Methods and compositions for increasing iduronate 2-sulfatase activity in the CNS

• US 10,011,651 B2
• Filed: 06/16/2014
• Issued: 07/03/2018
• Est. Priority Date: 10/09/2009
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen, Inc. (JCR Pharmaceuticals Co., Ltd.)
• Inventors: Pardridge, William M., Boado, Ruben J.
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US14/305,402
• Publication Number:
  US 20150004160A1
• Time in Patent Office: 1,478 Days
• Field of Search: None
• 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 increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter'"'"'s syndrome in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase (IDS) activity, wherein the fusion antibody comprises:

(a) a fusion protein comprising 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 a carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain; and

(b) an immunoglobulin light chain;

wherein the fusion antibody crosses a blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of 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 a 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 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 light chain is an immunoglobulin light chain of IgG.

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

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

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

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

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

32. The method of claim 1, wherein the fusion antibody crosses the BBB by binding a transferrin receptor.

16. A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter'"'"'s syndrome 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 a 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 a blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin.

17. The method of claim 16, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

18. The method of claim 16, wherein the fusion antibody comprises formylglycine.

19. The method of claim 16, wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to a brain, normalized per 50 kg body weight.

20. The method of claim 16, 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.

21. The method of claim 16, wherein the iduronate-2-sulfatase activity of the fusion antibody is at least about 10,000 units/mg.

23. The method of claim 16, wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity.

24. The method of claim 16, wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.

25. The method of claim 16, wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG.

26. The method of claim 16, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

27. The method of claim 16, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

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

29. The method of claim 16, wherein the fusion antibody crosses the BBB by binding an insulin receptor.

31. The method of claim 16, wherein the fusion antibody crosses the BBB by binding a transferrin receptor.

30. A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter'"'"'s syndrome 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 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 a carboxy terminus of the amino acid sequence of the immunoglobulin light chain; and

(b) an immunoglobulin heavy chain;

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