TREATMENT AND PROPHYLAXIS OF AMYLOIDOSIS
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 an amino acid sequence set forth as SEQ ID NO: 157 and comprising a 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.