Anti-transthyretin antibodies
The invention provides antibodies that specifically bind 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. An antibody that binds to human transthyretin comprising a mature heavy chain variable region comprising three heavy chain CDRs comprising the amino acid sequences of SEQ ID NOS:67-69 respectively, and a mature light chain variable region comprising three light chain CDRs comprising the amino acid sequences of SEQ ID NOS:80, 78 and 79, respectively.
2. The antibody of claim 1 , wherein the antibody has a human IgG1 isotype.
3. The antibody of claim 1 , wherein the antibody has a human IgG2 or IgG4 isotype.
4. The antibody of claim 1 , wherein the antibody is an intact antibody.
5. The antibody of claim 1 , wherein the antibody is a binding fragment.
6. The antibody of claim 5 , wherein the binding fragment is a single-chain antibody, Fab, or F(ab′) 2 fragment.
7. The antibody of claim 1 , wherein the mature light chain variable region is fused to a light chain constant region and the mature heavy chain variable region is fused to a heavy chain constant region.
8. The antibody of claim 7 , wherein the heavy chain constant region is a mutant form of a natural human heavy chain constant region which has reduced binding to an Fcγ receptor relative to the natural human heavy chain constant region.
9. The antibody of claim 7 , wherein the heavy chain constant region is of an IgG1 isotype.
10. The antibody of claim 7 , wherein the heavy chain comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:65 fused to a heavy chain constant region comprising the amino acid sequence of SEQ ID NO:101, 102, or 103, with or without the C-terminal lysine, and wherein the light chain comprises a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:76 fused to a light chain constant region comprising the amino acid sequence of SEQ ID NO:105.
11. The antibody of claim 7 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:82 with or without the C-terminal lysine and the light chain comprises the amino acid sequence of SEQ ID NO:86.
12. The antibody of claim 7 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:103 with or without the C-terminal lysine and/or the light chain constant region comprises the amino acid sequence of SEQ ID NO:105.
13. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
14. A nucleic acid encoding the heavy chain and light chain of the antibody in claim 1 .
15. The nucleic acid of claim 14 , wherein the nucleic acid encoding the mature heavy chain variable region comprises the nucleic acid sequence of SEQ ID NO:92, the nucleic acid encoding the heavy chain constant region comprises the nucleic acid sequence of SEQ ID NO:106, the nucleic acid encoding the mature light chain variable region comprises the nucleic acid sequence of SEQ ID NO:96, and the nucleic acid encoding the light chain constant region comprises the nucleic acid sequence of SEQ ID NO:108.
16. A recombinant expression vector comprising the nucleic acid of claim 14 .
17. A host cell transformed with the recombinant expression vector of claim 16 .
18. A method of producing an antibody, the method comprising: (a) culturing cells transformed with nucleic acids encoding the heavy and light chains of the antibody, so that the cells secrete the antibody; and (b) purifying the antibody from cell culture media; wherein the antibody is the antibody of claim 1 .
19. A method of treating a transthyretin-mediated amyloidosis in a subject, comprising administering to the subject an effective regime of the antibody of claim 1 .
20. A method of treating a subject having any of 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 an effective regime of the antibody of claim 1 .