Fusion antibodies that cross the blood-brain barrier in both directions

• US 7,741,446 B2
• Filed: 08/20/2007
• Issued: 06/22/2010
• 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.
• Primary Examiner(s): Kolker; Daniel E.
• Application Number:
  US11/841,623
• Publication Number:
  US 20080170994A1
• Time in Patent Office: 1,037 Days
• Field of Search: None
• US Class Current: 530/387.3
• 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 diagnostic and therapeutic macromolecular compositions that cross the blood-brain barrier, in some embodiments in both directions, while allowing their activity to remain substantially intact once across the barrier. Also provided are methods for using such compositions in the diagnosis or treatment of CNS disorders such as Alzheimer'"'"'s disease.

Claims

1. An antibody composition comprising a fusion antibody that

(i) is capable of crossing the blood-brain barrier (BBB) from the blood to the brain by binding to an endogenous BBB receptor-mediated transport system;

(ii) comprises an Fc region that enables crossing the BBB from the brain to the blood by binding to an Fc receptor; and

(iii) comprises a first and second antibody wherein the first antibody is an ScFv antibody that is covalently linked to either the carboxy terminus of the heavy chain of the second antibody or the carboxy terminus of the light chain of the second antibody,

wherein the affinity of the ScFv for its antigen is more than 20% of the immunoglobulin from which the ScFv was derived.

2. The antibody composition of claim 1, wherein the endogenous BBB receptor-mediated transport system that transports the composition across the BBB is selected from the group consisting of an insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and an IGF receptor.

3. The antibody composition of claim 1, wherein the fusion antibody is further capable of interacting with a pathological substance associated with a brain disorder.

4. The antibody composition of claim 3, wherein the fusion antibody comprises a monoclonal antibody (MAb) and an ScFv antibody.

5. The antibody composition of claim 4, wherein the fusion antibody is able to cross the BBB by binding an insulin receptor.

6. The antibody composition of claim 4 wherein the ScFv is able to bind to Amyloid B (An) peptide.

7. The antibody composition of claim 4, wherein the dissociation constant of the ScFv for its antigen is less than 100 nM.

8. The antibody composition of claim 4, wherein the ScFv is fused at its amino terminus to the carboxy terminus of the heavy chain of the MAb.

9. The antibody composition of claim 4, wherein the ScFv is fused at its amino terminus to the carboxy terminus of the light chain of the MAb.

10. The antibody composition of claim 3, wherein the pathological substance is of a type selected from the group consisting of proteins, nucleic acids, carbohydrates, carbohydrate polymers, lipids, glycolipids, small molecules, and combinations thereof.

11. The antibody composition of claim 10, wherein the pathological substance is a protein.

12. The antibody composition of claim 11, 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.

13. The antibody composition of claim 12, wherein the protein is Aβ

amyloid.

14. The antibody composition of claim 3, 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 antibody composition of claim 1, wherein the fusion antibody is able to cross the BBB by binding an insulin receptor.

16. The antibody composition of claim 1 wherein the ScFv is able to bind to Amyloid B (Aβ

) peptide.

17. The antibody composition of claim 1, wherein the ScFv is capable of binding to a BBB receptor.