Treatment and prophylaxis of amyloidosis

Abstract

Methods useful for effecting prophylaxis or treatment of amyloidosis, including AA Amyloidosis and AL amyloidosis, by administering peptides comprising neoepitopes, such as AA fragments from a C-terminal region of AA, and antibodies specific for neoepitopes of aggregated amyloid proteins, for example, antibodies specific for the C-terminal region of AA fibrils. Antibodies for inhibition of formation and/or increasing clearance of amyloid deposits in a patient thus effecting prophylaxis or treating amyloid disease.

What is claimed is: 
     
         1 . An isolated human, humanized, or chimeric antibody, or antigen-binding fragment thereof, that specifically binds to an epitope within residues 70-76 of human amyloid A peptide. 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , which specifically binds to an epitope within residues 70-76 of SEQ ID NO: 2. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , which specifically binds to an epitope comprising residues set forth as SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, or 11. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , which competes for binding to human amyloid A peptide with antibody 2A4 produced by ATCC Accession Number ______. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 1 , which competes for binding to human amyloid A peptide with an antibody having a light chain variable region set forth as residues 20-131 of SEQ ID NO: 152 and a heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 1 , which competes for binding to human amyloid A peptide with antibody 7D8 produced by ATCC Accession Number ______. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 1 , which competes for binding to human amyloid A peptide with an antibody having a light chain variable region set forth as residues 20-131 of SEQ ID NO: 153 and a heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , which is a humanized or chimeric version of antibody 2A4 produced by ATCC Accession Number ______ or a humanized or chimeric version of antibody 7D8 produced by ATCC Accession Number ______. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 8 , which comprises a light chain variable region comprising one or more complementarity regions of a 2A4 light chain variable region set forth as residues 20-131 of SEQ ID NO: 152 or one or more complementarity regions of a 7D8 light chain variable region set forth as residues 20-131 of SEQ ID NO: 153. 
     
     
         10 . The antibody or antigen-binding fragment of  claim 9 , which comprises a light chain variable region comprising three complementarity regions of a 2A4 light chain variable region set forth as residues 20-131 of SEQ ID NO: 152 or three complementarity regions of a 7D8 light chain variable region set forth as residues 20-131 of SEQ ID NO: 153. 
     
     
         11 . The antibody or antigen-binding fragment of  claim 10 , which comprises at least one light chain framework residue selected from the group consisting of L87 and L90 (Kabat numbering convention) occupied by Y and F, respectively, wherein the remainder of the light chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin light chain variable region. 
     
     
         12 . The antibody or antigen-binding fragment of  claim 10 , which comprises at least one light chain framework residue selected from the group consisting of +7, +14, +15, +17, +18, +50, +75, +88, +92, and +109 (linear numbering) occupied by T, S, L, D, Q, K, Y, L, F, and L, respectively, wherein the remainder of the light chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin light chain variable region. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 12 , which comprises at least one light chain framework residue selected from the group consisting of +75 and +92 (linear numbering) occupied by Y and F, respectively, wherein the remainder of the light chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin light chain variable region. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 11 , wherein the human acceptor immunoglobulin light chain variable region is a human kappa subgroup 2 light chain variable region (Kabat convention). 
     
     
         15 . The antibody or antigen-binding fragment of  claim 14 , wherein the human subgroup 2 light chain variable region is from human germline VKIIA19/A3. 
     
     
         16 . The antibody or antigen-binding fragment of  claim 15 , wherein the human Vk light chain variable region comprises a sequence set forth as SEQ ID NO: 166 or 167. 
     
     
         17 . The antibody or antigen-binding fragment of  claim 8 , wherein the light chain variable region comprises an amino acid sequence set forth as residues 20-131 of SEQ ID NO: 152, residues 20-131 of SEQ ID NO: 153, or set forth as SEQ ID NO: 155, 156, 157, 158, 159, 160, 174, 175, or 176. 
     
     
         18 . The antibody or antigen-binding fragment of  claim 8 , which comprises a heavy chain variable region comprising one or more complementarity regions of a 2A4 heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         19 . The antibody or antigen-binding fragment of  claim 18 , which comprises a heavy chain variable region comprising two complementarity regions of a 2A4 heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         20 . The antibody or antigen-binding fragment of  claim 19 , which comprises a heavy chain variable region comprising three complementarity regions of a 2A4 heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         21 . The antibody or antigen-binding fragment of  claim 20 , which comprises at least one heavy chain framework residue selected from the group consisting of H37, H49, H70, and H93 (Kabat numbering convention) occupied by I, A, F, or V, respectively, wherein the remainder of the heavy chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin heavy chain variable region. 
     
     
         22 . The antibody or antigen-binding fragment of  claim 20 , which comprises at least one heavy chain framework residue selected from the group consisting of +10, +15, +19, +37, +49, +73, +78, +79, +80, +87, +95, +99, +119 (linear numbering) occupied by R, K, K, I, A, F, Q, S, M, N, M, V, or A, respectively, wherein the remainder of the heavy chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin heavy chain variable region. 
     
     
         23 . The antibody or antigen-binding fragment of  claim 22 , which comprises at least one heavy chain framework residue selected from the group consisting of +37, +49, +73, and +99 (linear numbering) occupied by I, A, F, or V, respectively, wherein the remainder of the heavy chain variable region is occupied by a corresponding residue in a human acceptor immunoglobulin heavy chain variable region. 
     
     
         24 . The antibody or antigen-binding fragment of  claim 21 , wherein the human acceptor immunoglobulin heavy chain variable region is a human gamma subgroup 3 heavy chain variable region (Kabat convention). 
     
     
         25 . The antibody or antigen-binding fragment of  claim 24 , wherein the human gamma subgroup 3 heavy chain variable region comprises a sequence set forth as SEQ ID NO: 165. 
     
     
         26 . The antibody or antigen-binding fragment of  claim 8 , wherein the heavy chain variable region comprises an amino acid sequence set forth as residues 20-138 of SEQ ID NO: 154 or set forth as SEQ ID NO: 161, 162, or 163. 
     
     
         27 . The antibody or antigen-binding fragment of  claim 8 , which comprises a light chain variable region comprising three complementarity determining regions of a 2A4 light chain variable region set forth as residues 20-131 of SEQ ID NO: 152 or three complementarity regions of a 7D8 light chain variable region set forth as residues 20-131 of SEQ ID NO: 153, and a heavy chain variable region comprising three complementarity regions of a 2A4 heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         28 . The antibody or antigen-binding fragment of  claim 8 , which comprises a light chain variable region comprising three complementarity determining regions set forth as SEQ ID NOs: 168, 169, and 170, and a heavy chain variable region comprising three complementarity regions set forth as SEQ ID NOs: 171, 172, and 173. 
     
     
         29 . The antibody or antigen-binding fragment of  claim 8 , which comprises a light chain variable region comprising three complementarity determining regions set forth as SEQ ID NOs: 177, 169, and 170, and a heavy chain variable region comprising three complementarity regions set forth as SEQ ID NOs: 171, 172, and 173. 
     
     
         30 . The antibody or antigen-binding fragment of  claim 27 , which comprises a light chain variable region comprising an amino acid sequence set forth as residues 20-131 of SEQ ID NO: 152 or residues 20-131 of SEQ ID NO: 153, and a heavy chain variable region comprises an amino acid sequence set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         31 . The antibody or antigen-binding fragment of  claim 27 , which comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 155, 156, 157, 158, 159, 160, 174, 175, or 176; and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 161, 162, or 163. 
     
     
         32 . The antibody or antigen-binding fragment of  claim 31 , wherein the light chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 155, and the heavy chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 161. 
     
     
         33 . The antibody or antigen-binding fragment of  claim 31 , wherein the light chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 156, and the heavy chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 162. 
     
     
         34 . The antibody or antigen-binding fragment of  claim 31 , wherein the light chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 157, and the heavy chain variable region comprises an amino acid sequence set forth as SEQ ID NO: 163. 
     
     
         35 . An isolated antibody, or antigen-binding fragment thereof, which specifically binds to an epitope comprising X 1 EDX 2  in an aggregated amyloid protein, wherein X 1  and X 2  are any amino acid. 
     
     
         36 . The antibody or antigen-binding fragment of  claim 35 , wherein X 1  is H, T, F, S, P, A, L, C, Q, R, E, K, D, G, V, Y, I, or W, and wherein X 2  is T, S, E, R, I, V, F, D, A, G, M, L, N, P, C, K, Y, or Q. 
     
     
         37 . The antibody or antigen-binding fragment of  claim 36 , wherein X 1  is H, T, F, or A. 
     
     
         38 . The antibody or antigen-binding fragment of  claim 36 , wherein X 2  is T, S, E, D, or A. 
     
     
         39 . The antibody or antigen-binding fragment of  claim 37 , wherein X 1  is H or A and X 2  is T, S, or A. 
     
     
         40 . The antibody or antigen-binding fragment of  claim 37 , wherein X 1  is T and X 2  is E. 
     
     
         41 . The antibody or antigen-binding fragment of  claim 37 , wherein X 1  is F and X 2  is D. 
     
     
         42 . The antibody or antigen-binding fragment of  claim 36 , wherein X 1  is S and X 2  is E, F or A. 
     
     
         43 . The antibody or antigen-binding fragment of  claim 36 , wherein X 1  is P and X 2  is E, I or F. 
     
     
         44 . The antibody or antigen-binding fragment of  claim 36 , wherein the epitope consists of an amino acid sequence selected from the group consisting of GHEDT (SEQ ID NO: 3), HEDT (SEQ ID NO: 12), AEDS (SEQ ID NO: 13), AEDT (SEQ ID NO: 14), HEDA (SEQ ID NO: 15), and TEDE (SEQ ID NO: 16). 
     
     
         45 . The antibody or antigen-binding fragment of  claim 44 , which specifically binds to an aggregated amyloid protein at an epitope comprising an amino acid sequence GHGAEDS (SEQ ID NO:4). 
     
     
         46 . The antibody or antigen-binding fragment of  claim 35 , wherein the antibody binds to the amyloid protein in monomeric form with an affinity of less than about 10 7  M −1 . 
     
     
         47 . The antibody or antigen-binding fragment of  claim 35 , wherein the amyloid protein is serum amyloid A protein (SAA). 
     
     
         48 . The antibody or antigen-binding fragment of  claim 35 , wherein the amyloid protein is selected from the group consisting of immunoglobulin light chain protein, human islet amyloid precursor polypeptide (IAPP), beta amyloid peptide, transthyretin (TTR) and ApoA1. 
     
     
         49 . The antibody or antigen-binding fragment of  claim 48 , wherein the amyloid protein is immunoglobulin light chain protein. 
     
     
         50 . The antibody or antigen-binding fragment of  claim 49 , wherein the immunoglobulin light chain protein is Vλ6 Wil. 
     
     
         51 . The antibody or antigen-binding fragment of  claim 49 , wherein the immunoglobulin light chain protein is Vκ. 
     
     
         52 . The antibody or antigen-binding fragment of  claim 48 , wherein the amyloid protein is human islet amyloid precursor polypeptide (IAPP). 
     
     
         53 . The antibody or antigen-binding fragment of  claim 48 , wherein the amyloid protein is beta amyloid peptide. 
     
     
         54 . The antibody or antigen-binding fragment of  claim 48 , wherein the amyloid protein is transthyretin (TTR). 
     
     
         55 . The antibody or antigen-binding fragment of  claim 48 , wherein the amyloid protein is ApoA1. 
     
     
         56 . The antibody or antigen-binding fragment of  claim 35 , which is a human, humanized, or chimeric antibody or antigen-binding fragment. 
     
     
         57 . The antibody or antigen-binding fragment of  claim 56 , which specifically binds to an epitope within residues 70-76 of human amyloid A peptide. 
     
     
         58 . A method of therapeutically treating a subject having AA amyloidosis, comprising administering to the subject an effective dosage of the antibody or antigen-binding fragment of  claim 1  to thereby treat AA amyloidosis in the subject. 
     
     
         59 . The method of  claim 58 , wherein the subject is a human. 
     
     
         60 . The method of  claim 58 , wherein therapeutically treating comprises slowing the progression of AA amyloidosis. 
     
     
         61 . The method of  claim 58 , wherein therapeutically treating comprising inhibiting deposition of AA amyloid fibril aggregates. 
     
     
         62 . The method of  claim 58 , wherein therapeutically treating comprises clearing of AA amyloid fibril aggregates. 
     
     
         63 . The method of  claim 58 , wherein the subject suffers from an amyloid disease selected from the group consisting of rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, Crohn's disease, leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, Whipple's disease, Hodgkin's lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, hairy cell leukemia, Familial Mediterranean Fever, and Castleman's Disease. 
     
     
         64 . A method of prophylactically treating a subject susceptible to AA amyloidosis, comprising administering to the subject an effective dosage of the antibody or antigen-binding fragment of  claim 1  to thereby effect prophylaxis of AA amyloidosis in the subject. 
     
     
         65 . The method of  claim 64 , wherein the subject is a human. 
     
     
         66 . The method of  claim 64 , wherein prophylactically treating is delaying onset of AA amyloidosis. 
     
     
         67 . The method of  claim 64 , wherein prophylactically treating is reducing a risk of AA amyloidosis. 
     
     
         68 . A method of therapeutically treating a subject suffering from an amyloidosis associated with an aggregated amyloid protein comprising the amino acid sequence ED, comprising administering to the subject an antibody or antigen-binding fragment of  claim 30  to thereby treat the amyloidosis. 
     
     
         69 . The method of  claim 68 , wherein the subject is a human. 
     
     
         70 . The method of  claim 68 , wherein therapeutically treating comprises slowing the progression of amyloidosis. 
     
     
         71 . The method of  claim 68 , wherein therapeutically treating comprises inhibiting deposition of amyloid fibril aggregates. 
     
     
         72 . The method of  claim 68 , wherein therapeutically treating comprises clearing of amyloid fibril aggregates. 
     
     
         73 . The method of  claim 68 , wherein the amyloid protein comprises the sequence AEDV (SEQ ID NO: 23), and the amyloidogenic disease is AA amyloidosis, AL amyloidosis, amyloid polyneuropathy, Mediterranean fever, Muckle-Wells syndrome, reactive systemic amyloidosis associated with systemic inflammatory diseases, myeloma or macroglobulinemia associated amyloidosis, amyloidosis associated with immunocyte dyscrasia, monoclonal gammopathy, occult dyscrasia, and local nodular amyloidosis associated with chronic inflammatory diseases. 
     
     
         74 . A method of prophylactically treating a subject susceptible to an amyloidosis associated with an aggregated amyloid protein comprising the amino acid sequence ED, comprising administering to the subject an antibody or antigen-binding fragment of  claim 30  to thereby treat the amyloidosis. 
     
     
         75 . A method of detecting an amyloid deposit associated with AA amyloidosis in a subject comprising administering to the subject an antibody or antigen-binding fragment of  claim 1  bound to a detectable label, and detecting the detectable label in the subject. 
     
     
         76 . The method of  claim 75 , wherein the subject is a human. 
     
     
         77 . The method of  claim 75 , wherein the subject suffers from or is susceptible to an amyloid disease selected from the group consisting of rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, Crohn's disease, leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, Whipple's disease, Hodgkin's lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, hairy cell leukemia, Familial Mediterranean Fever, and Castleman's Disease. 
     
     
         78 . The method of  claim 75 , wherein the detectable label is a radiolabel. 
     
     
         79 . The method of  claim 78 , wherein the radiolabel is  125 I. 
     
     
         80 . The method of  claim 75 , wherein the detecting is performed by SPECT/CT imaging. 
     
     
         81 . The method of  claim 75 , wherein the detecting is performed by NMR spectroscopy. 
     
     
         82 . A method of detecting an amyloid deposit in a subject comprising administering to the subject the antibody or antigen-binding fragment of  claim 30  that is bound to a detectable label and detecting the detectable label. 
     
     
         83 . The method of  claim 82 , wherein the subject is a human. 
     
     
         84 . The method of  claim 82 , wherein the amyloidosis is AA amyloidosis, AL amyloidosis, Alzheimer's disease, Mild Cognitive Impairment, amyloid polyneuropathy, Mediterranean fever, Muckle-Wells syndrome, reactive systemic amyloidosis associated with systemic inflammatory diseases, myeloma or macroglobulinemia associated amyloidosis, amyloidosis associated with immunocyte dyscrasia, monoclonal gammopathy, occult dyscrasia, or local nodular amyloidosis associated with chronic inflammatory diseases. 
     
     
         85 . The method of  claim 82 , wherein the detectable label is a radiolabel. 
     
     
         86 . The method of  claim 85 , wherein the radiolabel is  125 I. 
     
     
         87 . The method of  claim 82 , wherein the detecting is performed by SPECT/CT imaging. 
     
     
         88 . The method of  claim 82 , wherein the detecting is performed by NMR spectroscopy. 
     
     
         89 . A method of therapeutically treating a subject having AA amyloidosis, comprising administering an agent that induces an immune response to residues 70-76 of amyloid A peptide effective to induce an immune response comprising antibodies against residues 70-76 of an amyloid A peptide and thereby treat AA amyloidosis in the subject. 
     
     
         90 . A method of prophylactically treating a subject susceptible to AA amyloidosis, comprising administering an agent that induces an immune response to residues 70-76 of amyloid A peptide effective to induce an immune response comprising antibodies against residues 70-76 of an amyloid A peptide to thereby effect prophylaxis of AA amyloidosis in the subject.