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

• US 8,834,874 B2
• Filed: 10/08/2010
• Issued: 09/16/2014
• Est. Priority Date: 10/09/2009
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Pardridge, William M., Boado, Ruben J.
• Primary Examiner(s): Kolker, Daniel E
• Assistant Examiner(s): Dutt, Aditi
• Application Number:
  US12/901,481
• Publication Number:
  US 20110110935A1
• Time in Patent Office: 1,439 Days
• Field of Search: None
• 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 fusion antibody comprising:

(a) an immunoglobulin that crosses a blood brain barrier (BBB), wherein the immunoglobulin comprises an immunoglobulin heavy chain and an immunoglobulin light chain; and

(b) 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, thereby forming a fusion protein;

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 and wherein the iduronate-2-sulfatase retains at least 20% of its activity compared to its activity as a separate entity.

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

3. The fusion antibody of claim 1, wherein the fusion antibody comprises a formylglycine.

4. The fusion antibody of claim 1, 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.

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

6. The fusion antibody of claim 1, wherein the immunoglobulin retains at least 20% of its activity compared to its activity as a separate entity.

7. The fusion antibody of claim 1, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

8. The fusion antibody 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.

9. The fusion antibody of claim 1, wherein the immunoglobulin light chain is an immunoglobulin light chain of lambda class.

10. The fusion antibody of claim 1, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

11. The fusion antibody 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.

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

13. The fusion antibody 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.

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

15. A pharmaceutical composition comprising a therapeutically effective amount of a fusion antibody of claim 1, and a pharmaceutically acceptable excipient.

16. The fusion antibody of claim 1, wherein the iduronate-2-sulfatase retains at least 50% of its activity compared to its activity as a separate entity.