Agents, Uses and Methods for the Treatment of Synucleinopathy

Abstract

The invention relates to novel monoclonal anti-alpha-synuclein antibodies. The antibodies can be used for treating a synucleinopathy such as Parkinson's disease (including idiopathic and inherited forms of Parkinson's disease), Diffuse Lewy Body Disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), Combined Alzheimer's and Parkinson disease, pure autonomic failure and multiple system atrophy.

1 - 56 . (canceled) 
     
     
         57 . A monoclonal antibody comprising:
 (a) heavy chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, and light chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6;   (b) heavy chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 33, and 3, and light chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6;   (c) heavy chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 34, and 3, and light chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6;   (d) heavy chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 35, and 3, and light chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6; or   (e) heavy chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 20, 21, and 22, and light chain CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NOs: 23, 24, and 25.   
     
     
         58 . The monoclonal antibody according to  claim 57 , comprising:
 (a) a heavy chain variable domain and light chain variable domain comprising the amino acid sequences of SEQ ID NOs: 7 and 8, respectively;   (b) a heavy chain variable domain and light chain variable domain comprising the amino acid sequences of SEQ ID NOs: 30 and 8, respectively;   (c) a heavy chain variable domain and light chain variable domain comprising the amino acid sequences of SEQ ID NOs: 31 and 8, respectively;   (d) a heavy chain variable domain and light chain variable domain comprising the amino acid sequences of SEQ ID NOs: 32 and 8, respectively; or   (b) a heavy chain variable domain and light chain variable domain comprising the amino acid sequences of SEQ ID NOs: 26 and 27, respectively.   
     
     
         59 . The monoclonal antibody of  claim 57 , which is selected from the group consisting of antibodies of subtype IgG1, IgG2, IgG3 or IgG4. 
     
     
         60 . The monoclonal antibody of  claim 57 , which is a single chain Fv, a disulphide-bonded Fv, a Fab fragment, a Fab′ fragment, and F(ab)2 fragment. 
     
     
         61 . The monoclonal antibody of  claim 57 , which comprises (a) a constant domain comprising the amino acid sequence of SEQ ID NO: 18 and a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 17, or (b) a constant domain comprising the amino acid sequence of SEQ ID NO: 28 and a kappa constant domain comprising the amino acid sequence of SEQ ID NO: 29. 
     
     
         62 . The monoclonal antibody of  claim 57 , which is a human, humanized, or chimeric antibody. 
     
     
         63 . A pharmaceutical composition comprising the monoclonal antibody of  claim 57  and a pharmaceutical acceptable carrier. 
     
     
         64 . A kit comprising the monoclonal antibody of  claim 57  and instructions for use. 
     
     
         65 . A nucleic acid encoding the heavy chain and/or light chain of the antibody of  claim 57 . 
     
     
         66 . An expression vector comprising the nucleic acid of  claim 65 . 
     
     
         67 . A host cell comprising the nucleic acid of  claim 65 . 
     
     
         68 . A method of treating a synucleinopathy, the method comprising administering to a subject in need thereof an effective amount of the antibody of  claim 57 . 
     
     
         69 . The method of  claim 68 , wherein the synucleinopathy is Parkinson's disease, idiopathic and inherited forms of Parkinson's disease, Gauchers Disease (GD), Diffuse Lewy Body Disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), Combined Alzheimer's and Parkinson disease, pure autonomic failure, or multiple system atrophy. 
     
     
         70 . A method of treating Parkinson's disease, the method comprising administering to a subject in need thereof an effective amount of the antibody of  claim 57 . 
     
     
         71 . A method of restoring motor function in a subject with Parkinson's disease, the method comprising administering to the subject an effective amount of the antibody of  claim 57 . 
     
     
         72 . A method of reducing alpha-synuclein aggregate formation in a subject, the method comprising administering to the subject an effective amount of the antibody of  claim 57 . 
     
     
         73 . A method of preparing a monoclonal antibody which binds to alpha-synuclein, the method comprising:
 (a) culturing the host cell of  claim 67  under conditions which allow expression of the antibody, and   (b) obtaining the antibody.   
     
     
         74 . A method of preparing the monoclonal antibody of  claim 58 , the method comprising:
 i) providing a nucleic acid construct encoding the VL region of the antibody and a nucleotide sequence encoding the constant CL region of an Ig, wherein said nucleotide sequence encoding the VL region of a selected antigen specific antibody and said nucleotide sequence encoding the CL region of an Ig are operably linked together, and wherein, in case of an IgG1 subtype, the nucleotide sequence encoding the CL region has been modified such that the CL region does not contain any amino acids capable of forming disulfide bonds or covalent bonds with other peptides comprising an identical amino acid sequence of the CL region in the presence of polyclonal human IgG or when administered to an animal or human being;   ii) providing a nucleic acid construct encoding the VH region of the antibody and a nucleotide sequence encoding a constant CH region of a human Ig, wherein the nucleotide sequence encoding the CH region has been modified such that the region corresponding to the hinge domain and, as required by the Ig subtype, other regions of the CH region, such as the CH3 region, does not comprise any amino acid residues which participate in the formation of disulphide bonds or covalent or stable non-covalent inter-heavy chain bonds with other peptides comprising an identical amino acid sequence of the CH region of the human Ig in the presence of polyclonal human IgG or when administered to an animal human being, wherein said nucleotide sequence encoding the VH region of a selected antigen specific antibody and said nucleotide sequence encoding the CH region of said Ig are operably linked together;   iii) providing a cell expression system for producing said monovalent antibody; and   iv) producing said monovalent antibody by co-expressing the nucleic acid constructs of (i) and (ii) in cells of the cell expression system of (iii).   
     
     
         75 . A method of detecting alpha-synuclein in a human subject, the method comprising:
 (a) administering to the subject the antibody of  claim 57 , wherein the antibody comprises a detectable label, and   (b) detecting the binding of the antibody to alpha-synuclein in the subject.   
     
     
         76 . A method of diagnosing a synucleinopathy in a human subject, said method comprising:
 (a) administering to said subject the antibody of  claim 57 , wherein the antibody comprises a detectable label,   (b) measuring the binding of the antibody to alpha-synuclein in the subject,   (c) comparing the level of alpha-synuclein in the subject with a control level of alpha-synuclein, and   (d) diagnosing the subject with a synucleinopathy if the level of alpha-synuclein in the subject is increased relative to the control level of alpha-synuclein.