Methods for Diagnosing and Treating CNS Disorders by Trans-Blood-Brain Barrier Delivery of Protein Compositions

• US 20080171055A1
• Filed: 08/20/2007
• Published: 07/17/2008
• Est. Priority Date: 08/18/2006
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Boado, Ruben J., Pardridge, William M.
• Granted Patent: US 8,497,246 B2
• Time in Patent Office: Days
• US Class Current: 424/172.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/1081 Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
• CPC Class Codes: C07K 16/18 against material from animals or humans
• 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 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods for treating or diagnosing CNS disorders by systemic administration of therapeutic or diagnostic protein compositions that are capable of crossing the blood-brain barrier, in some embodiments in both directions, while allowing their activity once across the barrier to remain substantially intact. The agents are transported across the blood-brain barrier via one or more endogenous receptor-mediated transport systems. Also provided are methods for manufacturing the compositions used in the methods described herein.

Claims

1. A method of treating a CNS disorder comprising systemically administering to an individual suffering from the disorder an effective amount of a composition comprising a first structure capable of crossing the BBB from the blood to the brain, a second structure capable of interacting with a pathological substance associated with the disorder, and a third structure capable of crossing the BBB from the brain to the blood.

2. The method of claim 1, wherein the first and third structures comprise an antibody to an endogenous BBB receptor mediated transport system.

3. The method of claim 1 wherein the CNS disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, bovine spongiform encephalopathy West Nile virus encephalitis, Neuro-AIDS, brain injury, spinal cord injury, metastatic cancer of the brain, metastatic breast cancer of the brain, primary cancer of the brain, or multiple sclerosis.

4. The method of claim 3, wherein the CNS disorder is Alzheimer'"'"'s disease.

5. The method of claim 1, wherein the second structure comprises a ScFv.

6. The method of claim 1, wherein the pathological substance is a protein.

7. The method of claim 6, wherein the protein is Aβ

amyloid, α

-synuclein, huntingtin protein, PrP prion protein, West Nile envelope protein, tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL), Nogo A, HER2, epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF), or oligodendrocyte surface antigen.

8. The method of claim 7, wherein the protein is Aβ

amyloid.

9. A method of diagnosing a CNS disorder comprising measuring the level of a composition in a body fluid of an individual, wherein the composition is capable of crossing the BBB from the blood to the brain, interacting with a pathological substance associated with a brain disorder, and crossing the BBB from the brain to the blood, and wherein the composition has been administered to the individual and has interacted with the pathological substance.

10. The method of claim 9, wherein the composition comprises an antibody.

11. The method of claim 9, wherein the composition comprises a ScFv.

12. The method of claim 9, wherein the pathological substance is of a type selected from the group consisting of proteins, nucleic acids, carbohydrates, carbohydrate polymers, lipids, glycolipids, and small molecules.

13. The method of claim 12, wherein the pathological substance is Aβ

amyloid, α

-synuclein, huntingtin Protein, PrP prion protein, West Nile envelope protein, tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL), Nogo A, HER2, epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF), or oligodendrocyte surface antigen.

14. The method of claim 9, wherein the brain disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, bovine spongiform encephalopathy, West Nile virus encephalitis, Neuro-AIDS, brain injury, spinal cord injury, metastatic cancer of the brain, metastatic breast cancer of the brain, primary cancer of the brain, or multiple sclerosis.

15. The method of claim 9, wherein the body fluid is blood, serum, or plasma.

16. The method of claim 9, further comprising systemically administering the composition to the individual prior to the measuring step.

17. A method of manufacturing an immunoglobulin fusion protein, wherein the fusion protein comprises an immunoglobulin heavy chain fused to an antibody structure, or comprises an immunoglobulin light chain fused to an antibody structure, comprising permanently integrating into a eukaryotic cell a single tandem expression vector, wherein the gene for the immunoglobulin fusion protein and another gene comprising a gene for the immunoglobulin light chain or the gene for the immunoglobulin heavy chain, are incorporated into a single piece of DNA.

18. The method of claim 17, wherein the fusion protein comprises an immunoglobulin heavy chain fused to an antibody structure and wherein both the gene for the fusion protein and the gene for the immunoglobulin light chain are incorporated into a single piece of DNA.

19. The method of claim 17, wherein the antibody structure is a ScFv.

20. The method of claim 19, wherein the ScFv is directed against a pathological substance associated with a brain disorder.