Human anti-alpha-synuclein antibodies

Abstract

Provided are human alpha-synuclein-specific autoantibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for α-synuclein are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for α-synuclein targeted immunotherapy and diagnosis, respectively.

1 . A human monoclonal anti-α-synuclein antibody. 
     
     
         2 . The antibody of  claim 1 , which is capable of specifically binding α-synuclein in the native monomer form. 
     
     
         3 . The antibody of  claim 1  or  2 , which is capable of binding α-synuclein in the oligomeric or aggregated form. 
     
     
         4 . The antibody of any one  claims 1  to  3 , wherein the antibody specifically binds α-synuclein compared to β-synuclein or γ-synuclein. 
     
     
         5 . The antibody of any one of  claims 1  to  4 , which recognizes an N-terminal 1-60  fragment or C-terminal 96-140  fragment of α-synuclein. 
     
     
         6 . The antibody of any one of  claims 1  to  4 , which does not recognize a truncated form of α-synuclein. 
     
     
         7 . The antibody of any one of  claims 1  to  6  or an α-synuclein binding fragment thereof comprising in its variable region at least one complementarity determining region (CDR) as depicted in  FIG. 1 . 
     
     
         8 . The antibody or binding fragment of  claim 7  comprising an amino acid sequence of the V H  and/or V L  region as depicted in  FIG. 1 . 
     
     
         9 . An antibody or antigen-binding molecule which competes with an antibody of any one of  claims 1  to  8  for specific binding to α-synuclein. 
     
     
         10 . The antibody of  claim 9 , which is a chimeric murine-human or a murinized antibody. 
     
     
         11 . The antibody of any one of  claims 1  to  10 , which is selected from the group consisting of a single chain Fv fragment (scFv), an F(ab′) fragment, an F(ab) fragment, and an F(ab′) 2  fragment. 
     
     
         12 . A polynucleotide encoding at least the binding domain or variable region of an immunoglobulin chain of the antibody of any one of  claims 1  to  11 . 
     
     
         13 . A vector comprising the polynucleotide of  claim 12 , optionally in combination with a polynucleotide of  claim 12  that encodes the variable region of the other immunoglobulin chain of the antibody. 
     
     
         14 . A host cell comprising a polynucleotide of  claim 10  or a vector of  claim 13 . 
     
     
         15 . A method for preparing an anti-α-synuclein antibody or immunoglobulin chain(s) thereof, said method comprising
 (a) culturing the cell of  claim 14 ; and 
 (b) isolating said antibody or immunoglobulin chain(s) thereof from the culture. 
 
     
     
         16 . An antibody or immunoglobulin chain(s) thereof encoded by a polynucleotide of  claim 12  or obtainable by the method of  claim 15 . 
     
     
         17 . The antibody of any one of  claim 1  to  11  or  16 , which is detectably labeled. 
     
     
         18 . The antibody of  claim 17 , wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal. 
     
     
         19 . The antibody of any one of  claims 1  to  11  or  16  to  18 , which is attached to a drug. 
     
     
         20 . A composition comprising the antibody of any one of  claims 1  to  11  or  16  to  19 , the polynucleotide of  claim 12 , the vector of  claim 13  or the cell of  claim 14 . 
     
     
         21 . The composition of  claim 20 , which is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier. 
     
     
         22 . The composition of  claim 21 , which is a vaccine. 
     
     
         23 . The pharmaceutical composition of  claim 21  or  22  further comprising an additional agent useful for treating a synucleinopathic disease. 
     
     
         24 . The composition of  claim 20 , which is a diagnostic composition, and optionally comprises reagents conventionally used in immuno or nucleic acid based diagnostic methods. 
     
     
         25 . Use of an antibody of any one of  claims 1  to  11  or  16  to  19  or an α-synuclein binding molecule having substantially the same binding specificities of any one thereof, the polynucleotide of  claim 12 , the vector of  claim 13  or the cell of  claim 14  for the preparation of a pharmaceutical or diagnostic composition for prophylactic and therapeutic treatment of a synucleinopathic disease, monitoring the progression of a synucleinopathic disease or a response to a synucleinopathic disease treatment in a subject. 
     
     
         26 . A method of diagnosing a synucleinopathic disease in a subject, the method comprising:
 (a) assessing a level of α-synuclein in a sample from the subject to be diagnosed with an antibody of any one of  claims 1  to  11  or  16  to  19 , an α-synuclein binding fragment thereof or an α-synuclein binding molecule having substantially the same binding specificities of any one thereof; and   (b) comparing the level of the α-synuclein to a reference standard that indicates the level of the α-synuclein in one or more control subjects,   
       wherein a difference or similarity between the level of the α-synuclein and the reference standard indicates that the subject has Parkinson's disease. 
     
     
         27 . The use of  claim 25  or the method of  claim 26 , wherein the synucleinopathic disease is selected from the group consisting of Parkinson's disease (PD), Parkinon's disease dementia (PDD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease (LBVAD), multiple systems atrophy (MSA), pure autonomic failure (PAF), neurodegeneration with brain iron accumulation type-1 (NBIA-I), Alzheimer's disease, Pick disease, juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disease), amyotrophic lateral sclerosis, traumatic brain injury and Down syndrome. 
     
     
         28 . A kit for the diagnosis of a synucleinopathic disease, said kit comprising an antibody of any one of  claims 1  to  11  or  16  to  19  or an α-synuclein binding molecule having substantially the same binding specificities of any one thereof, the polynucleotide of  claim 12 , the vector of  claim 13  or the cell of  claim 14 , optionally with reagents and/or instructions for use. 
     
     
         29 . Use of an α-synuclein binding molecule comprising at least one CDR of an antibody of any one of  claims 1  to  11  or  16  to  19  for the preparation of a composition for in vivo detection of or targeting a therapeutic and/or diagnostic agent to α-synuclein in the human or animal body. 
     
     
         30 . The use of  claim 29 , wherein said, wherein said in vivo imaging comprises positron emission tomography (PET), single photon emission tomography (SPECT), near infrared (NIR) optical imaging or magnetic resonance imaging (MRI).