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: 17;
b) a light chain variable domain L-CDR 2 comprising SEQ ID NO: 18:
c) a light chain variable domain L-CDR 3 comprising SEQ ID NO: 19:
d) a heavy chain variable domain H-CDR 1 comprising SEQ ID NO: 20:
e) a heavy chain variable domain H-CDR 2 comprising SEQ ID NO: 21: and
f) a heavy chain variable domain H-CDR 3 comprising SEQ ID NO: 22.
2. 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 by SEQ ID NO:170.
3. The antibody, or antigen-binding fragment thereof of claim 1 wherein said antibody or antigen-binding fragment thereof binds to at least 3 consecutive amino acids within the D Region of Sortilin as defined in SEQ ID NO: 170.
4. The antibody, or antigen-binding fragment thereof, or claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO:24.
5. 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:23.
6. 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 of SEQ ID NO: 24 and light chain variable domain of SEQ ID NO: 23.
7. 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.
8. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody is selected from the group consisting of: an antibody of subtype IgG1, IgG2, IgG3 or IgG4.
9. 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.
10. 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.
11. A pharmaceutical composition comprising an antibody, or an antigen binding fragment thereof of claim 1 and a pharmaceutically-acceptable carrier.
12. A kit comprising an antibody, or antigen-binding fragment thereof of claim 1 .
13. A nucleotide sequence encoding an antibody or antibody binding fragment of claim 1 .
14. A cell line comprising the nucleotide sequence of claim 13 .
15. 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 .
16. The method according to claim 15 , wherein the disease is frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.