Methods and compositions for increasing arylsulfatase A activity in the CNS

• US 9,975,955 B2
• Filed: 11/11/2014
• Issued: 05/22/2018
• Est. Priority Date: 12/02/2011
• 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): WEIDNER, ADAM M
• Application Number:
  US14/538,721
• Publication Number:
  US 20150064184A1
• Time in Patent Office: 1,288 Days
• Field of Search: None
• 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 fusion antibody comprising:

(a) an amino acid sequences of an immunoglobulin heavy chain; and

(b) a fusion protein comprising an amino acid sequence of an arylsulfatase A monomer covalently linked to the amino acid sequence of an immunoglobulin light chain,

wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa or lambda class and 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;

wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of cerebroside sulfate esters and sulfatide sphingolipids, and wherein the arylsulfatase A monomer retains at least 20% of its activity compared to its activity as a separate entity.

2. The fusion antibody of claim 1, wherein the amino acid sequence of the arylsulfatase A monomer is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain.

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

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

5. The fusion antibody of claim 1, wherein the fusion antibody crosses the BBB via the insulin receptor.

6. The fusion antibody of claim 1, wherein the fusion antibody crosses the BBB by binding a human insulin receptor.

7. 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) an amino acid sequence of an immunoglobulin heavy chain; and

(b) a fusion protein comprising an amino acid sequence of an arylsulfatase A monomer covalently linked to an amino acid sequence of an immunoglobulin light chain,

wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa or lambda class and 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;

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

8. The method of claim 7, wherein the amino acid sequence of the arylsulfatase is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain.

9. The method of claim 7, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

10. The method of claim 7, wherein the fusion antibody comprises formylglycine.

11. The method of claim 7, wherein the fusion antibody catalyzes hydrolysis of cerebroside sulfate esters and sulfatide sphingolipids.

12. The method of claim 7, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

13. The method of claim 7, wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.

14. The method of claim 7, wherein the fusion antibody crosses the BBB via the insulin receptor.

15. The method of claim 7, wherein the fusion antibody crosses the BBB by binding a human insulin receptor.

16. The method of claim 7, wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.