Methods of treating a tauopathy

1. A method of treating a tauopathy in an individual, the method comprising administering to the individual a pharmaceutical composition comprising an antibody that specifically binds Tau and a pharmaceutically acceptable excipient suitable for administration to a human, wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:9; and

(vii) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:11:

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

2. The method of claim 1 , wherein the antibody is encapsulated in a liposome.

3. The method of claim 1 , wherein the antibody is formulated with an agent that facilitates crossing the blood-brain barrier.

4. The method of claim 1 , wherein the antibody is fused, directly or via a linker, to a carrier molecule, a peptide or a protein that promotes the crossing of the blood-brain barrier.

5. The method of claim 1 , wherein the antibody is a Fv, scFv, Fab, F(ab′)2, or Fab′.

6. The method of claim 1 , wherein said administering results in reduction in one or more of:

a) the amount of free extracellular tau in brain tissue;

b) the neuron-to-neuron spread of tau;

c) the amount of intraneuron tau aggregates;

d) the degree of microglial and/or astrocyte activation;

e) the amount of phosphorylated or hyperphosphorylated tau;

f) the amount of total Tau;

g) the amount of intracellular N-terminal tau fragments; and

h) neuronal hyperactivity.

7. The method of claim 1 , further comprising administering at least one additional agent that treats the tauopathy.

8. The method of claim 1 , wherein said administering is intravenous.

9. The method of claim 1 , wherein said administering is intrathecal.

10. A pharmaceutical formulation, the formulation comprising: an antibody that specifically binds Tau and a pharmaceutically acceptable excipient suitable for administration to a human, wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

11. The pharmaceutical formulation of claim 10 , wherein the humanized light chain framework region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the amino acid substitutions depicted in Table 3.

12. The pharmaceutical formulation of claim 10 , wherein the humanized heavy chain framework region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the amino acid substitutions depicted in Table 2.

13. The pharmaceutical formulation of claim 10 , wherein the antibody is encapsulated in a liposome.

14. The pharmaceutical formulation of claim 10 , wherein the antibody is formulated with an agent that facilitates crossing the blood-brain barrier.

15. The pharmaceutical formulation of claim 10 , wherein the antibody is fused, directly or via a linker, to a carrier molecule, a peptide or a protein, wherein the carrier molecule, peptide, or protein promotes the crossing of the blood-brain barrier.

16. The pharmaceutical formulation of claim 10 , wherein the antibody is a Fv, scFv, Fab, F(ab′)2, or Fab′.

17. An antibody that specifically binds Tau, wherein the antibody comprises:

a) a light chain region comprising:

i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

18. The antibody of claim 17 , wherein the light chain region and the heavy chain region are present in separate polypeptides.

19. The antibody of claim 17 , wherein the light chain region and the heavy chain region are present in a single polypeptide.

20. The antibody of claim 17 , wherein the heavy chain region is of the isotype IgG1, IgG2, IgG3, or IgG4.

21. The antibody of claim 17 , wherein the antibody is a Fv, scFv, Fab, F(ab′)2, or Fab′.

22. The antibody of claim 17 , wherein the antibody comprises a covalently linked non-peptide synthetic polymer.

23. The antibody of claim 22 , wherein the synthetic polymer is a poly(ethylene glycol) polymer.

24. The antibody of claim 17 , wherein the antibody is fused, directly or via a linker, to a carrier molecule, a peptide or a protein, wherein the carrier molecule, peptide, or protein promotes the crossing of the blood-brain barrier.

25. A recombinant expression vector comprising a nucleotide sequence encoding the antibody of 17 , wherein the nucleotide sequence is operably linked to a transcriptional control element that is active in a eukaryotic cell.

26. An in vitro host cell genetically modified with the recombinant expression vector of claim 25 .

27. A sterile container comprising the pharmaceutical formulation of claim 10 .

28. The container of claim 27 , wherein the container is a syringe.

29. A method of monitoring progression of a tauopathy in an individual, the method comprising:

a) determining a first level of a Tau polypeptide in a biological sample obtained from the individual at a first time point;

b) determining a second level of a Tau polypeptide in a biological sample obtained from the individual at a second time point; and

c) comparing the second level of Tau with the first level of Tau,

wherein said determining comprises:

i) contacting the biological sample with an antibody of claim 17 ; and

ii) quantitating binding of the antibody to Tau polypeptide present in the sample.

30. The method of claim 29 , wherein the biological sample is cerebrospinal fluid, blood, plasma, serum, urine, or saliva.

31. The method of claim 29 , wherein the quantitated Tau polypeptide is total Tau polypeptide.

32. The method of claim 29 , wherein the quantitated Tau polypeptide is an N-terminal fragment of a full-length Tau polypeptide.

33. The method of claim 29 , wherein the first time point is a time point before initiation of a treatment regimen, and wherein the second time point is a time point after initiation of a treatment regimen.

34. A method of detecting a Tau polypeptide in a living individual in vivo, the method comprising:

a) administering to the individual an antibody of claim 17 ; and

b) detecting binding of the antibody to tau polypeptide in a brain tissue in the individual using an imaging method.

35. The method of claim 34 , wherein the antibody comprises a contrast agent suitable for use in the imaging method.

36. The method of claim 34 , wherein the imaging method is magnetic resonance imaging or positron emission tomography.

37. An in vitro method of detecting a Tau polypeptide in a biological sample obtained from an individual, the method comprising:

1) contacting the biological sample with an antibody that specifically binds Tau, wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:12: and

(iv) a humanized heavy chain framework region; and

2) detecting binding of the antibody to Tau polypeptide present in the sample.

38. The method of claim 37 , wherein the biological sample is blood, serum, plasma, urine, saliva, or cerebrospinal fluid.

39. The method of claim 37 , wherein the individual is suspected of having a tauopathy, has been diagnosed as having a tauopathy, or has a genetic predisposition to developing a tauopathy.

40. The method of claim 37 , wherein the method is quantitative.

41. The method of claim 37 , wherein the Tau polypeptide detected is total Tau polypeptide.

42. The method of claim 37 , wherein the Tau polypeptide detected is an N-terminal fragment of a full-length Tau polypeptide.

43. The method of claim 1 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3; and

(vii) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6; and

(iv) a humanized heavy chain framework region.

44. The method of claim 1 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:9; and

(vii) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

45. The pharmaceutical formulation of claim 10 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6; and

(iv) a humanized heavy chain framework region.

46. The pharmaceutical formulation of claim 10 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

47. The antibody of claim 17 , wherein the antibody comprises:

a) a light chain region comprising:

i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6; and

(iv) a humanized heavy chain framework region.

48. The antibody of claim 17 , wherein the antibody comprises:

a) a light chain region comprising:

i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.

49. The in vitro method of claim 37 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:2;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:3; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:4;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:5;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:6; and

(iv) a humanized heavy chain framework region.

50. The in vitro method of claim 37 , wherein the antibody comprises:

a) a light chain region comprising:

(i) a V L CDR1 comprising the amino acid sequence of SEQ ID NO:7;

(ii) a V L CDR2 comprising the amino acid sequence of SEQ ID NO:8;

(iii) a V L CDR3 comprising the amino acid sequence of SEQ ID NO:9; and

(iv) a humanized light chain framework region; and

b) a heavy chain region comprising:

(i) a V H CDR1 comprising the amino acid sequence of SEQ ID NO:10;

(ii) a V H CDR2 comprising the amino acid sequence of SEQ ID NO:11;

(iii) a V H CDR3 comprising the amino acid sequence of SEQ ID NO:12; and

(iv) a humanized heavy chain framework region.