JP2019532617A5 - - Google Patents

Claims (33)

Cardiomyopathy or cardiac hypertrophy, spinal canal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age-related macular degeneration, and ligaments in athletes or others performing extreme aerobic exercise or A pharmaceutical composition comprising an antibody for treating a subject having or at risk of any tendon disorder, said use comprising administering to said subject an effective amount of said antibody. It is to specifically bind to transthyretin and comprises three light chain CDR of the three heavy chain CDR and SEQ ID NO: 70 SEQ ID NO: 61, exceptionally positions H52 and L26 position is N or S, respectively Obtained, a pharmaceutical composition. The antibody comprises three Kabat heavy chain CDRs of CDR-H1 of SEQ ID NO:67, CDR-H2 of SEQ ID NO:68, and CDR-H3 of SEQ ID NO:69 , CDR-L1 of SEQ ID NO:77, CDR of SEQ ID NO:78. -L2, and includes a three Kabat light chain CDR of CDR-L3 of SEQ ID NO: 79, exceptionally positions and L26 position H52 can be a N or S, respectively, the pharmaceutical composition according to claim 1. The antibody, Kabat-Chothi a containing multiple polymer CDR-H1 (SEQ ID NO: 118) The pharmaceutical composition according to claim 1 or 2. 3. The pharmaceutical composition according to claim 1 or 2, wherein the antibody comprises the three Kabat heavy chain CDRs CDR-H1 of SEQ ID NO: 13, CDR-H2 of SEQ ID NO: 14, and CDR-H3 of SEQ ID NO: 15 . Before Symbol antibody comprises a Kabat-Chothi a double polymer CDR-H1 (SEQ ID NO: 117) The pharmaceutical composition according to claim 1, 2 or 4. The antibody is a monoclonal antibody, a pharmaceutical composition according to any one of claims 1-5. The antibody chimeric antibody, humanized antibody, or veneered (veneered) antibody, a pharmaceutical composition according to any one of claims 1-6. The antibody has a human IgG1 isotype, a pharmaceutical composition according to any one of claims 1-7. Wherein said antibody has a human IgG2 isotype or human IgG4 isotype, pharmaceutical composition according to any one of claims 1-7. The humanized antibody is at least 90% identical to any one of SEQ ID NOs: 19-23 with a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 5-12. A humanized mature light chain variable region having an amino acid sequence, with the exception that position H19 may be R or K, position H40 may be A or T, position H44 may be G or R, position H49. Can be S or A, H77 can be S or T, H82a can be N or S, H83 can be R or K, H84 can be A or S, and H89 The pharmaceutical composition according to claim 7, wherein the position can be V or M. In the humanized antibody all positions listed below are occupied by the specified amino acids, ie H 47 is occupied by L , H 108 is occupied by L and L 36 is occupied by F. The pharmaceutical composition according to claim 10 , which is The humanized antibody comprises a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOS:5-12 and an amino acid sequence at least 98% identical to any one of SEQ ID NOS:19-23. With the mature light chain variable region having an exception of H19 can be R or K, H40 can be A or T, H44 can be G or R, H49 can be S or A. H77 can be S or T, H82a can be N or S, H83 can be R or K, H84 can be A or S, and H89 can be V or The pharmaceutical composition according to claim 10 , which may be M. The mature heavy chain variable region of the humanized antibody has an amino acid sequence of any one of SEQ ID NOS: 5 to 12, and the mature light chain variable region of the humanized antibody is any of SEQ ID NOs: 19 to 23. The pharmaceutical composition according to claim 10 , which has one amino acid sequence. Mature heavy chain variable region of the humanized antibody has the amino acid sequence of SEQ ID NO: 11, and a mature light chain variable region of the humanized antibody has the amino acid sequence of SEQ ID NO: 19, as set forth in claim 13 Pharmaceutical composition . The humanized antibody is at least 90% identical to any one of SEQ ID NOs:74-76 with a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:64-66. A humanized mature light chain variable region having an amino acid sequence, with the exception that H82a can be N or S, H83 can be R or K, H84 can be A or S, H89. 8. The pharmaceutical composition according to claim 7 , wherein V can be V or M and L18 can be S or P. In the humanized antibody all positions listed below are occupied by the designated amino acids, ie H1 position is occupied by E, H47 position is occupied by L, L26 position is occupied by S, L36 position. 16. The pharmaceutical composition according to claim 15 , wherein is occupied by F and the L60 position is occupied by S. The humanized antibody comprises a mature heavy chain variable region having an amino acid sequence having at least 98% identity to any one of SEQ ID NOs: 64-66 and an amino acid sequence having at least 98% identity to any one of SEQ ID NOs: 74-76. And a mature light chain variable region having H.sub.82a at position N or S, H.sub.83 at position R or K, H.sub.84 at position A or S, and H.sub.89 at position V or M. in and obtained, and L18 position can be a S or P, pharmaceutical composition according to claim 15. The mature heavy chain variable region of the humanized antibody has any one of the amino acid sequences of SEQ ID NOs: 64-66, and the mature light chain variable region of the humanized antibody has any one of SEQ ID NOs: 74-76. The pharmaceutical composition according to claim 15 , having one amino acid sequence. Mature heavy chain variable region of the humanized antibody has the amino acid sequence of SEQ ID NO: 65, and a mature light chain variable region of the humanized antibody has the amino acid sequence of SEQ ID NO: 76, as set forth in claim 18 Pharmaceutical composition . Wherein the antibody is an intact antibody, a pharmaceutical composition according to any one of claims 1 to 19. Wherein the antibody is a binding fragment, a pharmaceutical composition according to any one of claims 1 to 19. 22. The pharmaceutical composition according to claim 21 , wherein the binding fragment is a single chain antibody fragment, a Fab fragment, or a Fab'2 fragment. Mature light chain variable region of the humanized antibody, is fused to the light chain constant region, and mature heavy chain variable region of the humanized antibody is fused to the heavy chain constant region, any of claims 7-20 The pharmaceutical composition according to item 1 . 24. The pharmaceutical composition of claim 23 , wherein the heavy chain constant region is a variant of the natural human heavy chain constant region that has reduced binding to Fcγ receptors as compared to the natural human heavy chain constant region. 25. The pharmaceutical composition according to claim 23 or 24 , wherein the heavy chain constant region is of the IgG1 isotype. The matured heavy chain variable region of the humanized antibody is fused to a heavy chain constant region having the sequence of SEQ ID NO: 103 with or without a C-terminal lysine , and/or the matured light chain variable region of the humanized antibody is 24. The pharmaceutical composition according to claim 23 fused to a light chain constant region having the sequence of SEQ ID NO: 104 or 105. A in vitro method for diagnosing a transthyretin mediated amyloidosis in a subject, see contains contacting an antibody that specifically binds a biological sample from said subject an effective amount of transthyretin, wherein The antibody comprises the three heavy chain CDRs of SEQ ID NO:61 and the three light chain CDRs of SEQ ID NO:70, with the exception that positions H52 and L26 may each be N or S, wherein said transthyretin-mediated amyloidosis Includes cardiomyopathy or cardiac hypertrophy, spinal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age-related macular degeneration in athletes or others performing extreme aerobic exercise, and A method associated with a condition selected from either ligament or tendon disorders . 28. The method of claim 27 , further comprising detecting binding of the antibody to transthyretin, wherein the presence of bound antibody indicates that the subject has transthyretin-mediated amyloidosis. Further comprising comparing binding of said antibody to said biological sample to binding of said antibody to a control sample, whereby increased binding of said antibody to said biological sample relative to said control sample is said subject 29. The method of claim 27 or 28 , wherein the method has transthyretin-mediated amyloidosis. 30. The method of claim 29 , wherein the biological sample and the control sample contain cells of the same tissue origin. The method according to any one of claims 27 to 30 , wherein the biological sample and/or the control sample is blood, serum, plasma, or solid tissue. 32. The method of claim 31 , wherein the solid tissue is from the heart, peripheral nervous system, autonomic nervous system, kidney, eye, or digestive tract. The transthyretin mediated amyloidosis, wherein the subject's heart, peripheral nervous system, autonomic nervous system, associated renal, ocular, or amyloid accumulation in the digestive tract, according to any one of claims 27-32 the method of.