Prevention and treatment of amyloidogenic diseases

Abstract

Disclosed are pharmaceutical compositions and methods for preventing or treating a number of amyloid diseases, including Alzheimer's disease, prion diseases, familial amyloid neuropathies and the like. The pharmaceutical compositions include immunologically reactive amounts of amyloid fibril components, particularly fibril-forming peptides or proteins. Also disclosed are therapeutic compositions and methods which use immune reagents that react with such fibril components.

1 - 57 . (canceled) 
     
     
         58 . A method of therapeutically treating an amyloid disease in a patient comprising administering to the patient an agent effective to produce an immune response comprising antibodies against an amyloid component or precursor to thereby treat the amyloid disease. 
     
     
         59 . The method of  claim 58 , wherein the amyloid disease is associated with a preexisting or coexisting inflammatory disease or condition, an infection, a neoplasm, or a lymphoproliferative disorder. 
     
     
         60 . The method of  claim 59 , wherein the inflammatory disease or condition is rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, or Crohn's disease. 
     
     
         61 . The method of  claim 59 , wherein the infection is leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, or Whipple's disease. 
     
     
         62 . The method of  claim 59 , wherein the neoplasm is Hodgkin's lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, or hairy cell leukemia. 
     
     
         63 . The method of  claim 58 , wherein the amyloid disease is associated with a heredofamilial amyloidosis. 
     
     
         64 . The method of  claim 58 , wherein the agent is selected from AA, AL, ATTR, AApoAl, Agel, Acys, Aβ, AB 2 M, AScr, Acal, AIAPP and synuclein-NAC fragment. 
     
     
         65 . The method of  claim 58 , wherein the agent is linked to a carrier molecule. 
     
     
         66 . The method of  claim 65 , wherein the carrier molecule is a T-cell epitope. 
     
     
         67 . The method of  claim 65 , wherein the carrier molecule is a tetanus toxoid epitope. 
     
     
         68 . The method of  claim 65 , wherein the carrier molecule is a diphtheria toxoid epitope. 
     
     
         69 . The method of  claim 58 , wherein the immune response is characterized by a serum titer of the antibodies of at least 1:1000 with respect to the amyloid component. 
     
     
         70 . The method of  claim 58 , wherein the immune response is characterized by a serum titer of the antibodies against the amyloid component that is greater than about four times higher than a serum titer of antibodies measured in a pre-treatment control serum sample. 
     
     
         71 . The method of  claim 58 , further comprising the step of administering an adjuvant that augments the immune response. 
     
     
         72 . The method of  claim 71 , wherein the adjuvant is QS21, monophosphoryl lipid, or alum. 
     
     
         73 . The method of  claim 58 , wherein the amyloid component or precursor is selected from the group consisting of Serum Amyloid A protein (ApoSSA), immunoglobulin light chain, immunoglobulin heavy chain, ApoAl, transthyretin, lysozyme, fibrogen α chain, gelsolin, cystatin C, Amyloid α protein precursor (P-APP), Beta 2  microglobulin, prion precursor protein (PrP), atrial natriuretic factor, keratin, islet amyloid polypeptide, a peptide hormone, synuclein and fragments thereof. 
     
     
         74 . The method of  claim 58 , wherein the amyloid component is a fibril amyloid component. 
     
     
         75 . The method of  claim 58 , whereby deposition of amyloid component fibril aggregates is inhibited. 
     
     
         76 . The method of  claim 58 , whereby amyloid component fibril aggregates are cleared. 
     
     
         77 . The method of  claim 58 , whereby progression of the amyloid disease is delayed. 
     
     
         78 . A method of reducing risk or delaying onset of amyloid disease in a patient at risk of amyloid disease comprising administering to the patient an agent, which produces an immune response comprising antibodies against an amyloid component or precursor, to thereby effect prophylaxis of the amyloid disease. 
     
     
         79 . The method of  claim 78 , wherein the patient has or is at risk for an amyloid disease associated with an inflammatory disease or condition, an infection, a neoplasm, or a lymphoproliferative disorder. 
     
     
         80 . The method of  claim 79 , wherein the inflammatory disease or condition is rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, or Crohn's disease. 
     
     
         81 . The method of  claim 79 , wherein the infection is leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, or Whipple's disease. 
     
     
         82 . The method of  claim 79 , wherein the neoplasm is Hodgkin's lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, or hairy cell leukemia. 
     
     
         83 . The method of  claim 78 , wherein the patient has or is at risk for an amyloid disease associated with a heredofamilial amyloidosis. 
     
     
         84 . The method of  claim 78 , wherein the agent is selected from AA, AL, ATTR, AApoAl, Agel, Acys, Aβ, AB 2 M, AScr, Acal, AIAPP and synuclein-NAC fragment. 
     
     
         85 . The method of  claim 78 , wherein the agent is linked to a carrier molecule. 
     
     
         86 . The method of  claim 85 , wherein the carrier molecule is a T-cell epitope. 
     
     
         87 . The method of  claim 85 , wherein the carrier molecule is a tetanus toxoid epitope. 
     
     
         88 . The method of  claim 85 , wherein the carrier molecule is a diphtheria toxoid epitope. 
     
     
         89 . The method of  claim 78 , wherein the immune response is characterized by a serum titer of the antibodies of at least 1:1000 with respect to the amyloid component. 
     
     
         90 . The method of  claim 78 , wherein the immune response is characterized by a serum titer of the antibodies against the amyloid component that is greater than about four times higher than a serum titer of antibodies measured in a pre-treatment control serum sample. 
     
     
         91 . The method of  claim 78 , further comprising the step of administering an adjuvant that augments the immune response. 
     
     
         92 . The method of  claim 91 , wherein the adjuvant is QS21, monophosphoryl lipid, or alum. 
     
     
         93 . The method of  claim 78 , wherein the amyloid component or precursor is selected from the group consisting of Serum Amyloid A protein (ApoSSA), immunoglobulin light chain, immunoglobulin heavy chain, ApoAl, transthyretin, lysozyme, fibrogen α chain, gelsolin, cystatin C, Amyloid α protein precursor (P-APP), Beta 2  microglobulin, prion precursor protein (PrP), atrial natriuretic factor, keratin, islet amyloid polypeptide, a peptide hormone, synuclein and fragments thereof. 
     
     
         94 . The method of  claim 78 , wherein the amyloid component is a fibril amyloid component. 
     
     
         95 . The method of  claim 78 , whereby deposition of amyloid component fibril aggregates is inhibited. 
     
     
         96 . The method of  claim 78 , whereby amyloid component fibril aggregates are cleared. 
     
     
         97 . A method of therapeutically treating an amyloid disease in a patient comprising administering to the patient an effective dosage of an antibody or antigen-binding fragment thereof that specifically binds to an amyloid component or precursor to thereby treat the amyloid disease. 
     
     
         98 . The method of  claim 97 , wherein the amyloid disease is associated with a preexisting or coexisting inflammatory disease or condition, an infection, a neoplasm, or a lymphoproliferative disorder. 
     
     
         99 . The method of  claim 98 , wherein the inflammatory disease or condition is rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, or Crohn's disease. 
     
     
         100 . The method of  claim 98 , wherein the infection is leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, or Whipple's disease. 
     
     
         101 . The method of  claim 98 , wherein the neoplasm is Hodgkin's lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, or hairy cell leukemia. 
     
     
         102 . The method of  claim 97 , wherein the disease is associated with a heredofamilial amyloidosis. 
     
     
         103 . The method of  claim 97 , wherein the antibody or antigen-binding fragment thereof binds to an aggregated amyloid fibril component with an affinity of greater than or equal to 10 6  M −1 . 
     
     
         104 . The method of  claim 97 , wherein the antibody or antigen-binding fragment thereof binds to a disaggregated amyloid fibril component with an affinity of less than 10 6  M −1 . 
     
     
         105 . The method of  claim 97 , wherein the antibody or antigen-binding fragment thereof binds to a precursor of an amyloid fibril component with an affinity of less than 10 6  M −1 . 
     
     
         106 . The method of  claim 97 , wherein the antibody is a human, chimeric, or humanized antibody. 
     
     
         107 . The method of  claim 106 , wherein the isotype of the antibody is human IgG1. 
     
     
         108 . The method of  claim 97 , wherein the antibody or antigen-binding fragment thereof is administered in multiple dosages. 
     
     
         109 . The method of  claim 97 , wherein the antibody or antigen-binding fragment thereof is administered as a sustained release composition. 
     
     
         110 . The method of  claim 97 , wherein the amyloid component or precursor is selected from the group consisting of Serum Amyloid A protein (ApoSSA), immunoglobulin light chain, immunoglobulin heavy chain, ApoAl, transthyretin, lysozyme, fibrogen α chain, gelsolin, cystatin C, Amyloid α protein precursor (P-APP), Beta 2  microglobulin, prion precursor protein (PrP), atrial natriuretic factor, keratin, islet amyloid polypeptide, a peptide hormone, synuclein and fragments thereof. 
     
     
         111 . The method of  claim 97 , wherein the amyloid component is a fibril amyloid component. 
     
     
         112 . The method of  claim 97 , whereby deposition of amyloid component fibril aggregates is inhibited. 
     
     
         113 . The method of  claim 97 , whereby amyloid component fibril aggregates are cleared. 
     
     
         114 . The method of  claim 97 , whereby progression of the amyloid disease is delayed. 
     
     
         115 . A method of reducing risk or delaying onset of an amyloid disease in a patient at risk of amyloid disease comprising administering to the patient an effective dosage of an antibody or antigen-binding fragment thereof that specifically binds to an amyloid component or precursor to thereby effect prophylaxis of the amyloid disease. 
     
     
         116 . The method of  claim 115 , wherein the patient has or is at risk for an amyloid disease associated with an inflammatory disease or condition, an infection, a neoplasm, or a lymphoproliferative disorder. 
     
     
         117 . The method of  claim 116 , wherein the inflammatory disease or condition is rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, or Crohn's disease. 
     
     
         118 . The method of  claim 116 , wherein the infection is leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, or Whipple's disease. 
     
     
         119 . The method of  claim 116 , wherein the neoplasm is Hodgkin's lymphoma, renal carcinoma, gut carcinoma, lung carcinoma, urogenital tract carcinoma, basal cell carcinoma, or hairy cell leukemia. 
     
     
         120 . The method of  claim 115 , wherein the patient has or is at risk for an amyloid disease associated with a heredofamilial amyloidosis. 
     
     
         121 . The method of  claim 115 , wherein the antibody or antigen-binding fragment thereof binds to an aggregated amyloid fibril component with an affinity of greater than or equal to 10 6  M −1 . 
     
     
         122 . The method of  claim 115 , wherein the antibody or antigen-binding fragment thereof binds to a disaggregated amyloid fibril component with an affinity of less than 10 6  M −1 . 
     
     
         123 . The method of  claim 115 , wherein the antibody or antigen-binding fragment thereof binds to a precursor of the amyloid fibril component with an affinity of less than 10 6  M −1 . 
     
     
         124 . The method of  claim 115 , wherein the antibody is a human, chimeric, or humanized antibody. 
     
     
         125 . The method of  claim 124 , wherein the isotype of the antibody is human IgG1. 
     
     
         126 . The method of  claim 115 , wherein the antibody or antigen-binding fragment thereof is administered in multiple dosages. 
     
     
         127 . The method of  claim 115 , wherein the antibody or antigen-binding fragment thereof is administered as a sustained release composition. 
     
     
         128 . The method of  claim 115 , wherein the amyloid component or precursor is selected from the group consisting of Serum Amyloid A protein (ApoSSA), immunoglobulin light chain, immunoglobulin heavy chain, ApoAl, transthyretin, lysozyme, fibrogen α chain, gelsolin, cystatin C, Amyloid α protein precursor (P-APP), Beta 2  microglobulin, prion precursor protein (PrP), atrial natriuretic factor, keratin, islet amyloid polypeptide, a peptide hormone, synuclein and fragments thereof. 
     
     
         129 . The method of  claim 115 , wherein the amyloid component is a fibril amyloid component. 
     
     
         130 . The method of  claim 115 , whereby deposition of amyloid component fibril aggregates is inhibited. 
     
     
         131 . The method of  claim 115 , whereby amyloid component fibril aggregates are cleared.