Anti-tau antibodies and uses thereof
Provided herein are antibodies that specifically bind Tau and methods of using the same.
1. A monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, the antibody comprising:
a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3) as set forth in SEQ ID NO: 196 and a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3) as set forth in SEQ ID NO: 411; or
a HCDR1, a HCDR2, and a HCDR3 as set forth in SEQ ID NO: 268 and a LCDR1, a LCDR2, and a LCDR3 as set forth in SEQ ID NO: 465.
2. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT.
3. The monoclonal antibody or antigen-binding fragment according to claim 1 or claim 2 , wherein the residue at position 49 of the light chain according to the method of Kabat is not cysteine.
4. The monoclonal antibody or antigen-binding fragment according to claim 3 , wherein the residue at position 49 of the light chain according to the method of Kabat is serine.
5. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 57 of the heavy chain according to the method of Kabat is not cysteine.
6. The monoclonal antibody or antigen-binding fragment according to claim 5 , wherein the residue at position 57 of the heavy chain according to the method of Kabat is serine.
7. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 34 of the light chain according to the method of Kabat is glutamate.
8. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 36 of the light chain according to the method of Kabat is not phenylalanine.
9. The monoclonal antibody or antigen-binding fragment according to claim 8 wherein the residue at position 36 of the light chain according to the method of Kabat is tyrosine.
10. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 46 of the light chain according to the method of Kabat is not arginine.
11. The monoclonal antibody or antigen-binding fragment according to claim 10 wherein the residue at position 46 of the light chain according to the method of Kabat is leucine.
12. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 94 of the heavy chain according to the method of Kabat is not lysine.
13. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the residue at position 71 of the heavy chain according to the method of Kabat is not arginine.
14. The monoclonal antibody or antigen-binding fragment according to claim 13 wherein position 71 of the heavy chain according to the Kabat method is valine.
15. The monoclonal antibody or antigen-binding fragment according to claim 1 or claim 2 , the antibody comprising:
a heavy chain variable domain (HCVD) comprising SEQ ID NO: 268 and a light chain variable domain (LCVD) comprising SEQ ID NO: 465;
a HCVD comprising SEQ ID NO: 268 and a LCVD comprising SEQ ID NO: 581;
a HCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 545;
a HCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 545;
a HCVD comprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 545;
a HCVD comprising SEQ ID NO: 384 and a LCVD comprising SEQ ID NO: 572; or
a HCVD comprising SEQ ID NO: 393 and a LCVD comprising SEQ ID NO: 572.
16. A monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein the antibody comprises the amino acid sequence of the antibody produced by the cell line having ATCC deposit number PTA-124523.
17. A monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein the antibody comprises the amino acid sequence of the antibody produced by the cell line having ATCC deposit number PTA-124524.
18. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein the antibody is a murine antibody, a chimeric antibody, or a humanized antibody.
19. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the antibody is IgG1.
20. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the antibody binds monomeric wild-type human 2N4R Tau with a K D of less than about 0.5 nM as measured by surface plasmon resonance.
21. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment binds to human Tau at an epitope comprising the amino acid sequence HVPG (SEQ ID NO: 1133).
22. The monoclonal antibody or antigen-binding fragment according to claim 21 , wherein the antibody or antigen-binding fragment is biepitopic and binds to human Tau at an epitope comprising the amino acid sequence HVPG (SEQ ID NO: 1133) within repeat region 2 or repeat region 4.
23. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein the antibody or antigen-binding fragment binds to human Tau at an epitope comprising the amino acid sequence HVPGG (SEQ ID NO: 79).
24. The monoclonal antibody or antigen-binding fragment according to claim 23 , wherein the antibody or antigen-binding fragment is biepitopic and binds to human Tau at an epitope comprising the amino acid sequence HVPGG (SEQ ID NO: 79) within repeat region 2 or repeat region 4.
25. The monoclonal antibody or antigen-binding fragment according to claim 1 ,
wherein the antibody or antigen-binding fragment binds human Tau at the epitope comprising the amino acid sequence HVPGG (SEQ ID NO: 79) within repeat region 2 with a binding preference that is at least about 10-fold greater than binding at an epitope comprising the amino acid sequence HKPGG (SEQ ID NO: 182) within repeat region 3 or than binding at an epitope comprising the amino acid sequence HQPGG (SEQ ID NO: 183) within repeat region 1, or
wherein the antibody or antigen-binding fragment binds human Tau at the epitope comprising the amino acid sequence HVPGG (SEQ ID NO: 79) within repeat region 4 with a binding preference that is at least about 10-fold greater than binding at an epitope comprising the amino acid sequence HKPGG (SEQ ID NO: 182) within repeat region 3 or than binding at an epitope comprising the amino acid sequence HQPGG (SEQ ID NO: 183) within repeat region 1,
as determined by a peptide binding assay.
26. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the antibody or antigen-binding fragment does not bind Tau at an epitope comprising the amino acid sequence HVSGG (SEQ ID NO: 184) within repeat region 2 or at an epitope comprising the amino acid sequence HVLGG (SEQ ID NO: 185) within repeat region 2.
27. A labeled antibody or antigen-binding fragment comprising a monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the LCDR3 comprises SEQ ID NO: 850 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1 comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118, and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT.
28. A nucleic acid molecule encoding a monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the LCDR3 comprises SEQ ID NO: 850 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1 comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118, and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT.
29. A vector comprising the nucleic acid molecule of claim 28 .
30. A cell that expresses the nucleic acid molecule of claim 28 .
31. A method of producing an anti-Tau antibody or antigen-binding fragment comprising culturing a cell according to claim 30 under conditions suitable for producing the antibody or antigen-binding fragment.
32. The method according to claim 31 further comprising recovering the antibody or antigen-binding fragment.
33. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.
34. A method for decreasing sarkosyl-insoluble Tau levels in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the LCDR3 comprises SEQ ID NO: 850 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1 comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118, and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT.
35. A method for inhibiting Tau aggregation in a subject in need thereof, the method comprising administering to the subject a monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the LCDR3 comprises SEQ ID NO: 850 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1 comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118, and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT.
36. A method of treating a Tauopathy in a subject in need thereof, the method comprising: administering to the subject a monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein:
the HCDR1 comprises SEQ ID NO: 594, the HCDR2 comprises SEQ ID NO: 596, the HCDR3 comprises SEQ ID NO: 598, the LCDR1 comprises SEQ ID NO: 738, the LCDR2 comprises SEQ ID NO: 740, and the LCDR3 comprises SEQ ID NO: 742 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 864, the HCDR2 comprises SEQ ID NO: 866, the HCDR3 comprises SEQ ID NO: 868, the LCDR1 comprises SEQ ID NO: 1008, the LCDR2 comprises SEQ ID NO: 1010, and the LCDR3 comprises SEQ ID NO: 1012 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 642, the HCDR2 comprises SEQ ID NO: 644, the HCDR3 comprises SEQ ID NO: 646, the LCDR1 comprises SEQ ID NO: 774, the LCDR2 comprises SEQ ID NO: 776, and the LCDR3 comprises SEQ ID NO: 778 as defined according to the method of Kabat;
the HCDR1 comprises SEQ ID NO: 912, the HCDR2 comprises SEQ ID NO: 914, the HCDR3 comprises SEQ ID NO: 916, the LCDR1 comprises SEQ ID NO: 1044, the LCDR2 comprises SEQ ID NO: 1046, and the LCDR3 comprises SEQ ID NO: 1048 as defined by IMGT;
the HCDR1 comprises SEQ ID NO: 732, the HCDR2 comprises SEQ ID NO: 734, the HCDR3 comprises SEQ ID NO: 736, the LCDR1 comprises SEQ ID NO: 846, the LCDR2 comprises SEQ ID NO: 848, and the LCDR3 comprises SEQ ID NO: 850 as defined according to the method of Kabat; or
the HCDR1 comprises SEQ ID NO: 1002, the HCDR2 comprises SEQ ID NO: 1004, the HCDR3 comprises SEQ ID NO: 1006, the LCDR1 comprises SEQ ID NO: 1116, the LCDR2 comprises SEQ ID NO: 1118, and the LCDR3 comprises SEQ ID NO: 1120 as defined by IMGT,
under conditions effective to treat the Tauopathy in the subject.
37. The method according to claim 36 , wherein the Tauopathy is Alzheimer's disease, frontotemporal dementia, or progressive supranuclear palsy.
38. The method according to claim 37 , wherein the frontotemporal dementia is Pick's disease.