Pharmaceutical composition
The present invention relates to methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with neurofibrillary tangles. In particular, the invention relates to antibodies, which specifically recognize and bind to phosphorylated pathological protein tau-conformers and to methods and compositions involving said antibodies for the therapeutic and diagnostic use in the treatment of tauopathies including Alzheimer's Disease (AD).
1. An isolated antibody or functional part thereof that binds to a mammalian Tau protein, wherein the antibody or functional part thereof comprises:
a) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 23; or
b) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and a light chain CDR1 comprising an amino acid sequence that is at least 85% identical to SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.
2. The antibody or functional part thereof of claim 1 , wherein the mammalian Tau is human Tau.
3. The antibody or functional part thereof of claim 1 , wherein the antibody or functional part thereof comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 23.
4. The antibody or functional part thereof of claim 1 , wherein the antibody or functional part thereof comprises a light chain CDR1 comprising an amino acid sequence that is at least 85% identical to SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.
5. The antibody or functional part thereof of claim 4 , wherein the light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 24.
6. The antibody or functional part thereof of claim 4 , wherein the light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 27.
7. The antibody or functional part thereof of claim 4 , wherein the light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 28.
8. The antibody or functional part thereof of claim 1 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, 2, or 3.
9. The antibody or functional part thereof of claim 1 , comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6, 7, 8, or 9.
10. The antibody or functional part thereof of claim 1 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, 2, or 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6, 7, 8, or 9.
11. The antibody or functional part thereof of claim 1 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6 or 7; or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9.
12. The antibody or functional part thereof of claim 1 , wherein the antibody is a monoclonal antibody.
13. The antibody or functional part thereof of claim 12 , wherein the antibody is of the IgG2a, IgG2b, or the IgG3 isotype.
14. The antibody or functional part thereof of claim 12 , wherein the antibody is a chimeric antibody or a humanized antibody.
15. An isolated antibody or functional part thereof comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.
16. An isolated antibody or functional part thereof comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.
17. A cell line that produces the antibody of claim 1 .
18. The cell line of claim 17 , which is a hybridoma cell line selected from 3A8A12G7 deposited on Aug. 25, 2010, as DSM ACC3086; 2B6A10C11 deposited on Aug. 25, 2010, as DSM ACC3084; 3A8E12H8 deposited on Aug. 25, 2010, as DSM ACC3085; 2B6G7A12 deposited on Aug. 25, 2010, as DSM ACC3087; 6H1A11C11 deposited on Aug. 25, 2010, as DSM ACC3080; and 6H1G6E6 deposited on Aug. 25, 2010, as DSM ACC3088.
19. A pharmaceutical composition comprising the antibody or functional part thereof of claim 1 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 , which comprises a second antibody or functional part thereof that binds to a second phospho-epitope on a mammalian Tau protein.
21. The pharmaceutical composition of claim 19 , which comprises a second antibody or functional part thereof that binds to a different amyloidogenic protein or peptide.
22. A method of treating or alleviating the symptoms of a neurodegenerative disease or disorder, wherein the neurodegenerative disease or disorder is caused by or associated with a tauopathy, comprising administering to a human in need thereof the pharmaceutical composition of claim 19 .
23. The method of claim 22 , wherein the neurodegenerative disease or disorder is caused by or associated with the formation of neurofibrillary lesions.
24. The method of claim 22 , wherein administering the antibody or functional part thereof results in the alleviation of cognitive deficits.
25. The method of claim 22 , wherein the alleviation of cognitive deficits comprises an arrest in the progression of the cognitive deficits and/or a restoration of cognitive memory capacity.
26. The method of claim 22 , wherein the neurodegenerative disease or disorder is selected from Alzheimer's Disease, Creutzfeldt-Jacob disease, Dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, and prion protein cerebral amyloid angiopathy, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and combinations thereof.
27. The method of claim 22 , wherein the neurodegenerative disease or disorder is Alzheimer's Disease.