Fusion proteins for delivery of erythropoietin to the CNS

• US 8,124,095 B2
• Filed: 01/15/2010
• Issued: 02/28/2012
• 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): Kolker, Daniel E
• Application Number:
  US12/688,842
• Publication Number:
  US 20100261647A1
• Time in Patent Office: 774 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 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 2319/30 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 a neurotrophin (e.g., erythropoietin (EPO)) across the blood brain barrier while allowing its activity to remain substantially intact. The neurotrophin (e.g., EPO) is transported across the blood brain barrier via one or more endogenous receptor-mediated transport systems.

Claims

1. A composition comprising a neurotherapeutic peptide covalently linked to an antibody that is capable of crossing the blood brain barrier (BBB) on an endogenous BBB receptor, wherein the neurotherapeutic peptide is erythropoietin (EPO), an EPO biosimilar, or an antibody to the EPO 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 is the insulin receptor.

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

5. The composition of claim 4, wherein the EPO, an EPO biosimilar, or an antibody to the EPO receptor is covalently linked at its amino terminus to the carboxy terminus of the MAb.

6. The composition of claim 5, wherein the EPO, an EPO biosimilar, or an antibody to the EPO receptor is covalently linked at its amino terminus to the carboxy terminus of the heavy chain of the MAb.

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

8. The composition of claim 7, wherein the chimeric antibody contains at least 80% human sequence.

9. The composition of claim 1, wherein the EPO, an EPO biosimilar, or an antibody to the EPO receptor is covalently linked at its amino terminus to the carboxy terminus of the antibody.

10. The composition of claim 1, wherein, after peripheral administration, the EPO, an EPO biosimilar, or an antibody to the EPO receptor has a plasma area under the concentration curve (AUC) that is at least 5-fold lower than the plasma AUC of a human EPO polypeptide that is not linked to said antibody and that is capable of crossing the BBB.

11. The composition of claim 1, wherein the composition is capable of crossing the BBB in an amount that is effective in treating a neurological disorder.

12. The composition of claim 1, wherein the neurotherapeutic peptide is erythropoietin (EPO).

13. The composition of claim 1, wherein the neurotherapeutic peptide is pegylated EPO.

14. A method for ameliorating a CNS disorder in an individual comprising peripherally administering to the individual an effective amount of the composition of claim 1.

15. The method of claim 14, 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 14, wherein the CNS disorder is an acute CNS disorder.

17. The method of claim 16, wherein the acute CNS disorder is selected from the group consisting of spinal cord injury, brain injury, focal brain ischemia and global brain ischemia.

18. The method of claim 14, wherein the CNS disorder is a chronic disorder.

19. The method of claim 18, wherein the chronic disorder is a chronic neurodegenerative disease.

20. The method of claim 19, wherein the chronic neurodegenerative disease is selected from the group consisting of Parkinson'"'"'s disease and a motor neuron disease.

21. The method of claim 14, wherein the effective amount is about 1 ug to 10 mg.

22. A method for ameliorating a CNS disorder in an individual comprising peripherally administering to the individual an effective amount of the composition of claim 12.