TDP-43 specific binding molecules
Provided are TAR DNA-binding protein of 43 kDa (TDP-43)-specific binding molecules including polypeptides such as human antibodies, as well as fragments, derivatives and variants thereof. Also provided are methods related to these TDP-43 specific binding molecules. Assays, kits, and solid supports related to TDP-43-specific binding molecules, including polypeptides such as, human antibodies are also disclosed. The TDP-43-specific binding molecule, antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for TDP-43 targeted immunotherapy and diagnosis, respectively.
1. A method of reducing the accumulation of pathological TAR-DNA-binding protein 43 kDa (TDP-43) deposits or reducing pathological TDP-43 distribution in a human subject in need thereof, the method comprising administering to the human subject an effective amount of an anti-TDP-43 antibody comprising:
(i) a heavy chain variable region (VH) comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; and a light chain variable region (VL) comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively; or
(ii) a VH comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:260, SEQ ID NO:261, and SEQ ID NO:262, respectively; and a VL comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:264, SEQ ID NO:265, and SEQ ID NO:266, respectively.
2. The method of claim 1 , wherein the VH is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:10 or (ii) SEQ ID NO:259.
3. The method of claim 1 , wherein the VL is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:14 or (ii) SEQ ID NO:263.
4. The method of claim 1 , wherein:
(i) the VH comprises the amino acid sequence of SEQ ID NO:10 and the VL comprises the amino acid sequence of SEQ ID NO:14; or
(ii) the VH comprises the amino acid sequence of SEQ ID NO:259 and the VL comprises the amino acid sequence of SEQ ID NO:263.
5. The method of claim 1 , wherein the antibody is a human antibody, humanized antibody, or chimeric antibody.
6. The method of claim 1 , wherein the antibody is a TDP-43-binding antibody fragment.
7. The method of claim 6 , wherein the TDP-43-binding antibody fragment is selected from the group consisting of a single chain Fv fragment (scFv), a F(ab′) fragment, a F(ab) fragment, and a F(ab′) 2 fragment.
8. The method of claim 1 , wherein the antibody is attached to a drug.
9. The method of claim 1 , wherein the antibody is a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
10. The method of claim 9 , further comprising administering an additional agent useful for treating a TDP-43 proteinopathy.
11. The method of claim 1 , wherein the human subject is suffering from a TDP-43 proteinopathy selected from the group consisting of argyrophilic grain disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ALS-Parkinsonism dementia complex of Guam, corticobasal degeneration, Dementia with Lewy bodies, Huntington's disease, Lewy body disease, motor neuron disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia, frontotemporal lobar degeneration with ubiquitin-positive inclusions, hippocampal sclerosis, inclusion body myopathy, inclusion body myositis, Parkinson's disease, Parkinson's disease dementia, Parkinson-dementia complex in Kii peninsula and Pick's disease.
12. A method of reducing the number or frequency of TAR-DNA-binding protein 43 kDa (TDP-43) positive inclusion-positive neurons in the brain or spinal cord in a human subject in need thereof, the method comprising administering to the human subject an effective amount of an anti-TDP-43 antibody, comprising:
(i) a heavy chain variable region (VH) comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; and a light chain variable region (VL) comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively; or
(ii) a VH comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:260, SEQ ID NO:261, and SEQ ID NO:262, respectively; and a VL comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:264, SEQ ID NO:265, and SEQ ID NO:266, respectively.
13. The method of claim 12 , wherein the VH is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:10 or (ii) SEQ ID NO:259.
14. The method of claim 12 , wherein the VL is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:14 or (ii) SEQ ID NO:263.
15. The method of claim 12 , wherein:
(i) the VH comprises the amino acid sequence of SEQ ID NO:10 and the VL comprises the amino acid sequence of SEQ ID NO:14; or
(ii) the VH comprises the amino acid sequence of SEQ ID NO:259 and the VL comprises the amino acid sequence of SEQ ID NO:263.
16. The method of claim 12 , wherein the antibody is a human antibody, humanized antibody, or chimeric antibody.
17. The method of claim 12 , wherein the antibody is a TDP-43-binding antibody fragment.
18. The method of claim 17 , wherein the TDP-43-binding antibody fragment is selected from the group consisting of a single chain Fv fragment (scFv), a F(ab′) fragment, a F(ab) fragment, and a F(ab′) 2 fragment.
19. The method of claim 12 , wherein the antibody is attached to a drug.
20. The method of claim 12 , wherein the antibody is a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
21. The method of claim 20 , further comprising administering an additional agent useful for treating a TDP-43 proteinopathy.
22. A method of reducing the amount or concentration of neuritic TAR-DNA-binding protein 43 kDa (TDP-43) protein in the brain or spinal cord in a human subject in need thereof, comprising administering to the human subject an effective amount of an anti-TDP-43 antibody comprising:
(i) a heavy chain variable region (VH) comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; and a light chain variable region (VL) comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively; or
(ii) a VH comprising VH complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:260, SEQ ID NO:261, and SEQ ID NO:262, respectively; and a VL comprising VL complementarity determining regions 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NO:264, SEQ ID NO:265, and SEQ ID NO:266, respectively.
23. The method of claim 22 , wherein the VH is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:10 or (ii) SEQ ID NO:259.
24. The method of claim 22 , wherein the VL is at least 80% identical to the amino acid sequence of (i) SEQ ID NO:14 or (ii) SEQ ID NO:263.
25. The method of claim 22 , wherein:
(i) the VH comprises the amino acid sequence of SEQ ID NO:10 and the VL comprises the amino acid sequence of SEQ ID NO:14; or
(ii) the VH comprises the amino acid sequence of SEQ ID NO:259 and the VL comprises the amino acid sequence of SEQ ID NO:263.
26. The method of claim 22 , wherein the antibody is a human antibody, humanized antibody, or chimeric antibody.
27. The method of claim 22 , wherein the antibody is a TDP-43-binding antibody fragment.
28. The method of claim 27 , wherein the TDP-43-binding antibody fragment is selected from the group consisting of a single chain Fv fragment (scFv), a F(ab′) fragment, a F(ab) fragment, and a F(ab′) 2 fragment.
29. The method of claim 22 , wherein the antibody is attached to a drug.
30. The method of claim 22 , wherein the antibody is a component of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
31. The method of claim 30 , further comprising administering an additional agent useful for treating a TDP-43 proteinopathy.