Agonistic autoantibodies to the alpha1-adrenergic receptor and the beta2-adrenergic receptor in alzheimer's and vascular dementia

Abstract

The invention relates to means for detecting, binding, removing and/or neutralising agonistic antibodies associated with dementia, preferably Alzheimer's disease or vascular dementia.

1 . A peptide, comprising of
 (i) the amino acid sequence LGYWAFGRVFCN (SEQ ID No. 1) or PAPEDETICQINEE (SEQ ID No. 2);   (ii) an amino acid sequence having a sequence with 70%, preferably 80% or more preferably 90% or 95% sequence identity to an amino acid sequence in accordance with (i);   (iii) an amino acid sequence (i) or (ii) which is modified by branch or extension with the same or another peptide according to amino acid sequence (i) or (ii) to form a homooligomeric or heterooligomeric peptide,   whereby any terminus of the peptide according to i) to iii) exhibits an additional group selected from an amino group, amide group, acetyl group, biotin group, desthio-biotin group, a marker, spacer, linker, GKK, SGKK, or no additional group.   
     
     
         2 . The peptide according to  claim 1  for use in medical diagnostics or as a medicament. 
     
     
         3 . The peptide according to  claim 1  or  2 ,
 characterized in that 
 the peptide binds to antibodies of patients suffering from dementia, preferably agonistic autoantibodies that bind the α 1 adrenergic and/or the β 2 -adrenergic receptor. 
 
     
     
         4 . An isolated nucleic acid molecule selected from the group comprising:
 a) a nucleic acid molecule consisting of a nucleotide sequence which encodes at least one peptide selected from the group consisting of peptides according to  claim 1 ;   b) a nucleic acid molecule which is complementary to a nucleotide sequence in accordance with a);   c) a nucleic acid molecule which undergoes hybridization with a nucleotide sequence according to a) or b) under stringent conditions;   d) a nucleic acid molecule consisting of a nucleotide sequence having a sequence with 90% sequence identity to a nucleotide sequence according to a), b) or c);   e) a nucleic acid molecule which, as a consequence of the genetic code, is degenerated into a nucleotide sequence according to a) through d).   
     
     
         5 . A solid phase for affinity chromatography or solid-phase extraction, or an immunoassay, such as ELISA, consisting of organic, inorganic, synthetic polymers or of mixed polymers, preferably glass, plastic, cross-linked agarose, cellulose, silica gel, polyamide and polyvinyl alcohols, or other synthetic material, such as a bead, slide or micro-titer plate, which are optionally chemically activated, that comprise one or more peptides according to at least one of  claims 1  to  3 , immobilized on the surface of the solid phase. 
     
     
         6 . An affinity chromatography apparatus, such as a column, comprising one or more peptides according to at least one of  claims 1  to  3  or a solid phase according to  claim 5  for plasmapheresis and binding of autoantibodies which react with the α 1 adrenergic and/or the β 2 -adrenergic receptor or all IgG, preferably from whole blood or plasma. 
     
     
         7 . A recognition molecule that binds antibodies of patients suffering from dementia, whereby the antibodies to be bound are preferably agonistic autoantibodies that bind the aradrenergic and/or the β 2 -adrenergic receptor, more preferably autoantibodies that bind the peptides of SEQ ID no. 1 and/or 2, or bind the peptides according to  claim 1 , whereby the recognition molecule is preferably selected from the group comprising of antibodies, such as a therapeutic antibody, antisense constructs, chelating agents, aptamers or spiegelmers. 
     
     
         8 . A pharmaceutical composition comprising a peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5  and/or a recognition molecule according to  claim 7  optionally together with a pharmaceutically tolerable carrier. 
     
     
         9 . A peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5 , a recognition molecule according to  claim 7  and/or a pharmaceutical composition according to  claim 8  for the diagnosis, therapy, prophylaxis or monitoring of disease progression of dementia. 
     
     
         10 . Use of a peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5 , an apparatus according to  claim 6 , a recognition molecule according to  claim 7  and/or a pharmaceutical composition according to  claim 8 , for the in vitro diagnosis of dementia. 
     
     
         11 . Use of a peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5 , an apparatus according to  claim 6 , a recognition molecule according to  claim 7  and/or a pharmaceutical composition according to  claim 8  in the production or screening of a drug for the treatment of dementia. 
     
     
         12 . The peptide, nucleic acid molecule, solid phase, recognition molecule and/or pharmaceutical composition according to  claim 9  or the use according to  claim 10  or  11 ,
 characterized in that 
 the dementia is Alzheimer's disease, vascular dementia, stroke or stroke-related dementia. 
 
     
     
         13 . Kit that comprises the peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5 , an apparatus according to  claim 6 , a recognition molecule according to  claim 7  and/or a pharmaceutical composition according to  claim 8 , for the in vitro diagnosis of dementia. 
     
     
         14 . Kit according to the preceding claim, comprising additionally of reagents for an enzyme-linked immunosorbent assay (ELISA) test, selected from the group comprising of slides, micro-titre plates, secondary antibodies, marker enzymes and/or corresponding marker enzyme substrate for antibody detection. 
     
     
         15 . Use of a specific ligand for human immunoglobulin in the manufacture of a column coupled to said ligand for the treatment of a patient suffering from dementia, said treatment comprising passing plasma of the patient, over the column under conditions which effect the binding of said specific ligand to immunoglobulin in the patient's plasma, thereby removing a significant portion of the immunoglobulin from the patient's plasma, and reinfusing the plasma to the patient. 
     
     
         16 . Use according to the preceding claim, wherein
 said specific ligand is selected from the group consisting of polyclonal anti-human immunoglobulin antibodies, monoclonal anti-human immunoglobulin antibodies, a fragment of such antibodies, recombinant molecules of the antibody idiotype, synthesized peptides, Protein A and Protein G and   removal of autoantibodies occurs, whereby the autoantibodies removed react with the α 1 adrenergic and/or the β 2 -adrenergic receptor, preferably removing a significant proportion of autoantibodies from the patients plasma that bind to the peptides described in the preceding claims.   
     
     
         17 . An in vitro method for binding and removing a portion of the immunoglobulin from plasma taken from a patient suffering from dementia, the method comprising
 a) providing a column coupled to a specific ligand for human immunoglobulin, which column is as defined in any one of  claim 15  or  16 ; and   b) passing the plasma over the column under conditions which effect the binding of said specific ligand to immunoglobulin in the plasma.   
     
     
         18 . A method for the treatment of dementia, preferably Alzheimer's disease, vascular dementia, stroke or stroke-related dementia, comprising the administration of a therapeutically relevant amount of an agent selected from a peptide according to any of  claims 1  to  3 , a nucleic acid molecule according to  claim 4 , a solid phase according to  claim 5 , an apparatus according to  claim 6 , a recognition molecule according to  claim 7  and/or a pharmaceutical composition according to  claim 8 , to a patient in need thereof, either via administration of the agent in vivo to the patient or ex vivo use of the agent in an apharese-based therapeutic method.