Lysosomal targeting peptides and uses thereof

Patent metadata

Field	Value
Publication number	US-9469683-B2
Application number	US-201414535505-A
Country	US
Kind code	B2
Filing date	Nov 7, 2014
Priority date	May 7, 2008
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

The present invention provides further improved compositions and methods for efficient lysosomal targeting based on the GILT technology. Among other things, the present invention provides methods and compositions for targeting lysosomal enzymes to lysosomes using furin-resistant lysosomal targeting peptides. The present invention also provides methods and compositions for targeting lysosomal enzymes to lysosomes using a lysosomal targeting peptide that has reduced or diminished binding affinity for the insulin receptor.

First claim

What is claimed is:

1. A targeted therapeutic fusion protein comprising:
a lysosomal enzyme which is α-N-Acetylglucosaminidase (Naglu);
an IGF-II mutein comprising amino acids 8-67 of SEQ ID NO: 1 and an Ala substitution at position Arg37 of SEQ ID NO:1, wherein the IGF-II mutein (i) has diminished binding affinity for the insulin receptor relative to the affinity of naturally-occurring human IGF-II for the insulin receptor, (ii) is resistant to furin cleavage and (iii) binds to the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner; and
a spacer between the lysosomal enzyme and the IGF-II mutein, wherein the spacer comprises the amino acid sequence Gly-Ala-Pro.

2. A pharmaceutical composition suitable for treating lysosomal storage disease comprising a targeted therapeutic fusion protein of claim 1 and a physiologically acceptable carrier or excipient.

3. The targeted therapeutic fusion protein of claim 1 , wherein the IGF-II mutein is fused via the spacer to the C-terminus of the lysosomal enzyme.

4. The targeted therapeutic fusion protein of claim 1 , wherein the IGF-II mutein is fused via the spacer to the N-terminus of the lysosomal enzyme.

5. The targeted therapeutic fusion protein of claim 1 , wherein the IGF-II mutein consists of amino acids 8-67 of SEQ ID NO:1 having an Ala substitution at position Arg37 of SEQ ID NO:1.

Assignees

• Biomarin Pharm Inc

Inventors

• Lebowitz Jonathan H
• Maga John

Classifications

• A61P43/00

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title

• C12Y302/0102

  Alpha-glucosidase (3.2.1.20) · CPC title

• C12N9/2408

  acting on alpha -1,4-glucosidic bonds · CPC title