Methods and compositions for increasing arylsulfatase A activity in the CNS

• US 8,715,661 B2
• Filed: 04/12/2013
• Issued: 05/06/2014
• 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): Stucker, Jeffrey
• Assistant Examiner(s): Weidner, Adam M
• Application Number:
  US13/862,250
• Publication Number:
  US 20130287773A1
• Time in Patent Office: 389 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) a fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an arylsulfatase A monomer (ASA), and (b) an immunoglobulin light chain;

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

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

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

5. The fusion antibody of claim 1, wherein the fusion protein further comprises a linker between the amino acid sequence of the arylsulfatase A and the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain.

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

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

8. The fusion antibody 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.

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

10. 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.

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

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

13. 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.

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

15. 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.

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

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

18. An isolated polynucleotide encoding the fusion antibody of claim 1.

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

20. The fusion antibody of claim 1, wherein the fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:

10.

21. The isolated polynucleotide of claim 18, wherein the isolated polynucleotide comprises the nucleic acid sequence of SEQ ID NO:

14.

22. A vector comprising the isolated polynucleotide of claim 18.

23. The vector of claim 22 comprising the nucleic acid sequence of SEQ ID NO:

14.

24. A host cell comprising the vector of claim 22.

25. The host cell of claim 24, wherein the host cell is a Chinese Hamster Ovary (CHO) cell.

26. A fusion antibody comprising:

(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), 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.