Targeted therapeutic proteins

Patent metadata

Field	Value
Publication number	US-10300113-B2
Application number	US-201715660936-A
Country	US
Kind code	B2
Filing date	Jul 26, 2017
Priority date	Apr 30, 2001
Publication date	May 28, 2019
Grant date	May 28, 2019

Abstract

Targeted therapeutics that localize to a specific subcellular compartment such as the lysosome are provided. The targeted therapeutics include a therapeutic agent and a targeting moiety that binds a receptor on an exterior surface of the cell, permitting proper subcellular localization of the targeted therapeutic upon internalization of the receptor. Nucleic acids, cells, and methods relating to the practice of the invention are also provided.

First claim

We claim:

1. A formulation for parenteral administration comprising: a target therapeutic comprising a therapeutic agent that is therapeutically active in a mammalian lysosome and a variant of human IGF-II having an amino acid sequence at least 70% identical to mature human IGF-II (SEQ ID NO:8) that binds an extracellular domain of human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner; and a pharmaceutically acceptable carrier.

2. The formulation of claim 1 , wherein the therapeutic agent is a lysosomal enzyme is selected from the group consisting of: acid-α 1,4-glucosidase; β-galactosidase; β-hexosaminidase A; β-hexosaminidase B; α-galactosidase A; glucocerebrosidase; arylsulfatase B; galactosylceramidase; acid sphingomyelinase; acid ceramidase; acid lipase; α-L-iduronidase; iduronate sulfatase; heparan N-sulfatase; α-N-acetylglucosaminidase; acetyl-CoA-glucosaminide acetyltransferase; N-acetylglucosamine-6-sulfatase; galactosamine-6-sulfatase; arylsulfatase B; β-glucuronidase; α-mannosidase; β-mannosidase; α-L-fucosidase; N-aspartyl-β-glucosaminidase; α-neuraminidase; lysosomal protective protein; α-N-acetyl-galactosaminidase; N-acetylglucosamine-1-phosphotransferase; and palmitoyl-protein thioesterase.

3. The formulation of claim 1 , wherein the variant of human IGF-II comprises a deletion or replacement of amino acids 1-7 of mature human IGF-II (SEQ ID NO:8).

4. The formulation of claim 1 , wherein the variant of human IGF-II comprises a deletion or a replacement of amino acids 62-67 of mature human IGF-II (SEQ ID NO:8).

5. The formulation of claim 1 , wherein the variant of human IGF-II comprises: (a) amino acids 8-67 of mature human IGF-II (SEQ ID NO: 8); (b) amino acids 1-61 of mature human IGF-II; or (c) amino acids 8-61 of mature human IGF-II.

6. The formulation of claim 1 , comprising a sterile diluent, a buffer, and a tonicity agent.

7. A method of treating a patient suffering from a lysosomal storage disease comprising administering to the patient the formulation of claim 1 .

8. The method of claim 7 , wherein the lysosomal storage disease is selected from the group consisting of: Pompe disease; Tay Sachs disease; Sandhoff disease; Fabry disease; Gaucher disease; Mucopolysaccharidosis (MPS) I; MPS II, MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, MPS VII; α-Mannosidosis; and Wolman disease.

9. A formulation for parenteral administration comprising: a therapeutic fusion protein comprising a lysosomal enzyme and a lysosomal targeting domain comprising a mutein of human IGF-II having an amino acid sequence at least 70% identical to mature human IGF-II (SEQ ID NO:8) that binds human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

10. The formulation of claim 9 , wherein the lysosomal enzyme is selected from the group consisting of: acid-α 1,4-glucosidase; β-galactosidase; β-hexosaminidase A; β-hexosaminidase B; α-galactosidase A; glucocerebrosidase; arylsulfatase B; galactosylceramidase; acid sphingomyelinase; acid ceramidase; acid lipase; α-L-iduronidase; iduronate sulfatase; heparan N-sulfatase; α-N-acetylglucosaminidase; acetyl-CoA-glucosaminide acetyltransferase; N-acetylglucosamine-6-sulfatase; galactosamine-6-sulfatase; arylsulfatase B; β-glucuronidase; α-mannosidase; β-mannosidase; α-L-fucosidase; N-aspartyl-β-glucosaminidase; α-neuraminidase; lysosomal protective protein; α-N-acetyl-galactosaminidase; N-acetylglucosamine-1-phosphotransferase; and palmitoyl-protein thioesterase.

11. The formulation of claim 9 , wherein the mutein of mature human IGF-II comprises a deletion or replacement of amino acids 1-7 of mature human IFG-II (SEQ ID NO:8).

12. The formulation of claim 9 , wherein the mutein of mature human IGF-II comprises a deletion or replacement of amino acids 62-67 of mature human IGF-II (SEQ ID NO:8).

13. The formulation of claim 9 , wherein the mutein of mature human IGF-II comprises: (a) amino acids 8-67 of mature human IGF-II (SEQ ID NO: 8); (b) amino acids 1-61 of mature human IGF-II; or (c) amino acids 8-61 of mature human IGF-II.

14. The formulation of claim 9 , wherein the fusion protein further comprises a bridge between the lysosomal enzyme and the lysosomal targeting domain.

15. The formulation of claim 9 , comprising a sterile diluent, a buffer, and a tonicity agent.

16. A method of treating a patient suffering from a lysosomal storage disease comprising administering to the patient the formulation of claim 9 .

17. The method of claim 16 , wherein the lysosomal storage disease is selected from the group consisting of: Pompe disease; Tay Sachs disease; Sandhoff disease; Fabry disease; Gaucher disease; Mucopolysaccharidosis (MPS) I; MPS II, MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, MPS VII; α-Mannosidosis; and Wolman disease.

Assignees

• Biomarin Pharm Inc

Inventors

• Lebowitz Jonathan
• Beverley Stephen M

Classifications

• C12N15/62

  DNA sequences coding for fusion proteins · CPC title

• C07K2319/75

  containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones · CPC title

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• C07K2319/61

  containing an enzyme fusion for detection (lacZ, luciferase) · CPC title

• C07K2319/50

  containing protease site · CPC title