Methods for diagnosing and treating CNS disorders by trans-blood-brain barrier delivery of protein compositions

• US 8,497,246 B2
• Filed: 08/20/2007
• Issued: 07/30/2013
• Est. Priority Date: 08/18/2006
• 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
• Assistant Examiner(s): MACFARLANE, STACEY NEE
• Application Number:
  US11/841,594
• Publication Number:
  US 20080171055A1
• Time in Patent Office: 2,171 Days
• Field of Search: None
• US Class Current: 514/17.7
• 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 and second antibody, wherein:

a. the first antibody is an ScFv antibody that is covalently linked to the carboxy terminus of the second antibody;

b. the second antibody comprises an Fc region capable of crossing the BBB from the brain to the blood; and

either

i) the first antibody is capable of crossing the Blood-Brain Barrier (BBB) from the blood to the brain by binding a receptor BBB transport system and the second antibody is capable of interacting with a pathological substance associated with the disorder;

or

ii) the second antibody is capable of crossing the Blood-Brain Barrier (BBB) from the blood to the brain by binding a receptor BBB transport system and the first antibody is capable of interacting with a pathological substance associated with the disorder,

wherein the ScFv retains at least 10% of its affinity compared to the affinity of the tetrameric immunoglobulin from which ScFv can be derived.

2. The method of claim 1, wherein the second antibody is 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 first antibody is capable of interacting with a pathological substance associated with the disorder.

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.

15. The method of claim 1 or claim 9, wherein the ScFv retains at least 20% of its affinity compared to the affinity of the tetrameric immunoglobulin from which ScFv can be derived.

9. A method of diagnosing a CNS disorder comprising measuring the level of an administered composition bound to a pathological substance in a body fluid of an individual, wherein the composition comprises a first and second antibody, wherein:

a. the first antibody is an ScFv antibody that is covalently linked to the carboxy terminus of the second antibody;

b. the second antibody comprises an Fc region capable of crossing the BBB from the brain to the blood; and

either

i) the first antibody is capable of crossing the Blood-Brain Barrier (BBB) from the blood to the brain by binding a receptor BBB transport system and the second antibody is capable of interacting with a pathological substance associated with the disorder;

or

ii) the second antibody is capable of crossing the Blood-Brain Barrier (BBB) from the blood to the brain by binding a receptor BBB transport system and the first antibody is capable of interacting with a pathological substance associated with the disorder,

wherein the ScFv retains at least 10% of its affinity compared to the affinity of the tetrameric immunoglobulin from which ScFv can be derived.

10. 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.

11. The method of claim 10, 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.

12. 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.

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

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