Methods and compositions for increasing arylsulfatase A activity in the CNS

• US 8,486,399 B2
• Filed: 09/10/2012
• Issued: 07/16/2013
• Est. Priority Date: 12/02/2011
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Pardridge, William M., Boado, Ruben J.
• Primary Examiner(s): Stucker, Jeffrey
• Assistant Examiner(s): Weidner, Adam M
• Application Number:
  US13/609,099
• Publication Number:
  US 20130142794A1
• Time in Patent Office: 309 Days
• Field of Search: None
• US Class Current: 424/134.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/40 characterized by post-translational modification
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2319/01 containing a localisation/targetting motif
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 9/16 acting on ester bonds (3.1)
• CPC Class Codes: C12N 9/2402 hydrolysing O- and S- glycosyl compounds (3.2.1)
• CPC Class Codes: C12Y 301/06008 Cerebroside-sulfatase (3.1.6.8)

Abstract

Provided herein are methods and compositions for treating a subject suffering from a deficiency in arylsulfatase A in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an arylsulfatase A.

Claims

1. A method for treating an arylsulfatase A (ASA) 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 arylsulfatase A activity, wherein the fusion antibody comprises:

(a) a fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an arylsulfatase A monomer; and

(b) an immunoglobulin light chain;

wherein the fusion antibody crosses the blood brain barrier (BBB) and the ASA retains at least 20% of its activity, on a molar basis, compared to its activity as a separate entity.

2. The method of claim 1, wherein the amino acid sequence of the arylsulfatase A is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain.

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

4. The method of claim 1, wherein the fusion antibody comprises formylglycine.

5. The method of claim 1, wherein the fusion antibody catalyzes hydrolysis of cerebroside sulfate esters and sulfatide sphingolipids.

6. The method of claim 1, wherein the ASA and the immunoglobulin each retains at least 20% of its activity, on a molar basis, compared to its activity as a separate entity.

7. The method of claim 1, wherein at least about 100 ug of arylsulfatase A enzyme are delivered to the brain, normalized per 50 kg body weight.

8. The method of claim 1, wherein the therapeutically effective dose comprises at least about 10 units/Kg of body weight.

9. The method of claim 1, wherein the arylsulfatase A specific activity of the fusion antibody is at least 10 units/mg of protein.

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

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 kappa or lambda class.

13. 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.

14. The method of claim 1, wherein the fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an arylsulfatase A comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:

10.

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 via an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the insulin-like growth factor (IGF) receptor.

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

18. The method of claim 1, wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.

19. The method of claim 1, wherein the arylsulfatase A (ASA) deficiency in the central nervous system is metachromatic leukodystrophy (MLD).