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: 402 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: 572.
2. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein:
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.
3. The monoclonal antibody or antigen-binding fragment according to claim 1 , 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 , the antibody comprising
a HCVD comprising SEQ ID NO: 402 and a LCVD comprising SEQ ID NO: 572.
16. The monoclonal antibody or antigen-binding fragment according to claim 1 , wherein the antibody is a humanized antibody.
17. The monoclonal antibody or antigen-binding fragment according to claim 1 wherein the antibody is human IgG1.
18. 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.
19. 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).
20. The monoclonal antibody or antigen-binding fragment according to claim 19 , 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.
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 HVPGG (SEQ ID NO: 79).
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 HVPGG (SEQ ID NO: 79) 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 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.
24. A monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds a human Tau, wherein the antibody is produced by the cell line having ATCC deposit number PTA-124524.
25. A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.