Anti-transthyretin antibodies
The invention provides antibodies that specifically bind to transthyretin (TTR). The antibodies can be used for treating or effecting prophylaxis of diseases or disorders associated with TTR accumulation or accumulation of TTR deposits (e.g., TTR amyloidosis). The antibodies can also be used for diagnosing TTR amyloidosis and inhibiting or reducing aggregation of TTR, among other applications.
1. A method of treating a transthyretin-mediated amyloidosis in a subject having the amyloidosis, comprising administering to the subject a therapeutically effective regime of a humanized, veneered or chimeric antibody that specifically binds transthyretin comprising three heavy chain CDRs of SEQ ID NO:1 and three light chain CDRs of SEQ ID NO:9 except that light chain position 55 by Kabat numbering can be cysteine (C) or serine (S).
2. The method of claim 1 , further comprising measuring aggregation of transthyretin in the subject or in a biological sample from the subject, wherein administering the antibody inhibits or reduces aggregation of transthyretin in the subject or in the biological sample from the subject.
3. The method of claim 1 , further comprising measuring transthyretin fibril formation in the subject or in a biological sample from the subject, wherein administering the antibody inhibits or reduces transthyretin fibril formation in the subject or in the biological sample from the subject.
4. The method of claim 1 , further comprising measuring transthyretin deposits in the subject or in a biological sample from the subject, wherein administering the antibody reduces transthyretin deposits in the subject or in the biological sample from the subject.
5. The method of claim 1 , further comprising measuring an amount of a non-toxic conformation of transthyretin in the subject or in a biological sample from the subject, wherein administering the antibody stabilizes a non-toxic conformation of transthyretin in the subject or in the biological sample from the subject.
6. The method of claim 1 , wherein the transthyretin-mediated amyloidosis is associated with a condition selected from cardiomyopathy or hypertrophy, familial amyloid polyneuropathy, central nervous system selective amyloidosis (CNSA), senile systemic amyloidosis, senile cardiac amyloidosis, spinal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age related macular degeneration, and a ligament or tendon disorder.
7. The method of claim 1 , wherein the transthyretin-mediated amyloidosis is a familial transthyretin amyloidosis or a sporadic transthyretin amyloidosis.
8. The method of claim 7 , wherein the familial transthyretin amyloidosis is familial amyloid cardiomyopathy (FAC), familial amyloid polyneuropathy (FAP), or central nervous system selective amyloidosis (CNSA).
9. The method of claim 7 , wherein the sporadic transthyretin amyloidosis is senile systemic amyloidosis (SSA) or senile cardiac amyloidosis (SCA).
10. The method of claim 1 , wherein the transthyretin-mediated amyloidosis is associated with amyloid accumulation in the heart, peripheral nervous system, autonomic nervous system, kidneys, eyes, or gastrointestinal tract of the subject.
11. The method of claim 1 , wherein the antibody comprises three Kabat heavy chain CDRs of SEQ ID NOS: 6-8, respectively and three light CDRs of SEQ ID NOS: 14, 15, and 17, respectively except that light chain position 55 by Kabat numbering can be C or S.
12. The method of claim 11 , wherein the antibody comprises a composite Kabat-Chothia CDR-H1 of SEQ ID NO:52.
13. The method of claim 1 , wherein the antibody has human IgG1 isotype.
14. The method of claim 1 , wherein the antibody has human IgG2 or IgG4 isotype.
15. The method of claim 1 , wherein the antibody comprises a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:4 or 5 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO: 12 or 13.
16. The method of claim 15 , wherein at least one of the following positions of the antibody by Kabat numbering is occupied by the amino acid as specified: heavy chain position 29 is occupied by phenylalanine (F), heavy chain position 93 is occupied by valine (V), light chain position 55 is occupied by S, and light chain position 85 is occupied by V.
17. The method of claim 15 , wherein at least two of the following positions of the antibody by Kabat numbering are occupied by the amino acid as specified: heavy chain position 29 is occupied by F, heavy chain position 93 is occupied by V, light chain position 55 is occupied by S, and light chain position 85 is occupied by V.
18. The method of claim 15 , wherein at least three of the following positions of the antibody by Kabat numbering are occupied by the amino acid as specified: heavy chain position 29 is occupied by F, heavy chain position 93 is occupied by V, light chain position 55 is occupied by S, and light chain position 85 is occupied by V.
19. The method of claim 15 , wherein all of the following positions of the antibody by Kabat numbering are occupied by the amino acid as specified: heavy chain position 29 is occupied by F, heavy chain position 93 is occupied by V, light chain position 55 is occupied by S, and light chain position 85 is occupied by V.
20. The method of claim 15 , wherein the antibody comprises a humanized mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:4 or 5 and a humanized mature light chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:12 or 13.
21. The method of claim 20 , wherein the antibody comprises a humanized mature heavy chain variable region having an amino acid sequence at least 98% identical to SEQ ID NO:4 or 5 and a humanized mature light chain variable region having an amino acid sequence at least 98% identical to SEQ ID NO:12 or 13.
22. The method of claim 15 , wherein the antibody comprises a humanized mature heavy chain variable region of SEQ ID NO:4 and a humanized mature light chain variable region of SEQ ID NO:12.
23. The method of claim 15 , wherein the antibody comprises a mature heavy chain variable region of SEQ ID NO:4 and a humanized mature light chain variable region of SEQ ID NO:13.
24. The method of claim 15 , wherein the antibody comprises a humanized mature heavy chain variable region of SEQ ID NO:5 and a humanized mature light chain variable region of SEQ ID NO:12.
25. The method of claim 15 , wherein the antibody comprises a humanized mature heavy chain variable region of SEQ ID NO:5 and a humanized mature light chain variable region of SEQ ID NO:13.
26. The method of claim 1 , wherein the antibody is an intact antibody.
27. The method of claim 1 , wherein the antibody is a binding fragment.
28. The method of claim 27 , wherein the binding fragment is a single-chain antibody, Fab, or F(ab′) 2 fragment.
29. The method of claim 1 , wherein a mature light chain variable region of the antibody is fused to a light chain constant region and a mature heavy chain variable region of the antibody is fused to a heavy chain constant region.
30. The method of claim 29 , wherein the heavy chain constant region is a mutant form of a natural human heavy chain constant region which has reduced binding to a Fcγ receptor relative to the natural human heavy chain constant region.
31. The method of claim 29 wherein the heavy chain constant region is of IgG1 isotype.
32. The method of claim 31 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the sequence of SEQ ID NO:23 with or without the C-terminal lysine and/or the mature light chain variable region is fused to a light chain constant region having the sequence of SEQ ID NO:25.
33. A method of treating a subject having a transthyretin-mediated amyloidosis associated with a condition selected from cardiomyopathy or hypertrophy, familial amyloid polyneuropathy, central nervous system selective amyloidosis (CNSA), senile systemic amyloidosis, senile cardiac amyloidosis, spinal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age related macular degeneration, and a ligament or tendon disorder, the method comprising administering to the subject a therapeutically effective regime of a humanized, veneered or chimeric antibody that specifically binds transthyretin comprising three heavy chain CDRs of SEQ ID NO:1 and three light chain CDRs of SEQ ID NO:9 except that light chain position 55 by Kabat numbering can be cysteine (C) or serine (S).