Fusion proteins for delivery of GDNF to the CNS

• US 8,741,260 B2
• Filed: 11/25/2008
• Issued: 06/03/2014
• Est. Priority Date: 10/07/2005
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Pardridge, William M., Boado, Ruben J.
• Primary Examiner(s): Stucker, Jeffrey
• Assistant Examiner(s): Fontainhas, Aurora M
• Application Number:
  US12/323,232
• Publication Number:
  US 20090156498A1
• Time in Patent Office: 2,016 Days
• US Class Current: 424/1.41
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 16/2881 against CD71
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/01 containing a localisation/targetting motif
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The invention provides compositions, methods, and kits for increasing transport of GDNF across the blood brain barrier while allowing its activity to remain substantially intact. The GDNF is transported across the blood brain barrier via one or more endogenous receptor-mediated transport systems.

Claims

1. A composition comprising a neurotherapeutic peptide comprising an amino acid sequence which is at least 80% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52), wherein the neurotherapeutic peptide is covalently linked at its amino terminus to the carboxy terminus of the heavy chain or light chain of an antibody that is capable of crossing the blood brain barrier (BBB) by binding on an endogenous BBB receptor.

2. The composition of claim 1 wherein the endogenous BBB receptor is selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.

3. The composition of claim 2 wherein the endogenous BBB receptor mediated transport system is the insulin BBB receptor mediated transport system.

4. The composition of claim 1, wherein the antibody is a monoclonal antibody (MAb).

5. The composition of claim 4 wherein the MAb is a chimeric MAb.

6. The composition of claim 5, wherein the chimeric antibody contains at least 80% human sequence.

7. The composition of claim 1, wherein the neurotherapeutic peptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

8. The composition of claim 7, wherein the neurotherapeutic peptide comprises the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

9. The composition of claim 4, wherein the neurotherapeutic peptide is covalently linked at its amino terminus to the carboxy terminus of the heavy chain of the MAb.

10. A composition for treating a neurological disorder comprising a neurotherapeutic peptide comprising an amino acid sequence which is at least 80% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52) covalently linked at its amino terminus to the carboxy terminus of the light chain or heavy chain of an immunoglobulin that is capable of crossing the blood brain barrier, wherein the composition is capable of crossing the BBB in an amount that is effective in treating the neurological disorder.

11. A recombinant mammalian cell comprising the composition of claim 10.

12. A method for treating Parkinson'"'"'s disease, a motor neuron disease, spinal cord injury, brain injury, focal brain ischemia, or global brain ischemia in an individual comprising peripherally administering to the individual an effective amount of a composition comprising a neurotherapeutic peptide comprising an amino acid sequence which is at least 80% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52), wherein the neurotherapeutic peptide is covalently linked at its amino terminus to the carboxy terminus of the heavy chain or light chain of an antibody that is capable of crossing the blood brain barrier (BBB) by binding an endogenous BBB receptor.

13. The method of claim 12, wherein the neurotherapeutic peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

14. The method of claim 12, wherein the neurotherapeutic peptide comprises the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

15. The method of claim 12 wherein the administering is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, transbuccal, intranasal, transdermal, and inhalation administration.

16. The method of claim 12, wherein the administering is intravenous, intramuscular, or subcutaneous.

17. The method of claim 12, wherein the individual is administered a dose of the composition that is about 1 to about 100 mg.

18. A method for treating drug addiction or alcohol addiction in an individual, comprising administering to the individual an effective amount of a composition comprising a neurotherapeutic peptide comprising an amino acid sequence which is at least 80% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52), wherein the neurotherapeutic peptide is covalently linked at its amino terminus to the carboxy terminus of the heavy chain or light chain of an antibody that is capable of crossing the blood brain barrier (BBB) by binding an endogenous BBB receptor.

19. The method of claim 18, wherein the neurotherapeutic peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

20. The method of claim 18, wherein the neurotherapeutic peptide comprises the amino acid sequence of mature human GDNF (SEQ ID NO:

52).

21. The method of claim 18, wherein the administering is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, transbuccal, intranasal, transdermal, and inhalation administration.

22. The method of claim 18, wherein the administering is intravenous, intramuscular, or subcutaneous.

23. The method of claim 18, wherein the individual is administered a dose of the composition that is about 1 to about 100 mg.