Targeted Therapeutic Lysosomal Enzyme Fusion Proteins and Uses Thereof

Patent metadata

Field	Value
Publication number	US-2016031963-A1
Application number	US-201514883169-A
Country	US
Kind code	A1
Filing date	Oct 14, 2015
Priority date	Nov 27, 2012
Publication date	Feb 4, 2016
Grant date	—

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 lysosomal enzyme, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids 8-67 of mature human IGF-II and (c) a spacer peptide between the lysosomal enzyme and the IGF-II peptide tag, wherein the spacer peptide comprises the amino acid sequence set out in SEQ ID NO:36.

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

3 . The targeted therapeutic fusion protein of claim 1 , wherein the lysosomal enzyme comprises an amino acid sequence at least 85% identical to a human a-N-acetylglucosaminidase (Naglu) protein.

4 . The targeted therapeutic fusion protein of claim 1 , wherein the lysosomal enzyme is a human a-N-acetylglucosaminidase (Naglu) protein.

5 . The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises amino acids 8-67 of mature human IGF-II.

6 . The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises amino acids 8-67 of mature human IGF-II having a mutation at residue Arg37.

7 . The targeted therapeutic fusion protein of claim 6 , wherein the mutation at residue Arg37 is a substitution of alanine for arginine.

8 . The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag consists of amino acids 8-67 of mature human IGF-II having a mutation at residue Arg37.

9 . The targeted therapeutic fusion protein of claim 8 , wherein the mutation at residue Arg37 is a substitution of alanine for arginine.

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

11 . A nucleic acid encoding the targeted therapeutic fusion protein of claim 1 .

12 . A cell containing the nucleic acid of claim 11 .

13 . A method of producing the targeted therapeutic fusion protein of claim 1 comprising the step of culturing cells according to claim 12 in a cell culture medium under conditions that permit expression of said targeted therapeutic fusion protein.

14 . 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 .

15 . The method of claim 14 , wherein the pharmaceutical composition is administered intrathecally.

16 . 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 3 .

17 . The method of claim 16 , 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

• 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

• 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

• A61P43/00

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

• A61K38/47

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