Anti-alpha-synuclein antibodies and methods of use
Provided herein are anti-human alpha-synuclein antibodies, including, for example, antibodies that bind to human alpha-synuclein which has a free N-terminal methionine residue, and methods of using the same.
1. A monoclonal antibody comprising a heavy chain variable domain comprising a CDRH1 sequence, a CDRH2 sequence, and a CDRH3 sequence, wherein the CDRH1 sequence is SEQ ID NO: 15 or 21, the CDRH2 sequence is SEQ ID NO: 16 or 22, and the CDRH3 sequence is SEQ ID NO: 17, and a light chain variable domain comprising a CDRL1 sequence, a CDRL2 sequence, and a CDRL3 sequence, wherein the CDRL1 sequence is SEQ ID NO: 18 or 23, the CDRL2 sequence is SEQ ID NO: 19 or 24, and the CDRL3 sequence is SEQ ID NO: 20 or 25.
2. The antibody according to claim 1 , wherein the antibody binds to alpha-synuclein that is monomeric or oligomeric alpha-synuclein.
3. The antibody according to claim 1 , wherein the antibody is a humanized antibody or a chimeric antibody.
4. The antibody according to claim 1 , wherein the antibody is conjugated to a blood-brain-barrier shuttle module, wherein the blood-brain-barrier shuttle module is an antibody or antibody fragment that binds to LRP1, LRP8, human transferrin receptor or human insulin-like growth factor receptor.
5. The antibody according to claim 1 , wherein the antibody further comprises:
a) an Fc region of an immunoglobulin heavy chain of human subclass IgG1,
b) an Fc region of an immunoglobulin heavy chain of human subclass IgG4,
c) an Fc region of an immunoglobulin heavy chain of human subclass IgG1 with amino acid residue substitutions L234A, L235A and P329G,
d) an Fc region of an immunoglobulin heavy chain of human subclass IgG4 with amino acid residue substitutions S228P, L235E and P329G,
e) a first Fc region of an immunoglobulin heavy chain of human subclass IgG4 with amino acid residue substitutions L234A, L235A, P329G, T366W and S354C and a second Fc region of an immunoglobulin heavy chain of human subclass IgG1 with amino acid residue substitutions L234A, L235A, P329G, T366S, L368A, Y407V and Y349C, or
f) a first Fc region of an immunoglobulin heavy chain of human subclass IgG4 with the mutations amino acid residue substitutions S228P, L235E, P329G, T366W and S354C and a second Fc region of an immunoglobulin heavy chain of human subclass IgG4 with amino acid residue substitutions S228P, L235E, P329G, T366S, L368A, Y407V and Y349C.
6. A pharmaceutical formulation comprising the antibody according to claim 1 and a pharmaceutically acceptable carrier.
7. A method for treating synucleinopathy, said method comprising administering an antibody of claim 1 to a subject in need thereof.
8. A method for treating Parkinson's Disease said method comprising administering an antibody of claim 1 to a subject in need thereof.