IP Library › Granted Patent US 12,214,007
Granted Patent B2
US 12,214,007 · App. 16/473,816 · Granted Feb 4, 2025

Fusion protein including BDNF

Inventors: Hiroyuki Sonoda (Kobe, JP); Kenichi Takahashi (Kobe, JP)
Assignee: JCR Pharmaceuticals Co., Ltd.
A61K38/017A61K38/185C07K16/18C12N15/66C07K2317/54C07K2317/55C07K2317/565C07K2317/567C07K2317/62C07K2319/00
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Quick Facts
Patent No.
US 12,214,007
App. No.
16/473,816
Granted
Feb 4, 2025
Kind
B2
Abstract

The present invention provides a fusion protein of BDNF and an anti-human transferrin receptor antibody, in which in a heavy chain variable region of the antibody, (a) CDR1 includes an amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 67, (b) CDR2 includes an amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14, and (c) CDR3 includes an amino acid sequence of SEQ ID NO: 15 or SEQ ID NO: 16.

Claims (104)

1. A fusion protein of human brain-derived neurotrophic factor (human BDNF) and an anti-human transferrin receptor antibody, selected from (1) or (2) below:

(1) the fusion protein wherein in a heavy chain variable region of the antibody,

(a) CDR1 comprises the amino acid sequence of SEQ ID NO: 66,

(b) CDR2 comprises the amino acid sequence of SEQ ID NO: 13,

(c) CDR3 comprises the amino acid sequence of SEQ ID NO: 15, and

(d) framework region 3 comprises the amino acid sequence of SEQ ID NO: 68,

wherein in a light chain variable region of the antibody,

(a) CDR1 comprises the amino acid sequence of SEQ ID NO: 6,

(b) CDR2 comprises the amino acid sequence of SEQ ID NO: 8, and

(c) CDR3 comprises the amino acid sequence of SEQ ID NO: 10, and

wherein the human BDNF binds to the N-terminus of the heavy chain of the antibody via a linker;

(2) the fusion protein wherein in a heavy chain variable region of the antibody,

(a) CDR1 comprises the amino acid sequence of SEQ ID NO: 67,

(b) CDR2 comprises the amino acid sequence of SEQ ID NO: 14,

(c) CDR3 comprises the amino acid sequence of SEQ ID NO: 16, and

(d) framework region 3 comprises the amino acid sequence of SEQ ID NO: 68, and

wherein in a light chain variable region of the antibody,

(a) CDR1 comprises the amino acid sequence of SEQ ID NO: 7,

(b) CDR2 comprises the amino acid sequence of SEQ ID NO: 9, and

(c) CDR3 comprises the amino acid sequence of SEQ ID NO: 10, and

wherein the human BDNF binds to the N-terminus of the heavy chain of the antibody via a linker.

2. The fusion protein according to claim 1 ,

wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69.

3. The fusion protein according to claim 2 ,

wherein the heavy chain amino acid sequence comprises the amino acid sequence of SEQ ID NO: 70 or SEQ ID NO: 72.

4. The fusion protein according to claim 1 ,

wherein the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22.

5. The fusion protein according to claim 1 ,

wherein the light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, or SEQ ID NO: 29.

6. The fusion protein according to claim 1 ,

wherein the antibody is a Fab antibody, a F(ab′) 2 antibody, or a F(ab′) antibody.

7. The fusion protein according to claim 1 ,

wherein the antibody is a single-chain antibody selected from the group consisting of scFab, scF(ab′), scF(ab′) 2 , and scFv.

8. The fusion protein according to claim 7 ,

wherein the light chain binds to a C-terminus of the heavy chain of the antibody via a linker sequence.

9. The fusion protein according to claim 8 ,

wherein the linker sequence is formed of 8 to 50 amino acid residues.

10. The fusion protein according to claim 8 ,

wherein the linker sequence is selected from the group consisting of the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence Gly-Gly-Gly, the amino acid sequence of SEQ ID NO: 3, the amino acid sequence of SEQ ID NO: 4, and the amino acid sequence of SEQ ID NO: 5, the amino acid sequence corresponding to three consecutive amino acid sequences of SEQ ID NO: 3, and the amino acid sequence consisting of 2 to 10 of the aforementioned amino acid sequences consecutively linked.

11. The fusion protein according to claim 1 ,

wherein the linker is a peptide including 1 to 50 amino acid residues.

12. The fusion protein according to claim 1 ,

wherein the linker is a peptide including the amino acid sequence selected from the group consisting of the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence of SEQ ID NO: 3, the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, and the amino acid sequence consisting of 2 to 10 of the aforementioned amino acid sequences consecutively linked.

13. The fusion protein according to claim 1 ,

wherein the human BDNF comprises

the amino acid sequence of SEQ ID NO: 51.

14. The fusion protein according to claim 1 ,

wherein the fusion protein having affinity to both of an extracellular region of a human transferrin receptor and an extracellular region of a monkey transferrin receptor.

15. The fusion protein according to claim 14 ,

wherein a dissociation constant of the anti-human transferrin receptor antibody with the extracellular region of the human transferrin receptor is equal to or less than 1×10 −10 M, and a dissociation constant of the anti-human transferrin receptor antibody with the extracellular region of the monkey transferrin receptor is equal to or less than 1×10 −9 M.

16. The fusion protein according to claim 1 ,

wherein the antibody is an antigen-binding fragment.

17. The fusion protein according to claim 16 ,

wherein the human BDNF binds to the N-terminus of the antigen-binding fragment via the linker.

18. The fusion protein according to claim 16 ,

wherein the antigen-binding fragment is a single-chain antibody.

19. The fusion protein according to claim 18 ,

wherein the light chain variable region binds to the C-terminus of the heavy chain variable region via a linker sequence.

20. The fusion protein according to claim 19 ,

wherein the linker sequence includes 8 to 50 amino acid residues.

21. The fusion protein according to claim 19 ,

wherein the linker sequence is selected from the group consisting of the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence Gly-Gly-Gly, the amino acid sequence of SEQ ID NO: 3, the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, the amino acid sequence corresponding to three consecutive amino acid sequences of SEQ ID NO: 3, and the amino acid sequence consisting of 2 to 10 of the aforementioned amino acid sequences consecutively linked.

22. The fusion protein according to claim 18 ,

wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 69 and a light chain variable region having the amino acid sequence of SEQ ID NO: 18.

23. The fusion protein according to claim 22 ,

wherein the antibody is formed of the amino acid sequence of SEQ ID NO: 57, and the human BDNF binds to the N-terminus of the heavy chain of the antibody via the linker.

24. The fusion protein according to claim 23 ,

wherein the antibody is formed of the amino acid sequence of SEQ ID NO: 57, the human BDNF is human pro-BDNF, and binds to the N-terminus of the heavy chain of the antibody via the linker, and the fusion protein comprises the amino acid sequence of SEQ ID NO: 59.

25. The fusion protein according to claim 23 ,

wherein the antibody is formed of the amino acid sequence of SEQ ID NO: 57, the human BDNF binds to the N-terminus of the heavy chain of the antibody via the linker, and the fusion protein comprises the amino acid sequence of SEQ ID NO: 60.

26. The fusion protein according to claim 16 ,

wherein the antigen-binding fragment is any one of Fab, F(ab′) 2 , or F(ab′).

27. The fusion protein according to claim 26 ,

wherein the human BDNF binds to the N-terminus of a heavy chain of any one of Fab, F(ab′) 2 , or F(ab′) via the linker.

28. The fusion protein according to claim 27 ,

wherein the light chain of the antibody is formed of the amino acid sequence of SEQ ID NO: 23, the heavy chain of the antibody is a Fab heavy chain formed of the amino acid sequence of SEQ ID NO: 61, and the human BDNF binds to the N-terminus of the heavy chain via the linker.

29. The fusion protein according to claim 28 ,

wherein the linker is a peptide including the amino acid sequence selected from the group consisting of the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence of SEQ ID NO: 3, the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, and the amino acid sequence consisting of 2 to 10 of the aforementioned amino acid sequences consecutively linked.

30. The fusion protein according to claim 28 ,

wherein the light chain comprises the amino acid sequence of SEQ ID NO: 23, and

wherein the human BDNF is human pro-BDNF, and a portion including the Fab heavy chain and human pro-BDNF binding to the N-terminus of the Fab heavy chain via the linker forms the amino acid sequence of SEQ ID NO: 63.

31. The fusion protein according to claim 28 ,

wherein the light chain comprises the amino acid sequence of SEQ ID NO: 23, and

wherein a portion including the Fab heavy chain and human BDNF binding to the N-terminus of the Fab heavy chain via the linker forms the amino acid sequence of SEQ ID NO: 65.

32. The fusion protein according to claim 16 ,

wherein the fusion protein further comprises an albumin-affinity peptide.

33. The fusion protein according to claim 32 ,

wherein the albumin-affinity peptide binds to the C-terminus of the antibody directly or via a linker sequence.

34. The fusion protein according to claim 32 ,

wherein the albumin-affinity peptide comprises the amino acid sequence represented by SEQ ID NO: 85.

35. The fusion protein according to claim 34 ,

wherein the heavy chain binds to the C-terminus of the human BDNF via the linker sequence, and the albumin-affinity peptide binds to the C-terminus of the heavy chain directly or via a linker sequence.

36. The fusion protein according to claim 35 ,

wherein the light chain comprises the amino acid sequence of SEQ ID NO: 23, and

wherein the human BDNF is human pro-BDNF, and the heavy chain binds to the C-terminus of human pro-BDNF via the linker sequence, and the albumin-affinity peptide binds to the C-terminus of the heavy chain via a linker sequence and thereby forms the amino acid sequence of SEQ ID NO: 87.

37. The fusion protein according to claim 35 ,

wherein the light chain comprises the amino acid sequence of SEQ ID NO: 23, and

wherein the heavy chain binds to the C-terminus of the human BDNF via the linker sequence, and the albumin-affinity peptide binds to the C-terminus of the heavy chain via a linker sequence and thereby forms the amino acid sequence of SEQ ID NO: 88.

38. The fusion protein according to claim 1 ,

wherein the linker is a peptide including the amino acid sequence consisting of at least five amino acids of SEQ ID NO: 3 consecutively linked.

39. A pharmaceutical composition comprising the fusion protein according to claim 1 as an active ingredient.

40. The pharmaceutical composition according to claim 39 , for improving a function of human BDNF in a patient, thereby alleviating a symptom of Huntington's disease that obtains benefits by exposing a brain to human BDNF.

41. A method of alleviating a symptom of Huntington's disease in a patient that obtains benefits by exposure to human BDNF, the method comprising:

administering a pharmaceutical composition containing a therapeutically effective amount of the fusion protein according to claim 1 to blood of the patient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2019
From: SONODA, HIROYUKI; TAKAHASHI, KENICHI
To: JCR PHARMACEUTICALS CO., LTD.
Reel/Frame 050362/0290 →
Priority Claims (1)
JP 2016-252147 · Dec 26, 2016 · national
Continuity (1)
Related Publication 20200384061A1 · Dec 10, 2020
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