HUMAN ANTI-ALPHA-SYNUCLEIN ANTIBODIES
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).