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.

1 - 90 . (canceled) 
     
     
         91 . An antibody or antigen-binding fragment thereof comprising 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 and further comprising at least one of:   (a) a light chain framework residue selected from the group consisting of +7, +14, +15, +17, +18, +50, +75, +88, +92 and +109 of SEQ ID NO: 152 according to 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; and   (b) a heavy chain framework residue selected from the group consisting of +10, +15, +19, +37, +49, +73, +78, +79, +80, +87, +95, +99 and +119 of SEQ ID NO: 154 according to linear numbering occupied by R, K, K, I, A, F, Q, S, M, N, M, V, and 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.   
     
     
         92 . The antibody or antigen-binding fragment thereof of  claim 92 , wherein the antibody comprises a light chain variable region comprising at least one light chain framework residue selected from the group consisting of +75 and +92 of SEQ ID NO: 152 according to 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. 
     
     
         93 . The antibody or antigen-binding fragment thereof of  claim 91 , wherein the antibody comprises a heavy chain variable region comprising at least one heavy chain framework residue selected from the group consisting of +37, +49, +73 and +99 of SEQ ID NO:
 154 according to 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.   
     
     
         94 . The antibody or antigen-binding fragment thereof of  claim 92 , wherein the antibody comprises a heavy chain variable region comprising at least one heavy chain framework residue selected from the group consisting of +37, +49, +73 and +99 of SEQ ID NO:
 154 according to 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.   
     
     
         95 . The antibody or antigen-binding fragment thereof of  claim 91 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 155-157 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         96 . The antibody or antigen-binding fragment thereof of  claim 92 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 155-157 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         97 . The antibody or antigen-binding fragment thereof of  claim 93 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 155-157 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         98 . The antibody or antigen-binding fragment thereof of  claim 94 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 155-157 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         99 . The method of  claim 94 , wherein the antibody comprises a light chain variable region comprising SEQ ID NO: 157 and a heavy chain variable region comprising SEQ ID NO: 163. 
     
     
         100 . An antibody or antigen-binding fragment thereof comprising 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 and further comprising at least one of:
 (a) a light chain framework residue selected from the group consisting of +7, +14, +15, +17, +18, +50, +75, +88, +92 and +109 of SEQ ID NO: 152 according to 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; and   (b) a heavy chain framework residue selected from the group consisting of +10, +15, +19, +37, +49, +73, +78, +79, +80, +87, +95, +99 and +119 of SEQ ID NO: 154 according to linear numbering occupied by R, K, K, I, A, F, Q, S, M, N, M, V, and 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.   
     
     
         101 . The antibody or antigen-binding fragment thereof of  claim 100 , wherein the antibody comprises a light chain variable region comprising at least one light chain framework residue selected from the group consisting of +75 and +92 of SEQ ID NO: 152 according to 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. 
     
     
         102 . The antibody or antigen-binding fragment thereof of  claim 100 , wherein the antibody comprises a heavy chain variable region comprising at least one heavy chain framework residue selected from the group consisting of +37, +49, +73 and +99 of SEQ ID NO:
 154 according to 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.   
     
     
         103 . The antibody or antigen-binding fragment thereof of  claim 101 , wherein the antibody comprises a heavy chain variable region comprising at least one heavy chain framework residue selected from the group consisting of +37, +49, +73 and +99 of SEQ ID NO:
 154 according to 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.   
     
     
         104 . The antibody or antigen-binding fragment thereof of  claim 100 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 158-160 and 174-176 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         105 . The antibody or antigen-binding fragment thereof of  claim 101 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 158-160 and 174-176 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         106 . The antibody or antigen-binding fragment thereof of  claim 102 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 158-160 and 174-176 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         107 . The antibody or antigen-binding fragment thereof of  claim 103 , wherein the antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 158-160 and 174-176 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 161-163. 
     
     
         108 . The antibody or antigen-binding fragment thereof of  claim 107 , wherein the antibody comprises a light chain variable region comprising SEQ ID NO: 176 and a heavy chain variable region comprising SEQ ID NO: 163. 
     
     
         109 . An antibody or antigen-binding fragment thereof comprising 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 and a heavy chain variable region comprising three complementarity determining regions of a 2A4 heavy chain variable region set forth as residues 20-138 of SEQ ID NO: 154.