Anti-TAUC3 antibodies and uses thereof
Anti-TauC3 antibodies that are at least several orders of magnitude more specific for TauC3 than for full length tau (2N4R) are described. Also described are methods of using anti-TauC3 antibodies.
1. An isolated anti-tauC3 antibody, which has a binding affinity (KD) for TauC3 from 1×10 −10 to 1×10 −12 M, and a binding affinity (KD) for a full length tau of from 1×10 −4 to 1×10 −8 M, wherein the antibody comprises (a) a variable heavy chain (V H ) polypeptide comprising CDR1 represented by SEQ ID NO: 7, CDR2 represented by SEQ ID NO: 8, and CDR3 represented by SEQ ID NO: 9, the variable heavy chain (V H ) polypeptide possessing at least 70% sequence identity to SEQ ID NO: 13; and (b) a variable light chain (V L ) polypeptide comprising CDR1 represented by SEQ ID NO: 10, CDR2 represented by SEQ ID NO: 11, and CDR3 represented by SEQ ID NO: 12, the variable light chain (V L ) polypeptide possessing at least 70% sequence identity to SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18; and is a humanized antibody or a chimeric antibody.
2. The anti-TauC3 antibody of claim 1 , wherein the off-rate K d for TauC3 is from 1×10 −4 to 1×10 −3 s −1 .
3. The anti-TauC3 antibody of claim 1 , wherein the variable heavy chain (V H ) polypeptide comprises SEQ ID NO: 13; and the variable light chain (V L ) polypeptide comprises a sequence selected from the group consisting of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18.
4. The anti-TauC3 antibody of claim 1 , which comprises a V L chain polypeptide possessing at least 95% sequence identity to SEQ ID NO: 13, and a V H chain polypeptide possessing at least 95% sequence identity to SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
5. The anti-TauC3 antibody of claim 1 , which has an aqueous solubility from about 50 mg/ml to about 200 mg/ml.
6. The anti-TauC3 antibody of claim 1 , which is a humanized antibody.
7. The anti-TauC3 antibody of claim 1 , which is a chimeric antibody.
8. The anti-TauC3 antibody of claim 1 , wherein, on the variable heavy chain (V H ) polypeptide, CDR1 is a polypeptide of SEQ ID NO: 7, CDR2 is a polypeptide of SEQ ID NO: 8, and CDR3 is a polypeptide of SEQ ID NO: 9; and on the light chain (V L ) polypeptide, CDR1 is a polypeptide of SEQ ID NO: 10, CDR2 is a polypeptide of SEQ ID NO: 11, and CDR3 is a polypeptide of SEQ ID NO: 12.
9. The anti-TauC3 antibody of claim 8 , wherein the variable heavy chain (V H ) polypeptide is a polypeptide of SEQ ID NO: 13 and the variable light chain (V L ) polypeptide is a polypeptide of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
10. The anti-TauC3 antibody of claim 1 , which is a humanized antibody having a binding affinity (KD) for TauC3 from about 10 pM to about 40 pM.
11. The anti-TauC3 antibody of claim 10 , which has a binding affinity (KD) for TauC3 from about 10 to about 35 pM.
12. A pharmaceutical compositions comprising an anti-TauC3 antibody according to claim 1 and one or more pharmaceutically acceptable excipient(s).
13. The pharmaceutical composition of claim 12 , wherein the anti-TauC3 comprises (a) a variable heavy chain (V H ) polypeptide comprising CDR1 represented by SEQ ID NO: 7, CDR2 represented by SEQ ID NO: 8, and CDR3 represented by SEQ ID NO: 9, and (b) a variable light chain (V L ) polypeptide comprising CDR1 represented by Seq. ID No. 10, CDR2 represented by SEQ. ID NO: 11, and CDR3 represented by SEQ ID NO: 12.
14. The pharmaceutical composition of claim 13 , wherein the anti-TauC3 antibody has an aqueous solubility of from about 50 mg/ml to about 200 mg/ml.
15. The pharmaceutical composition of claim 13 , wherein the anti-TauC3 antibody is a humanized antibody having a binding affinity (KD) for TauC3 from about 1×10 −11 M to about 4×10 −11 M.
16. The pharmaceutical composition of claim 13 , which has a binding affinity (KD) for TauC3 from about 10 pM to about 40 pM.
17. A method of treating a tauopathy in a subject comprising administering a therapeutically effective amount of an anti-TauC3 antibody to the subject, wherein the anti-TauC3 antibody comprises (a) a variable heavy chain (V H ) polypeptide comprising CDR1 represented by SEQ ID NO: 7, CDR2 represented by SEQ ID NO: 8, and CDR3 represented by SEQ ID NO: 9, the variable heavy chain (V H ) polypeptide possessing at least 70% sequence identity to SEQ ID NO: 13; and (b) a variable light chain (V L ) polypeptide comprising CDR1 represented by SEQ ID NO: 10, CDR2 represented by SEQ ID NO: 11, and CDR3 represented by SEQ ID NO: 12, the variable light chain (V L ) polypeptide possessing at least 70% sequence identity to SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18; and has a binding affinity (KD) for TauC3 from 1×10 −10 to 1×10 −12 M; a binding affinity (KD) for a full length tau of from 1×10 −4 to 1×10 −8 M; and is a humanized antibody or a chimeric antibody.
18. The method of claim 17 , wherein the antibody is a humanized antibody.
19. The method of claim 17 , wherein the tauopathy is selected from the group consisting of Alzheimer disease, progressive supranuclear palsy, frontotemporal dementia, traumatic brain injury, Pick's disease, corticobasal degeneration, and frontotemporal lobar degeneration.
20. The method of claim 19 , wherein the tauopathy is Alzheimer disease.