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 . A method of treating a human patient having AL amyloidosis comprising administering to the patient an effective dosage of an antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 157 and comprising the heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 163. 
     
     
         92 . The method of  claim 92 , wherein the AL amyloidosis is associated with peripheral or autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasia, myeloma, monoclonal gammopathy, occult dyscrasia, or a chronic inflammatory disease. 
     
     
         93 . The method of  claim 92 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage. 
     
     
         94 . The method of  claim 93 , wherein the dyscrasia is a malignancy. 
     
     
         95 . The method of  claim 94 , wherein the malignancy is multiple myeloma. 
     
     
         96 . A method of treating a human patient having AL amyloidosis comprising administering to the patient an effective dosage of an antibody or antigen-binding fragment thereof comprising:
 (a) a light chain variable region comprising three complementarity determining regions set forth as SEQ ID NOs: 168, 169, and 170, and further comprising 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) of SEQ ID NO: 152 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 variable region comprising three complementarity regions set forth as SEQ ID NOs: 171, 172, and 173, and further comprising 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 and +119 (linear numbering) of SEQ ID NO: 154 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.   
     
     
         97 . The method of  claim 96 , 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 (linear numbering) of SEQ ID NO: 152 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. 
     
     
         98 . The method of  claim 96 , 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 (linear numbering) of SEQ ID NO: 154 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. 
     
     
         99 . The method of  claim 98 , 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 (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. 
     
     
         100 . The method of  claim 96 , wherein the AL amyloidosis is associated with peripheral or autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasia, myeloma, monoclonal gammopathy, occult dyscrasia, or a chronic inflammatory disease. 
     
     
         101 . The method of  claim 100 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage. 
     
     
         102 . The method of  claim 101 , wherein the dyscrasia is a malignancy. 
     
     
         103 . The method of  claim 102 , wherein the malignancy is multiple myeloma.