Antibodies that recognize IAPP
The invention provides monoclonal antibody 3H6 and related antibodies. The 3H6 antibody binds to an epitope within residues 28-36 of IAPP. The antibodies of the invention are useful, for example, for treating disorders associated with IAPP accumulation, particularly accumulation of IAPP deposits. Such disorders include type 2 diabetes, metabolic syndrome, impaired insulin tolerance, impaired glucose tolerance, insulinomas, and related conditions.
1. An isolated monoclonal antibody that specifically binds to human IAPP comprising a mature heavy chain variable region comprising CDR1, CDR2 and CDR3 of SEQ ID NO: 14 and a mature light chain variable region comprising Kabat CDR1, CDR2 and CDR3 of SEQ ID NO: 25.
2. The antibody of claim 1 that is chimeric, veneered, or humanized.
3. The antibody of claim 1 , wherein the antibody is a single-chain Fv antibody or a Fab fragment.
4. The antibody of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 90% identical to H1 (SEQ ID NO: 14) and the mature light chain variable region has an amino acid sequence at least 90% identical to L1 (SEQ ID NO: 25).
5. The antibody of claim 4 , comprising Kabat CDR1, CDR2 and CDR3 of SEQ ID NO: 14 and Kabat CDR1, CDR2 and CDR3 of SEQ ID NO: 20.
6. The antibody of claim 5 , provided at least one of positions H1, H41, H78 and H94 is occupied by E, P, V and I, respectively, and at least one of positions L36, L45, and L86 is occupied by L, K, and H, respectively, wherein positions are defined by Kabat numbering.
7. The antibody of claim 6 , provided positions H1, H41, H78 and H94 are occupied by E, P, V and I, respectively, and positions L36, L45, and L86 are occupied by L, K, and H, respectively.
8. The antibody of claim 6 , provided positions H1 and H41 are occupied by E and P, respectively, and positions L36 and L45 are occupied by L and K, respectively, wherein positions are defined by Kabat numbering.
9. The antibody of claim 8 , provided position H94 defined by Kabat numbering is occupied by I.
10. The antibody of claim 9 , provided position H78 defined by Kabat numbering is occupied by V.
11. The antibody of claim 10 , provided position L86 defined by Kabat numbering is occupied by H.
12. The antibody of claim 4 , wherein the mature heavy chain variable region has an amino acid sequence at least 95% identical to H1 (SEQ ID NO: 14) and the mature light chain variable region has an amino acid sequence at least 95% identical to L1 (SEQ ID NO: 25).
13. The antibody of claim 4 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.
14. The antibody of claim 13 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the sequence of SEQ ID NO: 34 and/or the mature light chain variable region is fused to a light chain constant region having the sequence of SEQ ID NO: 36.
15. The antibody of 22 or 26, wherein the mature heavy chain variable region has an amino acid sequence designated H1 (SEQ ID NO: 14) and the mature light chain variable region has an amino acid sequence designated L1 (SEQ ID NO: 25).
16. The antibody of claim 4 , wherein the mature heavy chain variable region has an amino acid sequence designated H2 (SEQ ID NO: 15) and the mature light chain variable region has an amino acid sequence designated L1 (SEQ ID NO: 25).
17. The antibody of claim 4 , wherein the mature heavy chain variable region has an amino acid sequence designated H3 (SEQ ID NO: 16) and the mature light chain variable region has an amino acid sequence designated L2 (SEQ ID NO: 26).
18. The antibody of claim 13 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the sequence of SEQ ID NO: 34, 69, or 70 and/or the mature light chain variable region is fused to a light chain constant region having the sequence of SEQ ID NO: 36 or 72.
19. A pharmaceutical composition comprising an antibody as defined in claim 1 and a pharmaceutically-acceptable carrier.