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. A method of treating a neurodegenerative disorder 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 possessing at least 70% sequence identity to SEQ ID NO: 13, and a 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 about 10 pM to about 40 pM and a binding affinity (KD) for a full length tau of from 1×10 −4 to 1×10 −8 M, and wherein
the anti-TauC3 antibody is a humanized antibody, and
the variable heavy chain (V H ) polypeptide comprises CDR1 represented by SEQ ID NO: 7, CDR2 represented by SEQ ID NO: 8, and CDR3 represented by SEQ ID NO: 9; and
the variable light chain (V L ) polypeptide comprises CDR1 represented by SEQ ID NO: 10, CDR2 represented by SEQ ID NO: 11, and CDR3 represented by SEQ ID NO: 12.
2. The method of claim 1 , wherein the anti-TauC3 antibody has a binding affinity (KD) for TauC3 from about 10 pM to about 35 pM.
3. The method of claim 1 , wherein the anti-TauC3 antibody comprises a variable heavy chain (V H ) polypeptide possessing at least 80% sequence identity to SEQ ID NO: 13, and a variable light chain (V L ) polypeptide possessing at least 80% sequence identity to SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
4. The method of claim 1 , wherein the anti-TauC3 antibody comprises a variable heavy chain (V H ) polypeptide possessing at least 85% sequence identity to SEQ ID NO: 13, and a variable light chain (V L ) polypeptide possessing at least 85% 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 method of claim 1 , wherein the anti-TauC3 antibody comprises a variable heavy chain (V H ) polypeptide possessing at least 90% sequence identity to SEQ ID NO: 13, and a variable light chain (V L ) polypeptide possessing at least 90% sequence identity to SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.
6. The method of claim 1 , wherein the anti-TauC3 antibody comprises a variable heavy chain (V H ) polypeptide possessing at least 95% sequence identity to SEQ ID NO: 13, and a variable light chain (V L ) 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.
7. The method of claim 1 , wherein the variable heavy chain (VH) 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.
8. The method of claim 7 , wherein the variable heavy chain (VH) polypeptide is a polypeptide of SEQ ID NO: 13 and the variable light chain (V L ) polypeptide is a polypeptide of SEQ ID NO: 18.
9. The method of claim 1 , wherein the anti-TauC3 antibody is administered in an amount effective to inhibit pathological tau aggregation.
10. The method of claim 1 , wherein the anti-TauC3 antibody is administered in an amount effective to block spreading of pathological tau, tau fibrils and tau aggregates.
11. The method of claim 1 , wherein the neurodegenerative disorder is progressive supranuclear palsy.
12. The method of claim 1 , wherein the neurodegenerative disorder is frontotemporal dementia.
13. An antigen-binding fragment of an antibody comprising
(a) a heavy chain variable region comprising CDR1 identical to SEQ ID NO: 7, CDR2 identical to SEQ ID NO: 8, and CDR3 identical to SEQ ID NO: 9; and
(b) a light chain variable region comprising CDR1 identical to SEQ ID NO: 10, CDR2 identical to SEQ ID NO: 11, and CDR3 identical to SEQ ID NO: 12; and
having a binding affinity (KD) for TauC3 of from 1×10 −10 and 1×10 −12 and an off-rate (K d ) of 1×10 −3 s −1 or less, and a binding affinity (KD) for SEQ ID NO:1 of from 1×10 −4 to 1×10 −8 M, or no detectable binding with SEQ ID NO: 1.
14. The antigen-binding fragment of the antibody of claim 13 , which is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, or a scFv fragment.
15. The antigen-binding fragment of the antibody of claim 13 , which has an off-rate (Kd) from 1×10 −4 to 1×10 −3 s −1 .
16. 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; 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; and is a humanized antibody or a chimeric antibody.
17. The isolated anti-TauC3 antibody of claim 16 , which is the humanized antibody and has an off-rate K d for TauC3 from 1×10 −4 to 1×10 −3 s −1 .
18. The isolated anti-TauC3 antibody of claim 17 , which is the humanized antibody and has a binding affinity (KD) for TauC3 from about 10 pM to about 40 pM.
19. The isolated anti-TauC3 antibody of claim 18 , which has a binding affinity (KD) for TauC3 from about 10 to about 35 pM.