CD39-targeting antigen-binding protein and its use
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- SHANGHAI ORIGINCELL MEDICAL TECHNOLOGY CO LTD
- Filing Date
- 2024-06-03
- Publication Date
- 2026-06-09
Smart Images
Figure 2026518805000007 
Figure 2026518805000008 
Figure 2026518805000009
Abstract
Claims
1. An antibody or its antigen-binding fragment that can specifically bind to the CD39 protein, (1) 1 x 10 －８ The characteristic of being able to bind to CD39 with an M or lower KD value, (2) The property of being able to bind to human CD39, mouse CD39, or cynomolgus monkey CD39, (3) The property of being able to effectively inhibit the enzymatic activity of the CD39 protein, (4) A property that can inhibit the growth and / or proliferation of tumor cells, An antibody or its antigen-binding fragment having one or more of the following characteristics.
2. The antibody or antigen-binding fragment thereof according to claim 1, comprising at least one CDR in the antibody heavy chain variable region (VH) containing an amino acid sequence shown in any one of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 37, and SEQ ID NO:
41.
3. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 2, comprising HCDR3 having an amino acid sequence represented by any one of SEQ ID NO:3, SEQ ID NO:54, and SEQ ID NO:
55.
4. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising HCDR3 having an amino acid sequence shown in any one of SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:18, SEQ ID NO:24, SEQ ID NO:29, and SEQ ID NO:
33.
5. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, comprising HCDR2 having an amino acid sequence represented by any one of SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 23, and SEQ ID NO:
28.
6. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, comprising HCDR1 having an amino acid sequence represented by any one of SEQ ID NO: 1, SEQ ID NO: 53, and SEQ ID NO:
22.
7. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, comprising HCDR1 having an amino acid sequence shown in any one of SEQ ID NO: 1, SEQ ID NO: 9, SEQ ID NO: 17, and SEQ ID NO:
22.
8. Including HCDR1, HCDR2, and HCDR3, The aforementioned HCDR1, HCDR2, and HCDR3 are, (1) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 1, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
3. (2) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 9, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 10, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
11. (3) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 17, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 10, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
18. (4) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 22, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 23, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
24. (5) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 22, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 28, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
29. (6) The HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 22, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 28, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:
33. The amino acid sequence includes an amino acid sequence selected from the group consisting of the following: An antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.
9. An antibody or antigen-binding fragment according to any one of claims 1 to 8, comprising H-FR1, wherein the C-terminus of H-FR1 is directly or indirectly ligated to the N-terminus of HCDR1, and H-FR1 comprises the amino acid sequence shown in SEQ ID NO:
56.
10. The antibody or antigen-binding fragment thereof according to claim 9, wherein the H-FR1 comprises an amino acid sequence shown in any one of SEQ ID NO: 4, SEQ ID NO: 12, SEQ ID NO: 19, SEQ ID NO: 34, and SEQ ID NO:
38.
11. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, comprising H-FR2, wherein H-FR2 is located between HCDR1 and HCDR2, and H-FR2 comprises the amino acid sequence shown in SEQ ID NO:
57.
12. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, wherein the H-FR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 5, SEQ ID NO: 13, SEQ ID NO: 20, SEQ ID NO: 25, SEQ ID NO: 30, and SEQ ID NO:
35.
13. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, comprising H-FR3, wherein H-FR3 is located between HCDR2 and HCDR3, and H-FR3 comprises the amino acid sequence shown in SEQ ID NO:
58.
14. The antibody or antigen-binding fragment thereof according to claim 13, wherein the H-FR3 comprises an amino acid sequence shown in any one of SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 36, and SEQ ID NO:
40.
15. An antibody or antigen-binding fragment according to any one of claims 1 to 14, comprising H-FR4, wherein the N-terminus of H-FR4 is ligated to the C-terminus of HCDR3, and the H-FR4 comprises the amino acid sequence shown in SEQ ID NO:
59.
16. The antibody or antigen-binding fragment thereof according to claim 15, wherein the H-FR4 comprises an amino acid sequence shown in any one of SEQ ID NO: 7, SEQ ID NO: 15, and SEQ ID NO:
39.
17. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 16, comprising a VH having an amino acid sequence shown in any one of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 37, and SEQ ID NO:
41.
18. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, wherein the antibody is VHH.
19. The antibody or antigen-binding fragment thereof according to claim 18, wherein the VHH comprises an amino acid sequence shown in any one of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 37, and SEQ ID NO:
41.
20. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 19, comprising an antibody heavy chain constant region.
21. The antibody or antigen-binding fragment thereof according to claim 20, wherein the antibody heavy chain constant region is derived from a human IgG constant region.
22. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 21, wherein the antibody heavy chain constant region is derived from the human IgG4 constant region.
23. The antibody or antigen-binding fragment according to any one of claims 20 to 22, wherein the constant region of the antibody heavy chain comprises the amino acid sequence shown in SEQ ID NO:
44.
24. The antigen-binding fragments are Fab, Fab', Fv fragment, and F(ab'). ２ F(ab) ２ An antibody or antigen-binding fragment thereof according to any one of claims 1 to 23, comprising scFv, di-scFv and / or dAb.
25. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 24, wherein the antibody is selected from one or more of the group consisting of monoclonal antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies.
26. A bispecific antibody or antigen-binding fragment thereof comprising a first binding domain that specifically binds to the CD39 protein, wherein the first binding domain comprises the antibody or antigen-binding fragment thereof described in any one of claims 1 to 25.
27. The bispecific antibody or antigen-binding fragment thereof according to claim 26, wherein the first binding domain that specifically binds to CD39 is VHH that specifically binds to CD39.
28. A bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 27, comprising a second binding domain that specifically binds to the PD-L1 protein.
29. The bispecific antibody or antigen-binding fragment according to claim 28, wherein the second binding domain that specifically binds to the PD-L1 protein comprises a PD-L1 antibody or an antigen-binding fragment thereof.
30. The bispecific antibody or antigen-binding fragment according to claim 29, wherein the PD-L1 antibody or antigen-binding fragment comprises HCDR1 having the amino acid sequence shown in SEQ ID NO: 45, HCDR2 having the amino acid sequence shown in SEQ ID NO: 46, and HCDR3 having the amino acid sequence shown in SEQ ID NO:
47.
31. The bispecific antibody or antigen-binding fragment according to any one of claims 29 to 30, wherein the PD-L1 antibody or its antigen-binding fragment comprises a VH having the amino acid sequence shown in SEQ ID NO:
48.
32. The PD-L1 antibody or its antigen-binding fragment comprises an LCDR1 containing the amino acid sequence shown in SEQ ID NO: 49, an LCDR2 containing the amino acid sequence shown in SEQ ID NO: 50 (GNS), and an LCDR3 containing the amino acid sequence shown in SEQ ID NO: 51, according to any one of claims 29 to 31.
33. The bispecific antibody or antigen-binding fragment according to any one of claims 29 to 32, wherein the PD-L1 antibody or its antigen-binding fragment comprises a VL containing the amino acid sequence shown in SEQ ID NO:
52.
34. The bispecific antibody or antigen-binding fragment according to any one of claims 29 to 33, wherein the PD-L1 antibody or its antigen-binding fragment includes an antibody heavy chain constant region.
35. The bispecific antibody or antigen-binding fragment thereof according to claim 34, wherein the antibody heavy chain constant region is derived from the human IgG constant region.
36. The PD-L1 antibody or its antigen-binding fragment comprises the antibody light chain constant region, as described in any one of claims 29 to 35.
37. The bispecific antibody or antigen-binding fragment according to any one of claims 29 to 36, wherein the C-terminus of VHH that specifically binds to CD39 is directly or indirectly linked to the N-terminus of the PD-L1 antibody or its antigen-binding fragment.
38. The bispecific antibody or antigen-binding fragment according to any one of claims 29 to 36, wherein the N-terminus of VHH that specifically binds to CD39 is directly or indirectly linked to the C-terminus of the PD-L1 antibody or its antigen-binding fragment.
39. The bispecific antibody or antigen-binding fragment thereof according to claim 38, wherein the indirect linking includes linking via a linker.
40. The bispecific antibody or antigen-binding fragment thereof according to claim 39, wherein the linker comprises an amino acid sequence represented by (G4S)n, where n is a positive integer from 1 to 10.
41. A bispecific antibody or antigen-binding fragment according to any one of claims 29 to 40, comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises a heavy chain variable region of the PD-L1 antibody or its antigen-binding fragment, a heavy chain constant region of the PD-L1 antibody or its antigen-binding fragment, and VHH that specifically binds to the CD39, and the second polypeptide chain comprises a light chain variable region and a light chain constant region of the PD-L1 antibody or its antigen-binding fragment.
42. A bispecific antibody or antigen-binding fragment according to any one of claims 29 to 41, comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises a heavy chain variable region of the PD-L1 antibody or its antigen-binding fragment, a heavy chain constant region of the PD-L1 antibody or its antigen-binding fragment, a linker, and VHH that specifically binds to the CD39, and the second polypeptide chain comprises a light chain variable region and a light chain constant region of the PD-L1 antibody or its antigen-binding fragment.
43. A bispecific antibody or antigen-binding fragment according to any one of claims 29 to 42, comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises, in order from the N-terminus to the C-terminus, a heavy chain variable region of the PD-L1 antibody or its antigen-binding fragment, a heavy chain constant region of the PD-L1 antibody or its antigen-binding fragment, a linker, and VHH that specifically binds to the CD39, and the second polypeptide chain comprises a light chain variable region and a light chain constant region of the PD-L1 antibody or its antigen-binding fragment.
44. A bispecific antibody or antigen-binding fragment according to any one of claims 29 to 42, comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises, in order from the N-terminus to the C-terminus, a VHH that specifically binds to the CD39, a linker, a heavy chain variable region of the PD-L1 antibody or its antigen-binding fragment, and a heavy chain constant region of the PD-L1 antibody or its antigen-binding fragment, and the second polypeptide chain comprises a light chain variable region and a light chain constant region of the PD-L1 antibody or its antigen-binding fragment.
45. A polypeptide comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, or a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44.
46. One or more isolated nucleic acid molecules encoding an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, or a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44.
47. The nucleic acid molecule according to claim 46, further comprising a nucleic acid molecule encoding another protein.
48. The nucleic acid molecule according to claim 47, wherein the other protein comprises a chimeric antigen receptor (CAR).
49. A vector comprising a nucleic acid molecule according to any one of claims 46 to 48.
50. The vector according to claim 49, wherein the nucleic acid molecule encoding the other protein is located in the same vector as the nucleic acid molecule encoding the antibody or its antigen-binding fragment.
51. The vector according to claim 49, wherein the nucleic acid molecule encoding the other protein is located in a vector different from the nucleic acid molecule encoding the antibody or its antigen-binding fragment.
52. A cell comprising a nucleic acid molecule according to any one of claims 46 to 48, or a vector according to any one of claims 49 to 51.
53. The cell according to claim 52, comprising immune cells.
54. The cell according to claim 53, wherein the immune cell includes a T cell, an NK cell, and / or a macrophage.
55. The cell according to any one of claims 5 to 54, further comprising and / or expressing other proteins.
56. The cell according to claim 55, wherein the other protein includes a chimeric antigen receptor (CAR).
57. It is a combination of drugs, (1) An antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, or a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44, (2) Cells and, A combination of drugs containing [a specific ingredient].
58. The drug combination according to claim 57, wherein the cells include modified cells or unmodified cells.
59. The combination of drugs according to any one of claims 57 to 58, wherein the modified cells contain and / or express CAR.
60. The drug combination according to any one of claims 57 to 59, wherein the aforementioned cells include immune cells.
61. The drug combination according to any one of claims 57 to 60, wherein the cells include T cells, NK cells, and / or macrophages.
62. A method for producing an antibody or antigen-binding fragment according to any one of claims 1 to 25, or a bispecific antibody or antigen-binding fragment according to any one of claims 26 to 44, comprising culturing cells according to any one of claims 52 to 56 under conditions in which an antibody or antigen-binding fragment according to any one of claims 1 to 25, or a bispecific antibody or antigen-binding fragment according to any one of claims 26 to 44, is expressed.
63. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44, a nucleic acid molecule according to any one of claims 46 to 48, a vector according to any one of claims 49 to 51, a cell according to any one of claims 52 to 56, and / or a combination of drugs according to any one of claims 57 to 61, and optionally a pharmaceutically acceptable carrier.
64. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44, a nucleic acid molecule according to any one of claims 46 to 48, a vector according to any one of claims 49 to 51, a cell according to any one of claims 52 to 56, a combination of drugs according to any one of claims 57 to 61, and / or a pharmaceutical composition according to claim 63 in the manufacture of a drug for preventing and / or treating a disease and / or disorder.
65. The use according to claim 64, wherein the disease and / or disorder includes a tumor.
66. The use according to claim 65, wherein the tumor includes solid cancers and / or hematological tumors.
67. The use according to any one of claims 65 to 66, wherein the tumor includes a tumor affected by CD39 activity.
68. Methods for preventing and / or treating diseases and / or disorders, A method comprising administering to a subject requiring the use of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 25, a bispecific antibody or antigen-binding fragment thereof according to any one of claims 26 to 44, a nucleic acid molecule according to any one of claims 46 to 48, a vector according to any one of claims 49 to 51, a cell according to any one of claims 52 to 56, a combination of drugs according to any one of claims 57 to 61, and / or a pharmaceutical composition according to claim 63.
69. The method according to claim 68, wherein the disease and / or disorder includes a tumor.
70. The method according to claim 69, wherein the tumor includes solid cancers and / or hematological cancers.
71. The method according to any one of claims 69 to 70, wherein the tumor includes a tumor affected by CD39 activity.