Methods and compositions for increasing arylsulfatase A activity in the CNS

• US 8,920,801 B2
• Filed: 02/28/2014
• Issued: 12/30/2014
• 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): Emch, Gregory S
• Assistant Examiner(s): Weidner, Adam M
• Application Number:
  US14/194,463
• Publication Number:
  US 20140294822A1
• Time in Patent Office: 305 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 fusion antibody comprising:

(a) an arylsulfatase A (ASA) monomer, and (b) a single-chain antibody;

wherein the fusion antibody crosses the blood brain barrier (BBB).

2. The fusion antibody of claim 1, wherein the ASA monomer is covalently linked to the carboxy terminus of the single-chain antibody.

3. The fusion antibody of claim 1, wherein the ASA monomer is covalently linked to the amino terminus of the single-chain antibody.

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

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

6. The fusion antibody of claim 1, wherein the fusion antibody further comprises a linker between the ASA monomer and the single-chain antibody.

7. The fusion antibody of claim 1, wherein the ASA specific activity of the fusion antibody is at least about 10 units/mg of protein.

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

9. The fusion antibody of claim 1, wherein the ASA and the single-chain antibody each retains at least 20% of its activity, on a molar basis, compared to its activity as a separate entity.

10. The fusion antibody of claim 1, wherein the single-chain antibody 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.

11. The fusion antibody of claim 1, wherein the single-chain antibody 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 by binding 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 the fusion antibody of claim 1, and a pharmaceutically acceptable excipient.

16. The fusion antibody of claim 1, wherein the fusion antibody catalyzes hydrolysis of 2-sulfate groups of cerebroside sulfate esters and sulfatide sphingolipids.

17. The fusion antibody of claim 1, wherein the single-chain antibody comprises a VH region and a VL region.

18. The fusion antibody of claim 1, wherein the single-chain antibody is a single-chain Fab, Fab′

, F(ab)2, or Fv antibody.

19. The fusion antibody of claim 18, wherein the single-chain antibody is a single-chain Fv (ScFv) antibody.

20. A fusion antibody comprising:

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

wherein the fusion antibody crosses the blood brain barrier (BBB), wherein the amino acid sequence of the arylsulfatase A is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain.