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. A method of therapeutically treating a human patient having AL amyloidosis characterized by the presence of amyloid light chain-type (AL) protein fibrils comprising administering to the patient an effective dosage of an antibody or fragment thereof that specifically binds to an epitope comprising X 1 EDX 2 in an aggregated AL protein, wherein X 1 is H, T, S, P, A, L, C, Q, R, or E, and wherein X 2 is T, S, E, R, I, F, A, G, M, L, N, or P, to thereby treat AL amyloidosis.
2. The method of claim 1 , 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.
3. The method of claim 2 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage.
4. The method of claim 3 , wherein the dyscrasia is a malignancy.
5. The method of claim 4 , wherein the malignancy is multiple myeloma.
6. The method of claim 1 , wherein the antibody or fragment thereof specifically binds to an epitope comprising an amino acid sequence AEDS (SEQ ID NO: 13) in an aggregated AL protein.
7. The method of claim 1 , wherein the antibody or fragment thereof is a chimeric antibody, a human antibody, a humanized antibody, a single chain antibody, a tetrameric antibody, a tetravalent antibody, a multispecific antibody, a domain-specific antibody, a domain-deleted antibody, a fusion protein, a Fab fragment, a Fab' fragment, a F(ab') 2 fragment, a Fv fragment, or a ScFv fragment.
8. The method of claim 7 , wherein the antibody or fragment thereof is a chimeric or humanized antibody or fragment thereof.
9. The method of claim 1 , wherein the antibody or fragment thereof binds to monomeric AL protein with an affinity of less than about 10 7 M −1 .
10. A method of therapeutically treating a human patient having AL amyloidosis characterized by the presence of amyloid light chain-type (AL) protein fibrils comprising administering to the patient an effective dosage of an antibody raised to a peptide comprising GHEDT (SEQ ID NO: 3), or a fragment of the antibody, to thereby treat AL amyloidosis.
11. The method of claim 10 , wherein the antibody or fragment thereof is a chimeric antibody, a human antibody, a humanized antibody, a single chain antibody, a tetrameric antibody, a tetravalent antibody, a multispecific antibody, a domain-specific antibody, a domain-deleted antibody, a fusion protein, a Fab fragment, a Fab' fragment, a F(ab') 2 fragment, a Fv fragment, or a ScFv fragment.
12. The method of claim 11 , wherein the antibody or fragment thereof is a chimeric or humanized antibody or fragment thereof.
13. The method of claim 10 , wherein the antibody or fragment thereof binds to monomeric AL protein with an affinity of less than about 10 7 M −1 .
14. A method of therapeutically treating a human patient having AL amyloidosis characterized by the presence of amyloid light chain-type (AL) protein fibrils comprising administering to the patient an effective dosage of an antibody 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.
15. A method of therapeutically treating a human patient having AL amyloidosis characterized by the presence of amyloid light chain-type (AL) protein fibrils comprising administering to the patient an effective dosage of an antibody, which is a humanized version of murine monoclonal antibody 2A4 produced by ATCC Accession Number PTA-9662.
16. A method of reducing risk or delaying onset of AL amyloidosis characterized by the presence of amyloid light chain-type protein fibrils in a human patient at risk of AL amyloidosis comprising administering to the patient an effective dosage of an antibody 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.
17. A method of reducing risk or delaying onset of AL amyloidosis characterized by the presence of amyloid light chain-type protein fibrils in a human patient at risk of AL amyloidosis comprising administering to the patient an effective dosage of an antibody, which is a humanized version of murine monoclonal antibody 2A4 produced by ATCC Accession Number PTA-9662.