Targeted therapeutic lysosomal enzyme fusion proteins and uses thereof

Patent metadata

Field	Value
Publication number	US-9845346-B2
Application number	US-201514883169-A
Country	US
Kind code	B2
Filing date	Oct 14, 2015
Priority date	Nov 27, 2012
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

The present invention relates in general to therapeutic fusion proteins useful to treat lysosomal storage diseases and methods for treating such diseases. Exemplary therapeutic fusion proteins comprise a lysosomal enzyme, a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide. Also provided are compositions and methods for treating Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome), comprising a targeted therapeutic fusion protein comprising alpha-N-acetylglucosaminidase (Naglu), a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide.

First claim

What is claimed:

1. A targeted therapeutic fusion protein comprising (a) a human α-N-acetylglucosaminidase (Naglu) protein comprising amino acids 1-743 or 24-743 of SEQ ID NO: 1, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) and (c) a spacer peptide between the lysosomal enzyme and the peptide tag, wherein the spacer peptide comprises the amino acid sequence of SEQ ID NO:36.

2. The targeted therapeutic fusion protein of claim 1 , wherein the spacer peptide consists of the amino acid sequence of SEQ ID NO:36.

3. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II).

4. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises all of amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) having except for a mutation at residue 37.

5. The targeted therapeutic fusion protein of claim 4 , wherein the mutation at residue 37 is a substitution of alanine for arginine.

6. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag consists of all of amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) except for a mutation at residue 37.

7. The targeted therapeutic fusion protein of claim 6 , wherein the mutation at residue 37 is a substitution of alanine for arginine.

8. A pharmaceutical composition comprising the targeted therapeutic fusion protein of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

9. A method for treating a lysosomal storage disease in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the targeted therapeutic fusion protein of claim 1 .

10. The method of claim 9 , wherein the pharmaceutical composition is administered intrathecally.

11. A method for reducing glycosaminoglycan levels in a subject suffering from Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome) comprising administering to said subject an effective amount of a pharmaceutical composition comprising the targeted fusion protein of claim 1 .

12. The method of claim 11 , wherein the pharmaceutical composition is administered intrathecally.

Assignees

• Biomarin Pharm Inc
• Biomarin Pharmaceurical Inc

Inventors

• Aoyagi-Scharber Mika
• Christianson Teresa Margaret
• Dvorak-Ewell Melita
• Wendt Daniel J
• Long Shinong
• Lebowitz Jonathan
• Gold Daniel Solomon

Classifications

• C07K2319/06

  containing a lysosomal/endosomal localisation signal · CPC title

• A61K38/47

  acting on glycosyl compounds (3.2), e.g. cellulases, lactases · CPC title

• C12N9/2402 Primary

  hydrolysing O- and S- glycosyl compounds (3.2.1) · CPC title

• C12Y302/0105

  Alpha-N-acetylglucosaminidase (3.2.1.50) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title