Granted Patent B2

US 12,331,123 · App. 18/057,104 · Granted Jun 17, 2025

Inventors: Lars Christian Biilmann Rønn (Valby, DK); Ibrahim John Malik (Valby, DK); Jeffrey B. Stavenhagen (Valby, DK); Søren Christensen (Valby, DK); Jan Egebjerg (Valby, DK); Arnout Gerritsen (Utrecht, NL); Edward van den Brink (Utrecht, NL); Paul Parren (Utrecht, NL); Rob de Jong (Utrecht, NL)

Assignee: H. Lundbeck A/S

C07K16/286A61K39/3955A61P25/28C07K16/28A61K2039/505C07K2317/20C07K2317/21C07K2317/24C07K2317/33C07K2317/34C07K2317/76C07K2317/92

Abstract

Claims (46)

1. An antibody, or an antigen-binding fragment thereof, comprising:

a) a light chain variable domain L-CDR1 comprising SEQ ID NO:97;

b) a light chain variable domain L-CDR 2 comprising SEQ ID NO:98;

c) a light chain variable domain L-CDR 3 comprising SEQ ID NO:99;

d) a heavy chain variable domain H-CDR 1 comprising SEQ ID NO: 100;

e) a heavy chain variable domain H-CDR 2 comprising SEQ ID NO: 101; and

f) a heavy chain variable domain H-CDR 3 comprising SEQ ID NO: 102.

2. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 104.

3. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising SEQ ID NO: 103.

4. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises both the heavy chain variable domain comprising SEQ ID NO: 104 and light chain variable domain comprising SEQ ID NO:103.

5. The antibody or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragments exhibits one or more of the following properties:

(i) a binding affinity (K D ) for Sortilin between 0.5-10 nM;

(ii) a capability to reduce and/or inhibit PGRN binding to Sortilin;

(iii) a capability to reduce and/or inhibit clearance of PGRN by Sortilin-expressing cells;

(iv) a capability to reduce and/or inhibit the endocytosis of PGRN by Sortilin-expressing cells;

(v) a capability to increase the amount and/or concentration of PGRN in the plasma in human-Sortilin-expressing knock-in mice and/or

(vi) a capability to increase the amount and/or concentration of PGRN in the brain (vii).

6. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, according to claim 1 and a pharmaceutically-acceptable carrier.

7. A kit comprising the antibody, or antigen-binding fragment thereof, of claim 1 .

8. A nucleic acid sequence encoding an antibody or antibody binding fragment thereof, of claim 1 .

9. A cell line comprising the nucleic acid sequence of claim 8 .

10. 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 antigen-binding fragment thereof, according to claim 1 .

11. The method of claim 10 , wherein the disease is frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) or Alzheimer's Disease (AD).

12. An antibody, or an antigen-binding fragment thereof, comprising:

a) a light chain variable domain L-CDR1 comprising SEQ ID NO:105;

b) a light chain variable domain L-CDR 2 comprising SEQ ID NO:106;

c) a light chain variable domain L-CDR 3 comprising SEQ ID NO:107;

d) a heavy chain variable domain H-CDR 1 comprising SEQ ID NO: 108;

e) a heavy chain variable domain H-CDR 2 comprising SEQ ID NO: 109; and

f) a heavy chain variable domain H-CDR 3 comprising SEQ ID NO: 110.

13. The antibody or antigen-binding fragment thereof, according to claim 12 , wherein said antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 112.

14. The antibody or antigen-binding fragment thereof, according to claim 12 , wherein said antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising SEQ ID NO:111.

15. The antibody or antigen-binding fragment thereof, according to claim 12 , wherein the antibody or antigen-binding fragment thereof comprises both the heavy chain variable domain comprising SEQ ID NO: 112 and light chain variable domain comprising SEQ ID NO: 111.

16. The antibody or antigen-binding fragment thereof, of claim 12 , wherein the antibody or antigen-binding fragments exhibits one or more of the following properties:

(i) a binding affinity (K D ) for Sortilin between 0.5-10 nM;

(ii) a capability to reduce and/or inhibit PGRN binding to Sortilin;

(iii) a capability to reduce and/or inhibit clearance of PGRN by Sortilin-expressing cells;

(iv) a capability to reduce and/or inhibit the endocytosis of PGRN by Sortilin-expressing cells;

(v) a capability to increase the amount and/or concentration of PGRN in the plasma in human-Sortilin-expressing knock-in mice and/or

(vi) a capability to increase the amount and/or concentration of PGRN in the brain (vii).

17. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, according to claim 12 and a pharmaceutically-acceptable carrier.

18. A kit comprising the antibody, or antigen-binding fragment thereof, of claim 12 .

19. A nucleic acid sequence encoding an antibody or antibody binding fragment thereof, of claim 12 .

20. A cell line comprising the nucleic acid sequence of claim 19 .

21. 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 antigen-binding fragment thereof, according to claim 12 .

22. The method of claim 21 , wherein the disease is frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) or Alzheimer's Disease (AD).

Assignments (3)

Priority Claims (1)

Continuity (4)

References Cited (189)