Anti-Tau antibodies and methods of use

1. An isolated antibody that binds to human Tau, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 605; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 606; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 607; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 608; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 609; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 610.

2. The isolated antibody of claim 1 , wherein the antibody binds to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau.

3. The isolated antibody of claim 1 , wherein the antibody binds an epitope within amino acids 2 to 24 of mature human Tau.

4. The isolated antibody of claim 1 , which is a monoclonal antibody.

5. The isolated antibody of claim 1 , which is a humanized or chimeric antibody.

6. The isolated antibody of claim 1 , which is an antibody fragment that binds human Tau.

7. The isolated antibody of claim 1 , wherein the human Tau comprises the sequence of SEQ ID NO: 2.

8. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to SEQ ID NO: 603; or

b) a light chain variable region (VL) comprising a sequence that is at least 95% identical to SEQ ID NO: 604; or

c) a VH as in (a) and a VL as in (b); or

d) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to SEQ ID NO: 614; or

e) a light chain variable region (VL) comprising a sequence that is at least 95% identical to SEQ ID NO: 615; or

f) a VH as in (d) and a VL as in (e); or

g) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to SEQ ID NO: 619; or

h) a light chain variable region (VL) comprising a sequence that is at least 95% identical to SEQ ID NO: 620; or

i) a VH as in (g) and a VL as in (h).

9. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 603, 614, and 619; and a light chain variable region comprising a sequence selected from SEQ ID NOs: 604, 615, and 620.

10. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 340, 603, 614, and 619; and a light chain variable region comprising a sequence selected from SEQ ID NOs: 604, 615, and 620.

11. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 603, 614, and 619; and a light chain variable region comprising a sequence selected from SEQ ID NOs: 341, 604, 615, and 620.

12. The isolated antibody of claim 1 , wherein the antibody comprises or (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 340 and a light chain variable region comprising a sequence selected from SEQ ID NOs: 604, 615, and 620; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 603 and a light chain variable region comprising a sequence selected from SEQ ID NOs: 341, 604, 615, and 620; or (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 614 and a light chain variable region comprising a sequence selected from SEQ ID NOs: 341, 604, 615, and 620; or (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 619 and a light chain variable region comprising a sequence selected from SEQ ID NOs: 341, 604, 615, and 620; or (e) a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 603, 614, and 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 341; or (f) a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 340, 603, 614, and 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 604; or (g) a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 340, 603, 614, and 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 615; or (h) a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 340, 603, 614, and 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 620.

13. The isolated antibody of claim 1 , wherein the antibody comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 603 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 604; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 614 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 615; or (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 620.

14. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a heavy chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 613; or

b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain comprising the amino acid sequence of SEQ ID NO: 613; or

c) a heavy chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 618; or

d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain comprising the amino acid sequence of SEQ ID NO: 618; or

e) a heavy chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 623; or

f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 623.

15. The isolated antibody of claim 1 , wherein the antibody binds each of monomeric Tau.

16. The isolated antibody of claim 1 , wherein the antibody binds to human monomeric Tau with a K D of less than 1 nM.

17. The isolated antibody of claim 16 , wherein K D is determined by surface plasmon resonance.

18. An immunoconjugate comprising the isolated antibody of claim 1 and a second therapeutic agent.

19. A labeled antibody comprising the antibody of claim 1 and a detectable label.

20. A pharmaceutical composition comprising the isolated antibody of claim 1 and a pharmaceutically acceptable carrier.

21. A method of treating a tauopathy comprising administering to an individual with a Tau protein related disease the antibody of claim 1 .

22. The method of claim 21 , wherein the tauopathy is selected from Alzheimer's Disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jacob disease, Dementia pugilistica, Down Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotetemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-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, Tangle only dementia, Postencephalitic Parkinsonism, and Myotonic dystrophy.

23. The method of claim 21 , wherein the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

24. The method of claim 21 , wherein the method comprises administering at least one additional therapy.

25. The method of claim 24 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

26. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering the antibody of claim 1 .

27. A method of reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual, comprising administering the antibody of claim 1 .

28. A method of detecting neurofibrillary tangles, neuropil threads, or dystrophic neuritis comprising contacting a sample with the antibody of claim 1 .

29. The method of claim 28 , wherein the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.

30. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising SEQ ID NO: 603; or

b) a light chain variable region (VL) comprising SEQ ID NO: 604; or

c) a VH as in (a) and a VL as in (b); or

d) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 614; or

e) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 615; or

f) a VH as in (d) and a VL as in (e); or

g) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 619; or

h) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 620; or

i) a VH as in (g) and a VL as in (h).

31. The isolated antibody of claim 30 , which is an antibody fragment that binds human Tau.

32. The isolated antibody of claim 1 , which binds cynomolgus monkey Tau.

33. An isolated nucleic acid that encodes the antibody of claim 1 .

34. A host cell comprising the nucleic acid of claim 33 .

35. A method of producing an antibody comprising culturing the host cell of claim 34 under conditions suitable for producing the antibody.

36. The isolated antibody of claim 1 , wherein the antibody is an IgG1 or an IgG4 antibody.

37. The isolated antibody of claim 36 , wherein the antibody is an IgG4 antibody.

38. The isolated antibody of claim 37 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

39. The isolated antibody of claim 38 , wherein the antibody comprises an S228P mutation.

40. An isolated antibody that binds to human Tau, wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain comprising the amino acid sequence of SEQ ID NO: 613; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain comprising the amino acid sequence of SEQ ID NO: 618; or (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 623.

41. An isolated antibody that binds to human Tau, wherein the antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 611 or SEQ ID NO: 612 and a light chain consisting of the amino acid sequence of SEQ ID NO: 613; or (b) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 616 or SEQ ID NO: 617 and a light chain consisting of the amino acid sequence of SEQ ID NO: 618; or (c) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 621 or SEQ ID NO: 622 and a light chain consisting of the amino acid sequence of SEQ ID NO: 623.

42. An isolated monoclonal antibody that binds to human Tau, wherein the antibody comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 603 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 604; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 614 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 615; or (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 619 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 620.