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. An antibody specifically binding human transthyretin, comprising a heavy chain and a light chain, wherein the heavy chain comprises a mature heavy chain variable region having the amino acid sequence of SEQ ID NO:9, and wherein the light chain comprises a mature light chain variable region having the amino acid sequence of SEQ ID NO:17.
2. 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.
3. The antibody of claim 2 , 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.
4. The antibody of claim 2 , wherein the heavy chain constant region is of IgG1 isotype.
5. The antibody of claim 2 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the amino acid sequence of any one of SEQ ID NOS:25-27, with or without the C-terminal lysine, and the mature light chain variable region is fused to a light chain constant region having the amino acid sequence of SEQ ID NO:28.
6. The antibody of claim 2 , wherein the mature heavy chain variable region fused to a heavy chain constant region comprises the amino acid sequence of SEQ ID NO:35 with or without the C-terminal lysine and the mature light chain variable region fused to a light chain constant region comprises the amino acid sequence of SEQ ID NO:37.
7. The antibody of claim 1 , wherein a heavy chain signal peptide is linked to the mature heavy chain variable region and a light chain signal peptide is linked to the mature light chain variable region.
8. The antibody of claim 7 , wherein the heavy chain signal peptide comprises the amino acid sequence of SEQ ID NO:49 and the light chain signal peptide comprises the amino acid sequence of SEQ ID NO: 51.
9. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
10. A nucleic acid encoding the heavy chain and light chain of the antibody of claim 1 .
11. The nucleic acid of claim 10 , wherein the mature heavy chain variable region is encoded by the nucleotide sequence of SEQ ID NO:60 and the mature light chain variable region is encoded by the nucleotide sequence of SEQ ID NO:62.
12. A nucleic acid encoding the antibody of claim 2 , wherein the heavy chain constant region is encoded by the nucleotide sequence of SEQ ID NO:46 and the light chain constant region is encoded by the nucleotide sequence of SEQ ID NO:47.
13. The nucleic acid of claim 10 , wherein the nucleic acid further encodes signal peptides fused to the mature heavy and light chain variable regions.
14. The nucleic acid of claim 13 , wherein the heavy chain signal peptide is encoded by the nucleotide sequence of SEQ ID NO:50 and the light chain signal peptide is encoded by the nucleotide sequence of SEQ ID NO:52.
15. A recombinant expression vector comprising the nucleic acid of claim 10 .
16. A host cell transformed with the recombinant expression vector of claim 10 .
17. 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 .
18. A method of producing a cell line producing an antibody, the method comprising: (a) introducing a vector encoding heavy and light chains of the antibody and a selectable marker into cells; (b) propagating the cells under conditions to select for cells having increased copy number of the vector; (c) isolating single cells from the selected cells; and (d) banking cells cloned from a single cell selected based on yield of antibody, wherein the antibody is the antibody of claim 1 .