Agent, uses and methods for treatment
The present invention relates to monoclonal anti-Sortilin antibodies which have been found useful in correcting a deficient level of progranulin (PGRN). In particular, these antibodies can be used in the treatment of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
1. An antibody, or an antigen-binding fragment thereof, comprising:
a) a light chain variable domain L-CDR1 comprising SEQ ID NO: 49;
b) a light chain variable domain L-CDR 2 comprising SEQ ID NO: 50;
c) a light chain variable domain L-CDR 3 comprising SEQ ID NO: 51;
d) a heavy chain variable domain H-CDR 1 comprising SEQ ID NO: 52;
e) a heavy chain variable domain H-CDR 2 comprising SEQ ID NO: 53 and
f) a heavy chain variable domain H-CDR 3 comprising SEQ ID NO: 54.
2. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO:56.
3. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising SEQ ID NO:55.
4. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises both the heavy chain variable domain comprising SEQ ID NO:56 and light chain variable domain comprising SEQ ID NO:55.
5. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antigen-binding fragment is selected from the group consisting of an Fv fragment and a Fab-like fragment.
6. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody is selected from the group consisting of an antibody of subtypes IgG1, IgG2, IgG3 or IgG4.
7. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein said antibody or antigen-binding fragment thereof binds to the D Region of Sortilin as defined in SEQ ID NO: 170.
8. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein said antibody or antigen-binding fragment thereof binds to at least 3-7 consecutive amino acids within the D Region of Sortilin as defined in SEQ ID NO: 170.
9. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragment exhibits one or more of the following properties:
a) a binding affinity (KD) for Sortilin between 0.5-10 nM;
b) capability to reduce and/or inhibit PGRN binding to Sortilin;
c) capability to reduce and/or inhibit clearance of PGRN by Sortilin-expressing cells;
d) capability to reduce and/or inhibit the endocytosis of PGRN by Sortilin-expressing cells;
e) capability to increase the amount and/or concentration of PGRN in the brain, and/or
f) capability to increase the amount and/or concentration of PGRN in the plasma in human-Sortilin-expressing knock-in mice.
10. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragment thereof is a human, humanized, recombinant or chimeric antibody.
11. A pharmaceutical composition comprising an antibody, or an antigen binding fragment thereof, of claim 1 and a pharmaceutically-acceptable carrier.
12. A method of treating a disease associated with decreased PGRN levels in the brain of a patient, comprising administering an effective dosage of an antibody, or an antigen-binding fragment thereof, of claim 1 .
13. The method according to claim 12 , wherein the disease is frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.
14. A kit comprising an antibody, or antigen-binding fragment thereof, of claim 1 .
15. An antibody, or antigen-binding fragment thereof, of claim 1 which has been produced or manufactured in a cell line comprising a mammal non-human cell line, an insect, yeast or bacterial cell line.
16. The antibody, or antigen binding fragment thereof, of claim 15 produced in a CHO cell line, HEK cell line, BHK-21 cell line, murine cell line, myeloma cell line, fibrosarcoma cell line, PER.C6 cell line, HKB-11 cell line, CAP cell line and HuH-7 human cell line.
17. A method of making a pharmaceutical composition comprising combining an antibody, or an antigen-binding fragment thereof, of claim 1 , with a pharmaceutically-acceptable carrier.
18. A nucleic acid sequence encoding an antibody or antibody binding fragment of claim 1 .
19. A cell line comprising the nucleic acid sequence of claim 18 .