Targeted therapeutic lysosomal enzyme fusion proteins and uses thereof

Patent metadata

Field	Value
Publication number	US-9771408-B2
Application number	US-201514883211-A
Country	US
Kind code	B2
Filing date	Oct 14, 2015
Priority date	Nov 27, 2012
Publication date	Sep 26, 2017
Grant date	Sep 26, 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 is:

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: 71.

2. The targeted therapeutic fusion protein of claim 1 , wherein the spacer peptide consists of the amino acid sequence of SEQ ID NO: 71.

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) 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

Inventors

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

Classifications

• A61K38/00 Primary

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K38/47

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

• C07K14/65 Primary

  Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 · CPC title

• C07K2319/06

  containing a lysosomal/endosomal localisation signal · CPC title

• A61P43/00

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