Therapeutic fusion protein comprising an alpha-n-acetylglucosaminidase and a lysosomal targeting moiety

Patent metadata

Field	Value
Publication number	US-11065307-B2
Application number	US-201715715748-A
Country	US
Kind code	B2
Filing date	Sep 26, 2017
Priority date	Jun 25, 2010
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

Among other things, the present invention provides methods and compositions of treating Sanfilippo syndrome type B (Sanfilippo B) by, e.g., intrathecal (IT) administration of a Naglu protein. A suitable Naglu protein can be a recombinant, gene-activated or natural protein. In some embodiments, a suitable Naglu protein is a recombinant Naglu protein. In some embodiments, a recombinant Naglu protein is a fusion protein containing a Naglu domain and a lysosomal targeting moiety. In some embodiments, the lysosomal targeting domain is an IGF-II moiety.

First claim

We claim:

1. A therapeutic fusion protein comprising
an alpha-N-acetylglucosaminidase (Naglu) domain;
a lysosomal targeting moiety, and

a linker between the lysosomal targeting moiety and the Naglu domain;
wherein the lysosomal targeting moiety is a peptide that binds cation-independent mannose-6-phosphate receptor (CI-MPR) or bis-phosphorylated oligosaccharides;

wherein the Naglu domain has alpha-N-acetylglucosaminidase activity and comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1;
wherein the linker comprises the amino acid sequence of residues 721-777 of SEQ ID NO: 6;
wherein once administered intrathecally, the therapeutic fusion protein is targeted to lysosomes.

2. The therapeutic fusion protein of claim 1 , wherein the lysosomal targeting moiety is an insulin-like growth factor-II (IGF-II) moiety.

3. The therapeutic fusion protein of claim 1 wherein the lysosomal targeting moiety is fused via the linker to the C-terminus of the Naglu domain.

4. A pharmaceutical composition comprising the therapeutic fusion protein of claim 1 and a surfactant.

5. The pharmaceutical composition of claim 4 , wherein the surfactant is present in the pharmaceutical composition at a concentration from 0.001-0.5%.

6. The pharmaceutical composition of claim 4 , wherein the surfactant is present in the pharmaceutical composition at a concentration of 0.2%.

7. The pharmaceutical composition of claim 4 , wherein the surfactant is a poloxamer.

8. The pharmaceutical composition of claim 7 , wherein the poloxamer is poloxamer 188.

Assignees

• Shire Human Genetic Therapies

Inventors

• Concino Michael F
• Calias Pericles
• Pan Jing
• Holmes Kevin
• Martini Paolo
• Romashko Alla
• Meiyappan Muthuraman
• Zhang Bohong
• Iskenderian Andrea
• Lundberg Dianna
• Norton Angela
• Strack-Logue Bettina
• Yan Huang
• Alessandrini Mary
• Pfeifer Richard

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C12N9/2402

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

• C12Y302/01045

  Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K9/0085

  Brain, e.g. brain implants; Spinal cord · CPC title