Agents, uses and methods for the treatment of synucleinopathy
The invention relates to combinational treatment using a monoclonal anti-alpha-synuclein antibody and an additional medicament. 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 together with another medicament of the invention.
1. A method of treating 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's disease, and multiple system atrophy in a subject, said method comprising administering
(I) a monoclonal antibody or antigen-binding fragment thereof comprising:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:1;
(ii) a Heavy Chain CDR2 having the amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:33, SEQ ID NO:34, or SEQ ID NO:35;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:3;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:4;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:5; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:6; or
(II) a monoclonal antibody or antigen-binding fragment thereof comprising:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:20;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:21;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:22;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:23;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:24; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:25; and
an additional medicament selected from the group comprising pramipexole, VX-765, ABT-957, PF-06447475, NB-360, Neuropore NPT100-18A, NPT200-11, EGCG, Bapineuzemab, Solanezumab, Gantenerumab, Crenezumab, Aducanumab, C16H15NO4, BMS-986016, GSK2831781, IMP321, ELN484228, NCGC607, Miglustat, Eliglustat, Rasagiline, Selegiline, Ropinirole, Bromocriptine, Entacapone, Tolcapone and Istradefyline.
2. The method according to claim 1 , wherein the treatment is chronic.
3. The method according to claim 1 , wherein the chronic treatment is for at least 2 weeks.
4. The method according to claim 1 , wherein the subject is human.
5. The method according to claim 1 wherein said monoclonal antibody and additional medicament are administered approximately simultaneously or wherein the medicaments are taken separately.
6. The method according to claim 1 , wherein the antibody or a fragment thereof, comprises:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:1;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:2;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:3;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:4;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:5; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:6.
7. The method according to claim 6 , wherein the antibody comprises the heavy chain variable domain of SEQ ID NO:7 or the light chain variable domain of SEQ ID NO:8.
8. The method according to claim 7 , wherein the antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:7 and a light chain consisting of a variable domain of SEQ ID NO:8.
9. The method according to claim 1 , wherein the antibody or a fragment thereof, comprises:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:1;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:2;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:33;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:4;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:5; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:6.
10. The method according to claim 9 , wherein the antibody comprises the heavy chain variable domain of SEQ ID NO:30 or the light chain variable domain of SEQ ID NO:8.
11. The method according to claim 10 , wherein the antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:30 and a light chain consisting of a variable domain of SEQ ID NO:8.
12. The method according to claim 1 , wherein the antibody or a fragment thereof, comprises:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:1;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:2;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:34;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:4;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:5; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:6.
13. The method according to claim 12 , wherein the antibody comprises the heavy chain variable domain of SEQ ID NO:31 or the light chain variable domain of SEQ ID NO:8.
14. The method according to claim 13 , wherein the antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:31 and a variable domain of SEQ ID NO:8.
15. The method according to claim 1 , wherein the antibody or a fragment thereof, comprises:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:1;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:2;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:35;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:4;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:5; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:6.
16. The method according to claim 15 , wherein the antibody comprises the heavy chain variable domain of SEQ ID NO:32 or the light chain variable domain of SEQ ID NO:8.
17. The method according to claim 16 , wherein the antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:32 and a variable domain of SEQ ID NO:8.
18. The method according to claim 1 , wherein the antibody or a fragment thereof, comprises:
(i) a Heavy Chain CDR1 having the amino acid sequence of SEQ ID NO:20;
(ii) a Heavy Chain CDR2 having the amino acid sequence of SEQ ID NO:21;
(iii) a Heavy Chain CDR3 having the amino acid sequence of SEQ ID NO:22;
(iv) a Light Chain CDR1 having the amino acid sequence of SEQ ID NO:23;
(v) a Light Chain CDR2 having the amino acid sequence of SEQ ID NO:24; and
(vi) a Light Chain CDR3 having the amino acid sequence of SEQ ID NO:25.
19. The method according to claim 18 , wherein the antibody comprises a heavy chain variable domain of SEQ ID NO:26 or the light chain variable domain of SEQ ID NO:27.
20. The method according to claim 19 , wherein the antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:26 and a variable domain of SEQ ID NO:27.