulfatase activity or at least about 25,000 units of iduronate-2-sulfatase activity/Kg of body weight.

23. The method of claim 18, wherein the iduronate-2-sulfatase specific activity of the fusion antibody is at least about 10,000 units/mg.

25. The method of claim 18, wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity.

26. The method of claim 18, wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.

27. The method of claim 18, wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG.

28. The method of claim 18, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

29. The method of claim 18, wherein the immunoglobulin light chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:

4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

6.

30. The method of claim 18, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

31. The method of claim 18, wherein the fusion antibody crosses the BBB vie an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.

32. The method of claim 18, wherein the fusion antibody crosses the BBB by binding an insulin receptor

33. A method for treating an iduronate-2-sulfatase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase activity, wherein the fusion antibody comprises:

(a) a fusion protein comprising the amino acid sequences of an immunoglobulin light chain and an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain;

or

(b) an immunoglobulin heavy chain;

wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin.

34. The method of claim 33, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

35. The method of claim 33, wherein the post-translational modification comprises a cysteine to formylglycine conversion.

36. The method of claim 33, wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to the brain, normalized per 50 kg body weight.

37. The method of claim 33, wherein the therapeutically effective dose comprises at least about 250,000 units of α

-L-iduronidase activity or at least about 25,000 units of iduronate-2-sulfatase activity/Kg body weight.

38. The method of claim 33, wherein the iduronate-2-sulfatase specific activity of the fusion antibody is about 10,000 units/mg.

39. The method of claim 33, wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity.

40. The method of claim 33, wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity.

41. The method of claim 33, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

42. The method of claim 33, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of kappa class.

43. The method of claim 33, wherein the immunoglobulin heavy chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:

1, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

2, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

3.

44. The method of claim 33, wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG.

45. The method of claim 33, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

46. The method of claim 33, wherein the immunoglobulin light chain comprises a CDR I corresponding to the amino acid sequence of SEQ ID NO:

4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

6.

47. The method of claim 33, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

48. The method of claim 33, wherein the fusion antibody crosses the BBB vie an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.

49. The method of claim 33, wherein the fusion antibody crosses the BBB the insulin receptor

50. A fusion antibody comprising:

(a) a fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain and

(b) an immunoglobulin light chain;

wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin.

51. The fusion antibody of claim 50, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

52. The fusion antibody of claim 50, wherein fusion antibody comprises a formylglycine.

53. The fusion antibody of claim 50, wherein the fusion protein further comprises a linker between the amino acid sequence of the iduronate-2-sulfatase and the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain.

54. The fusion antibody of claim 50, wherein the iduronate-2-sulfatase specific activity of the fusion antibody is at least about 10,000 units/mg.

55. The fusion antibody of claim 50, wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity.

56. The fusion antibody of claim 50, wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity.

57. The fusion antibody of claim 50, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

58. The fusion antibody of claim 50, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of kappa class.

59. The fusion antibody of claim 50, wherein the immunoglobulin heavy chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:

1, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

2, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

3.

60. The fusion antibody of claim 50, wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG.

61. The fusion antibody of claim 50, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

62. The fusion antibody of claim 50, wherein the immunoglobulin light chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:

4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO;

5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO;

6.

63. The fusion antibody of claim 50, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

64. The fusion antibody of claim 50, wherein the fusion antibody crosses the BBB vie an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.

65. The fusion antibody of claim 50, wherein the fusion antibody crosses the BBB by binding an insulin receptor.

66. A pharmaceutical composition comprising a therapeutically effective amount of a fusion antibody of claim 50, and a pharmaceutically acceptable excipient.

67. An isolated polynucleotide encoding the fusion antibody of claim 50.

68. The isolated polynucleotide of claim 67, wherein the isolated polynucleotide comprises the nucleic acid sequence of SEQ ID NO:

14.

69. A vector comprising the isolated polynucleotide of claim 67.

70. The vector of claim 67 comprising the nucleic acid sequence of SEQ ID NO:

14.

71. A host cell comprising the vector of claim 69.

72. The host cell of claim 71, wherein the host cell is a Chinese Hamster Ovary (CHO) cell.