Antibody Therapy for Amyloid Beta Disease

Abstract

The present disclosure relates generally to a protocol to treat or prevent diseases or conditions associated with pathological forms of amyloid beta (Aβ), including Alzheimer's disease. Enabled herein is a reagent for use in the treatment and prophylaxis of Aβ-associated pathological conditions.

1 . An isolated Fab 2286-like antibody which binds to Aβ 1-40  and a C-terminally elongated form thereof, said antibody comprising a modified Fab 2286 wherein a mature heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 1 with the proviso that the amino acid residue at position 50 is not glutamic acid (E), wherein the numbering of the amino acid sequence WIGE in Fab 2286 (SEQ ID NO:1) represents residues 47 to 50 or comprising one or more other amino acid substitutions, additions and/or deletions to the amino acid sequence of SEQ ID NO: 1. 
     
     
         2 . The isolated Fab 2286-like antibody of  claim 1  herein the amino acid at position 50 is selected from the list consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, pyrrolysine and selenocysteine. 
     
     
         3 . The isolated Fab 2286-like antibody of  claim 1  wherein the amino acid at position 50 is a basic amino acid selected from arginine, lysine and histidine. 
     
     
         4 . The isolated Fab 2886-like antibody of  claim 1  wherein the amino acid at position 50 is alanine. 
     
     
         5 . The isolated Fab 2286-like antibody of  claim 1  wherein the amino acid at position 50 is arginine. 
     
     
         6 . The isolated Fab 2286-like antibody of  claim 1  wherein the C-terminally elongated form of Aβ 1-40  is selected from Aβ 1-42 , Aβ 1-43 , Aβ 3-42 , Aβ 4-42 , Aβ pyroGlu3-42  and Aβ pyroGlu11-42 . 
     
     
         7 . The isolated Fab 2286-like antibody of  claim 1  conjugated to constant regions of light and heavy chains. 
     
     
         8 . The isolated Fab 2286-like antibody of  claim 7  comprising a heavy chain variable region selected from SEQ ID NO:9 and 11. 
     
     
         9 . A mammalianized form of the isolated Fab 2286-like antibody of  claim 1 . 
     
     
         10 . The mammalianized form of the isolated Fab 2286-like antibody of  claim 9  wherein the antibody is humanized. 
     
     
         11 . An isolated nucleic acid molecule encoding an amino acid chain of the antibody of any one of  claims 1  to  10 . 
     
     
         12 . The isolated nucleic acid molecule of  claim 11  comprised within an expression vector. 
     
     
         13 . An isolated cell comprising the nucleic acid molecule of  claim 11  or  12 . 
     
     
         14 . A pharmaceutical composition comprising the antibody of any one of  claims 1  to  10 , together with one or more pharmaceutically acceptable carriers, diluents and/or excipients. 
     
     
         15 . The isolated Fab 2286-like antibody of any one of  claims 1  to  10  for use in the treatment of pathogenic Aβ disease. 
     
     
         16 . The isolated Fab 2286-like antibody of  claim 15  wherein the Aβ disease is associated with or characterized by pathogenic forms of Aβ selected from Aβ 1-42 , Aβ 1-43 , Aβ 3-42 , Aβ 4-42 , Aβ pyroGlu3-42  and Aβ pyroGlu11-42  in tissue or fluid. 
     
     
         17 . The isolated Fab 2286-like antibody of  claim 16  wherein the tissue is brain tissue. 
     
     
         18 . The isolated Fab 2286-like antibody of  claim 16  wherein the fluid is circulatory blood fluid. 
     
     
         19 . The isolated Fab 2286-like antibody of any one of  claims 15  to  18  wherein the disease is selected from Alzheimer's disease, Down's syndrome, cognitive impairment or memory loss, Parkinson's disease, multi-infarct dementia, cerebral amyloid angiopathy, glaucoma, and a vascular disorder caused by pathogenic Aβ peptide in blood vessels. 
     
     
         20 . The isolated Fab 2286-like antibody of  claim 19  wherein the vascular disorder is stroke or hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). 
     
     
         21 . The isolated Fab 2286-like antibody of  claim 19  wherein the disease is Alzheimer's disease. 
     
     
         22 . A method of treating or ameliorating symptoms of a neurological condition selected from Alzheimer's disease, Down's syndrome, cognitive impairment or memory loss, Parkinson's disease, multi-infarct dementia, cerebral amyloid angiopathy, glaucoma, stroke and HCHWA-D or other adverse event of the systemic vasculature in a subject, the method comprising administering to the subject, an effective amount of an Fab 2286-like antibody comprising a mature heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1 with the proviso that the amino acid residue at position 50 is not gluatimic acid (E) using a numbering system where the amino acid sequence WIGE of Fab 2286 (SEQ ID NO:1) is at positions 47 to 50 or having one or more other amino acid substitutions, additions and/or deletions thereto. 
     
     
         23 . The method of  claim 22  wherein the amino acid at position 50 is selected from the list consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, pyrrolysine and selenocysteine. 
     
     
         24 . The method of  claim 22  wherein the amino acid at position 50 is a basic amino acid selected from arginine, lysine and histidine. 
     
     
         25 . The method of  claim 22  wherein the amino acid at position 50 is alanine. 
     
     
         26 . The method of  claim 22  wherein the amino acid at position 50 is arginine. 
     
     
         27 . A method for the treatment or prophylaxis of Alzheimer's disease in a subject, said method comprising administering to the subject an effective amount of the Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         28 . A method of delaying development of a symptom associated with Alzheimer's disease in a subject comprising administering to the subject an effective dosage of a pharmaceutical composition comprising an Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         29 . A method of inhibiting or suppressing the formation of amyloid plaques and/or Aβ accumulation in a subject comprising administering to the subject an effective dose of a pharmaceutical composition comprising an Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         30 . A method of reducing amyloid plaques and/or reducing or slowing Aβ accumulation in a subject comprising administering to the subject an effective dose of a pharmaceutical composition comprising an Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         31 . A method of removing or clearing amyloid plaques and/or Aβ accumulation in a subject comprising administering to the subject an effective dose of a pharmaceutical composition comprising an Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         32 . A method of reducing Aβ peptide in a tissue, inhibiting and/or reducing accumulation of Aβ peptide in a tissue, or inhibiting and/or reducing toxic effects of Aβ peptide in a tissue in a subject comprising administering to the subject an effective dose of a pharmaceutical composition comprising an Fab 2286-like antibody of any one of  claims 1  to  10 . 
     
     
         33 . The method of any one of  claims 22  to  32  wherein the subject is a human. 
     
     
         34 . The method of  claim 33  wherein the antibody is intravenously or intracerebrally administered. 
     
     
         35 . A kit comprising the antibody of any one of  claims 1  to  10 . 
     
     
         36 . The kit of  claim 35  further comprising an antibody labeled with a reporter molecule or enzyme specific to the Fab 2286-like antibody. 
     
     
         37 . Use of the antibody of any one of  claims 1  to  10  in the manufacture of a medicament in the treatment of pathogenic Aβ disease. 
     
     
         38 . Use of  claim 37  wherein the Aβ disease is selected from the list consisting of Alzheimer's disease, Down's syndrome, cognitive impairment or memory loss, Parkinson's disease, multi-infarct dementia, cerebral amyloid angiopathy, glaucoma, and a vascular disorder caused by pathogenic Aβ peptide in blood vessels. 
     
     
         39 . Use of  claim 38  wherein the vascular disorder is stroke or hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). 
     
     
         40 . Use of  claim 37  wherein the Aβ disease is Alzheimer's disease. 
     
     
         41 . Use of Fab 2286-like antibody of any one of  claims 1  to  10  in the treatment of pathogenic Aβ disease via a peripheral sink. 
     
     
         42 . Use of  claim 41  wherein the Aβ disease is selected from the list consisting of Alzheimer's disease, Down's syndrome, cognitive impairment or memory loss, Parkinson's disease, multi-infarct dementia, cerebral amyloid angiopathy, glaucoma, pre-eclampsia and a vascular disorder caused by pathogenic Aβ peptide in blood vessels. 
     
     
         43 . Use of  claim 42  wherein the vascular disorder is stroke or hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). 
     
     
         44 . Use of  claim 41  wherein the Aβ disease is Alzheimer's disease. 
     
     
         45 . A method of detecting a toxic form of Aβ in a sample from a subject, said method comprising identifying binding between the Aβ form and Fab 2286-like antibody. 
     
     
         46 . The method of  claim 45  wherein the Fab 2286-like antibody is labeled with a reporter molecule. 
     
     
         47 . The method of  claim 45  wherein the Fab 2286-like antibody is identified by a labeled anti-immunoglobulin antibody. 
     
     
         48 . The method of  claim 45  or  46  or  47  for the detection of a disease selected from the list consisting of Alzheimer's disease, Down's syndrome, cognitive impairment or memory loss, Parkinson's disease, multi-infarct dementia, cerebral amyloid angiopathy, glaucoma, pre-eclampsia and a vascular disorder caused by pathogenic Aβ peptide in blood vessels. 
     
     
         49 . The method of  claim 48  for the detection of Alzheimer's disease. 
     
     
         50 . The method of  claim 48  for the detection of stroke or hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). 
     
     
         51 . The method of  claim 48  for the detection of pre-eclampsia. 
     
     
         52 . The method of  claim 51  wherein the toxic form of Aβ is detected in urine. 
     
     
         53 . A dipstick comprising Fab 2286-like antibody immobilized thereon for use in detecting toxic forms of Aβ in a biological sample. 
     
     
         54 . The dipstick of  claim 53  wherein the sample is urine. 
     
     
         55 . The dipstick of  claim 54  in the diagnosis of pre-eclampsia. 
     
     
         56 . An isolated polynucleotide encoding the amino acid sequence set forth in SEQ ID NO:19 or an amino acid sequence having at least 90% similarity thereto after optimal alignment. 
     
     
         57 . The isolated polynucleotide of  claim 56  as set forth in SEQ ID NO:18 or a sequence having at lest 90% identity thereto after optimal alignment or a nucleotide sequence which hybridizes to the complement of SEQ ID NO:18 under medium or high stringency conditions. 
     
     
         58 . The isolated polynucleotide of  claim 52  comprising the nucleotide sequence of SEQ ID NO:18.