Macromolecular compositions that cross the blood-brain barrier and methods of use thereof
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.
1. A fusion antibody that is capable of crossing a blood-brain barrier (BBB), wherein the fusion antibody comprises a first antibody and a second antibody, wherein
(i) the first antibody is a dual domain single-chain antibody that is linked to a carboxy terminus of the second antibody, and the first antibody comprises a VH region and a VL region;
(ii) the first antibody retains an average of at least about 20% of its activity, compared to its activity as a separate entity; and
(iii) the first antibody targets an endogenous BBB receptor transport system and the second antibody targets a pathological substance associated with a brain disorder or the first antibody targets a pathological substance associated with a brain disorder and the second antibody targets an endogenous BBB receptor transport system,
and wherein the fusion antibody comprises an Fc region that enables crossing the BBB from brain to blood by binding to an Fc receptor.
2. The fusion antibody of claim 1 , wherein the fusion antibody is capable of crossing the BBB from the blood to the brain by binding to an endogenous receptor of the BBB selected from the group consisting of an insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and an insulin-like growth factor (IGF) receptor.
3. The fusion antibody of claim 1 , wherein the fusion antibody is capable of crossing the BBB from the blood to the brain by binding to an insulin receptor.
4. The fusion antibody of claim 1 , wherein the pathological substance is of a type selected from the group consisting of a protein, a nucleic acid, a carbohydrate, a carbohydrate polymer, a lipid, a glycolipid, a small molecule, and a combination thereof.
5. The fusion antibody of claim 1 , wherein the pathological substance is a protein.
6. The fusion antibody of claim 5 , 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.
7. The fusion antibody of claim 5 , wherein the protein is Aβ amyloid.
8. The fusion antibody of claim 1 , 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.
9. The fusion antibody of claim 1 , wherein the first antibody is capable of binding to Amyloid B (Aβ) peptide.
10. The fusion antibody of claim 1 , wherein a dissociation constant of the first antibody for its antigen is less than 100 nM.
11. The fusion antibody of claim 1 , wherein the first antibody is fused at its amino terminus to the carboxy terminus of a heavy chain of the second antibody.
12. The fusion antibody of claim 1 , wherein the first antibody is fused at its amino terminus to the carboxy terminus of a light chain of the second antibody.
13. The fusion antibody of claim 1 , wherein the second antibody is a monoclonal antibody (MAb).
14. The fusion antibody of claim 1 , wherein the second antibody is capable of binding to a BBB receptor.
15. The fusion antibody of claim 1 , wherein the second antibody comprises a CH 2 region, a CH 3 region, and a VH region.
16. The fusion antibody of claim 15 , wherein first antibody is covalently linked to the carboxyl terminus of the CH 3 region.
17. The fusion antibody of claim 15 , wherein the VH region is derived from an antibody that is generated in vivo or by a recombinant method.
18. The fusion antibody of claim 17 , wherein the recombinant method comprises selection of libraries of recombinant antibodies in phage or vectors.
19. The fusion antibody of claim 15 , wherein the first antibody is generated in vivo or by a recombinant method.
20. The fusion antibody of claim 19 , wherein the recombinant method comprises selection of libraries of recombinant antibodies in phage or vectors.
21. The fusion antibody of claim 1 , wherein the first antibody is a single-chain Fab, Fab′, F(ab) 2 , or Fv antibody.
22. The fusion antibody of claim 21 , wherein the first antibody is a single-chain Fv (ScFv) antibody.