US2012321555A1PendingUtilityA1

Treatment and prophylaxis of amyloidosis

Assignee: SCHENK DALE BPriority: Dec 28, 2007Filed: Apr 30, 2012Published: Dec 20, 2012

Est. expiryDec 28, 2027(~1.5 yrs left)· nominal 20-yr term from priority

Inventors:Dale B. Schenk Peter A. Seubert Jonathan S. Wall Jose Saldanha

A61P 9/00A61P 7/00A61P 43/00A61P 35/02A61P 25/02A61P 25/28A61P 35/00A61P 31/06A61P 31/04A61P 29/00A61P 31/08A61P 25/00A61P 19/04A61P 17/06A61P 13/12A61P 11/00A61P 17/00A61P 1/04A61P 19/02A61P 17/02A61P 19/00C07K 2317/34A61K 49/16C07K 16/18C07K 2317/24C07K 2317/56Y10S530/809A61K 49/00C07K 2317/567C07K 2317/565A61K 39/0008A61K 2039/505C07K 2317/52A61K 51/1018C07K 2317/32C07K 2317/92A61K 39/395

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Claims

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.

Claims

exact text as granted — not AI-modified

1 - 90 . (canceled) 
     
     
         91 . A method of detecting an amyloid deposit in a subject comprising:
 (a) administering to the subject an antibody or antigen-binding fragment, which antibody or antigen-binding fragment 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 determining regions set forth as SEQ ID NOs: 171, 172, and 173, and which antibody or antigen-binding fragment is bound to a detectable label; and   (b) detecting the detectable label in the subject.   
     
     
         92 . The method of  claim 91 , wherein the amyloid deposit is characterized by the presence of amyloid A protein fibrils. 
     
     
         93 . The method of  claim 92 , wherein the subject suffers from or is susceptible to amyloid A amyloidosis associated with rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter&#39;s syndrome, Adult Still&#39;s disease, Bechet&#39;s syndrome, Crohn&#39;s disease, leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, Whipple&#39;s disease, Hodgkin&#39;s lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, hairy cell leukemia, Familial Mediterranean Fever, or Castleman&#39;s Disease. 
     
     
         94 . The method of  claim 91 , wherein the amyloid deposit is characterized by the presence of amyloid light chain-type (AL) protein fibrils. 
     
     
         95 . The method of  claim 94 , wherein the subject suffers from or is susceptible to amyloid AL amyloidosis 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. 
     
     
         96 . The method of  claim 95 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage. 
     
     
         97 . The method of  claim 96 , wherein the dyscrasia is a malignancy. 
     
     
         98 . The method of  claim 97 , wherein the malignancy is multiple myeloma. 
     
     
         99 . The method of  claim 91 , wherein the subject is a human. 
     
     
         100 . The method of  claim 91 , wherein the antibody or fragment is a monoclonal antibody, a murine antibody, 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. 
     
     
         101 . The method of  claim 100 , wherein the antibody or fragment is a chimeric or humanized antibody or fragment thereof. 
     
     
         102 . The method of  claim 101 , wherein the isotype of the chimeric or humanized antibody is human IgG1. 
     
     
         103 . The method of  claim 101 , wherein the antibody is a chimeric or humanized version of murine monoclonal antibody 2A4 (ATCC Accession Number PTA-9662). 
     
     
         104 . The method of  claim 103 , wherein the antibody comprises a light chain variable region set forth as any one of SEQ ID NOs: 155, 156, and 157, and a heavy chain variable region set forth as any one of SEQ ID NOs: 161, 162, and 163. 
     
     
         105 . The method of  claim 104 , wherein the antibody or antigen-binding fragment comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 157 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 163. 
     
     
         106 . The method of  claim 91 , wherein the antibody or antigen-binding fragment comprises a light chain variable region comprising an amino acid sequence set forth as residues 20-131 of SEQ ID NO: 152 and a heavy chain variable region comprising an amino acid sequence set forth as residues 20-138 of SEQ ID NO: 154. 
     
     
         107 . The method of  claim 91 , wherein the antibody is murine monoclonal antibody 2A4 (ATCC Accession Number PTA-9662). 
     
     
         108 . The method of  claim 91 , wherein the antibody or antigen-binding fragment binds to monomeric amyloid protein with an affinity of less than about 10 7  M −1 . 
     
     
         109 . The method of  claim 91 , wherein the detectable label is a radiolabel. 
     
     
         110 . The method of  claim 107 , wherein the radiolabel is  125 I. 
     
     
         111 . The method of  claim 91 , wherein the detecting is performed by SPECT/CT imaging. 
     
     
         112 . The method of  claim 91 , wherein the detecting is performed by NMR spectroscopy. 
     
     
         113 . A method of detecting an amyloid deposit characterized by the presence of amyloid light chain-type (AL) protein fibrils in a subject comprising:
 (a) 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, or R, and wherein X 2  is T, S, E, R, I, F, D, A, G, M, L, N, or P; and   (b) detecting the detectable label in the subject.   
     
     
         114 . The method of  claim 113 , wherein the subject suffers from or is at risk for AL amyloidosis associate 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. 
     
     
         115 . The method of  claim 114 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage. 
     
     
         116 . The method of  claim 115 , wherein the dyscrasia is a malignancy. 
     
     
         117 . The method of  claim 116 , wherein the malignancy is multiple myeloma. 
     
     
         118 . The method of  claim 113 , wherein the subject is a human. 
     
     
         119 . The method of  claim 113 , wherein the antibody or fragment is a monoclonal antibody, a murine antibody, 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. 
     
     
         120 . The method of  claim 119 , wherein the antibody or fragment is a chimeric or humanized antibody or fragment thereof. 
     
     
         121 . The method of  claim 113 , wherein the antibody or antigen-binding fragment binds to monomeric amyloid protein with an affinity of less than about 10 7  M −1 . 
     
     
         122 . The method of  claim 113 , 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. 
     
     
         123 . The method of  claim 113 , wherein the detectable label is a radiolabel. 
     
     
         124 . The method of  claim 123 , wherein the radiolabel is  125 I. 
     
     
         125 . The method of  claim 113 , wherein the detecting is performed by SPECT/CT imaging. 
     
     
         126 . The method of  claim 113 , wherein the detecting is performed by NMR spectroscopy. 
     
     
         127 . A method of detecting an amyloid deposit is characterized by the presence of amyloid light chain-type (AL) protein fibrils in a subject comprising:
 (a) 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; and   (b) detecting the detectable label in the subject.   
     
     
         128 . The method of  claim 127 , wherein the subject suffers from or is at risk for AL amyloidosis associate 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. 
     
     
         129 . The method of  claim 128 , wherein the AL amyloidosis is associated with a dyscrasia of the B lymphocyte lineage. 
     
     
         130 . The method of  claim 129 , wherein the dyscrasia is a malignancy. 
     
     
         131 . The method of  claim 130 , wherein the malignancy is multiple myeloma. 
     
     
         132 . The method of  claim 127 , wherein the subject is a human. 
     
     
         133 . The method of  claim 127 , wherein the antibody or fragment is a monoclonal antibody, a murine antibody, 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. 
     
     
         134 . The method of  claim 133 , wherein the antibody or fragment is a chimeric or humanized antibody or fragment thereof. 
     
     
         135 . The method of  claim 127 , wherein the antibody or antigen-binding fragment binds to monomeric amyloid protein with an affinity of less than about 10 7  M −1 . 
     
     
         136 . The method of  claim 127 , 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. 
     
     
         137 . The method of  claim 127 , wherein the detectable label is a radiolabel. 
     
     
         138 . The method of  claim 137 , wherein the radiolabel is  125 I. 
     
     
         139 . The method of  claim 127 , wherein the detecting is performed by SPECT/CT imaging. 
     
     
         140 . The method of  claim 127 , wherein the detecting is performed by NMR spectroscopy.

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