Method of treating bone cancers

Abstract

The present disclosure provides compositions and methods for treating osteosarcoma, such as osteosarcoma in a patient who has previously received at least one first-tier osteosarcoma treatment but has failed treatment. The methods comprise promoting the opening of Cx43 hemichannels in bone cells by, for example, using a composition comprising an anticonnexin 43 antibody.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480043966.5 (22) Application Date 2024.05.23 (30) Priority Data 63 / 504,162 2023.05.24 US (85) PCT International Application Entering National Phase Date 2025.12.29 (86) PCT International Application Application Data PCT / US2024 / 030843 2024.05.23 (87) PCT International Application Publication Data WO2024 / 243439 EN 2024.11.28 (71) Applicant Alamabu Therapeutics Co., Ltd. Address New Jersey, USA (72) Inventors Zhang Yanfeng, Yang Xiugao, Wu Yongyong (74) Patent Agency Beijing Liu Shen Law Firm 11105 Patent Attorney Zhang Wenhui (51) Int.Cl. C07K 16 / 28 (2006.01) A61K 39 / 395 (2006.01) (54) Invention Title: Method for Treating Bone Cancer (57) Abstract: This disclosure provides compositions and methods for treating bone cancer, such as osteosarcoma in patients who have previously received at least one line of osteosarcoma treatment but have failed. The method includes promoting the opening of Cx43 hemichannels in bone cells by, for example, using a composition containing an anti-connector protein 43 antibody. Claims: 4 pages Description: 70 pages Sequence Listing (electronic publication) Drawings: 12 pages CN 121568960 A 2026.02.24 CN 1 21 56 89 60 A

Claims

1. A method of treating bone cancer in a subject of need, comprising administering to the subject at least one dose of an anti-connector protein 43 (Cx43) antibody or an antigen-binding fragment thereof, wherein the anti-Cx43 antibody comprises The heavy chain variable region comprises the following HCDR amino acid sequence: HCDR1: SEQ ID NO: 1; HCDR2: SEQ ID NO: 2; HCDR3: SEQ ID NO: 3; and The light chain variable region comprises the following LCDR amino acid sequence: LCDR1: SEQ ID NO: 4; LCDR2: SEQ ID NO: 5; LCDR3: SEQ ID NO:

6.

2. The method according to claim 1, wherein the at least one dose of anti-Cx43 antibody or its antigen-binding fragment is about 0.001 mg / kg to about 300 mg / kg.

3. The method according to claim 1 or 2, wherein the at least one dose of anti-Cx43 antibody or its antigen-binding fragment is about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, about 12 mg / kg, about 18 mg / kg, about 24 mg / kg, about 30 mg / kg or about 36 mg / kg.

4. The method according to any one of claims 1 to 3, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of about once daily to about once every 12 months.

5. The method according to any one of claims 1 to 4, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

6. The method according to any one of claims 1 to 5, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of approximately once every 3 weeks.

7. The method according to any one of claims 1 to 6, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered intravenously, intradermally, intratumorally, intramuscularly, intraperitoneally, or subcutaneously.

8. The method according to any one of claims 1 to 7, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered intravenously.

9. The method of claim 8, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered over a period of about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 150 minutes, about 180 minutes, or longer.

10. The method according to any one of claims 1 to 9, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered in a pharmaceutically acceptable composition.

11. The method according to any one of claims 1 to 10, wherein the anti-Cx43 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence according to SEQ ID NO: 7, and / or a light chain variable region having an amino acid sequence according to SEQ ID NO:

8.

12. The method according to any one of claims 1 to 11, wherein the anti-Cx43 antibody comprises a heavy chain having an amino acid sequence according to any one of SEQ ID NO: 9 and 11-13, and / or a light chain having an amino acid sequence according to SEQ ID NO:

10.

13. The method according to any one of claims 1 to 12, wherein the anti-Cx43 antibody is a humanized antibody.

14. The method according to any one of claims 1 to 13, wherein the anti-Cx43 antibody or its antigen-binding fragment enhances the opening of the Cx43 hemichannel in the subject.

15. The method according to any one of claims 1 to 14, wherein the bone cancer is osteosarcoma.

16. The method of claim 15, wherein the osteosarcoma is (i) Resectable or unresectable; (ii) Stage IA, Stage IB, Stage II-A, Stage II-B, Stage III, Stage IV-A, or Stage IV-B; (iii) Low-level or high-level; and / or (iv) Primary osteosarcoma, osteoblastic osteosarcoma, chondrogenic osteosarcoma, fibroblastic osteosarcoma, small cell osteosarcoma, capillary dilatational osteosarcoma, periosteal osteosarcoma, classical osteosarcoma, osteoblastic osteosarcoma-sclerosing osteosarcoma, chondroblastoma-like osteosarcoma, chondromycinoid osteosarcoma, clear cell osteosarcoma, malignant fibrous histiocytoma-like osteosarcoma, giant cell rich osteosarcoma and / or epithelioid osteosarcoma.

17. The method according to any one of claims 1 to 16, wherein the subject has received at least one standard osteosarcoma treatment, including chemotherapy, surgery, immunotherapy, radiotherapy, or a combination thereof, but the treatment has failed.

18. The method according to any one of claims 1 to 17, wherein the subject has failed treatment with methotrexate, doxorubicin, cisplatin and ifosfamide, apatinib, anlotinib, vincristine, vincristine, docetaxel, paclitaxel, irinotecan, bortezomib, albumin-bound paclitaxel, nedaplatin (Aqupla), pemetrexed, etoposide, gemcitabine, lobaplatin, recombinant human endostatin, eribulin, dacarbazine, pazopanib, immune checkpoint inhibitors, surgery, radiotherapy, or combinations thereof.

19. The method according to any one of claims 1 to 18, wherein after treatment with the anti-Cx43 antibody or its antigen-binding fragment, the subject achieves: (i) Progression-free survival of at least 1 month, 2 months, 3 months, at least 4 months, at least 5 months or at least 6 months; (ii) Overall survival improved by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months; (iii) Improvement in EQ-5D score; (iv) Improvement in disease progression as assessed by PERCIST, RECIST and / or ICDS criteria; (v) Improvement in pain score as assessed by the NRS; and / or (vi) The tumor size is reduced by at least 1%, at least 2%, at least 3%, at least 5%, at least 8%, at least 10%, at least 15%, at least 20%, or at least 30%.

20. The method according to any one of claims 1 to 19, wherein the subject achieves complete or partial remission from treatment with the anti-Cx43 antibody or its antigen-binding fragment.

21. A method of treating bone cancer in a subject in need, comprising administering to the subject at least one dose of an anti-connector protein 43 (Cx43) antibody or an antigen-binding fragment thereof, wherein the at least one dose of the anti-Cx43 antibody is from about 0.01 mg / kg to about 300 mg / kg.

22. The method of claim 21, wherein the at least one dose of the anti-Cx43 antibody or its antigen-binding fragment is about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, about 12 mg / kg, about 18 mg / kg, about 24 mg / kg, about 30 mg / kg, or about 36 mg / kg.

23. The method of claim 21 or 22, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of about once daily to about once every 12 months.

24. The method according to any one of claims 21 to 23, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

25. The method according to any one of claims 21 to 24, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered at a frequency of about once every 3 weeks.

26. The method according to any one of claims 21 to 25, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered intravenously, intradermally, intratumorally, intramuscularly, intraperitoneally, subcutaneously, or locally.

27. The method according to any one of claims 21 to 26, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered intravenously.

28. The method of claim 27, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered over a period of about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 150 minutes, about 180 minutes, or longer.

29. The method according to any one of claims 21 to 28, wherein the anti-Cx43 antibody or its antigen-binding fragment is administered in a pharmaceutically acceptable composition.

30. The method according to any one of claims 21 to 29, wherein the anti-Cx43 antibody or its antigen-binding fragment comprises The heavy chain variable region comprises the following HCDR amino acid sequence: HCDR1: SEQ ID NO: 1; HCDR2: SEQ ID NO: 2; HCDR3: SEQ ID NO: 3; and The light chain variable region comprises the following LCDR amino acid sequence: LCDR1: SEQ ID NO: 4; LCDR2: SEQ ID NO: 5; LCDR3: SEQ ID NO:

6.

31. The method according to any one of claims 21 to 30, wherein the anti-Cx43 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence according to SEQ ID NO: 7, and / or a light chain variable region having an amino acid sequence according to SEQ ID NO:

8.

32. The method according to any one of claims 21 to 31, wherein the anti-Cx43 antibody comprises a heavy chain having an amino acid sequence according to any one of SEQ ID NO: 9 and 11-13, and / or a light chain having an amino acid sequence according to SEQ ID NO:

10.

33. The method according to any one of claims 21 to 32, wherein the anti-Cx43 antibody is a humanized antibody.

34. The method according to any one of claims 21 to 33, wherein the anti-Cx43 antibody or its antigen-binding fragment enhances the opening of the Cx43 hemichannel in the subject.

35. The method according to any one of claims 21 to 34, wherein the bone cancer is osteosarcoma.

36. The method of claim 35, wherein the osteosarcoma is (i) Resectable or unresectable; (ii) Stage IA, Stage IB, Stage II-A, Stage II-B, Stage III, Stage IV-A, or Stage IV-B; (iii) Low-level or high-level; and / or (iv) Primary osteosarcoma, osteoblastic osteosarcoma, chondrogenic osteosarcoma, fibroblastic osteosarcoma, small cell osteosarcoma, capillary dilatational osteosarcoma, periosteal osteosarcoma, classical osteosarcoma, osteoblastic osteosarcoma-sclerosing osteosarcoma, chondroblastoma-like osteosarcoma, chondromycinoid osteosarcoma, clear cell osteosarcoma, malignant fibrous histiocytoma-like osteosarcoma, giant cell rich osteosarcoma and / or epithelioid osteosarcoma.

37. The method according to any one of claims 21 to 36, wherein the subject has received at least one standard osteosarcoma treatment, including chemotherapy, surgery, radiotherapy, immunotherapy, or a combination thereof, but the treatment has failed.

38. The method according to any one of claims 21 to 37, wherein the subject has failed treatment with methotrexate, doxorubicin, cisplatin and ifosfamide, apatinib, anlotinib, vincristine, vincristine, docetaxel, paclitaxel, irinotecan, bortezomib, albumin-bound paclitaxel, nedaplatin (Aqupla), pemetrexed, etoposide, gemcitabine, lobaplatin, recombinant human endostatin, eribulin, dacarbazine, pazopanib, immune checkpoint inhibitors, surgery, radiotherapy, or combinations thereof.

39. The method according to any one of claims 21 to 38, wherein after treatment with the anti-Cx43 antibody or its antigen-binding fragment, the subject achieves: (i) Progression-free survival of at least 1 month, 2 months, 3 months, at least 4 months, at least 5 months or at least 6 months; (ii) Overall survival improved by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months; (iii) Improvement in EQ-5D score; (iv) Improvement in disease progression as assessed by PERCIST, RECIST and / or ICDS criteria; (v) Improvement in pain score as assessed by the NRS; and / or (vi) The tumor size is reduced by at least 1%, at least 2%, at least 3%, at least 5%, at least 8%, at least 10%, at least 15%, at least 20%, or at least 30%.

40. The method according to any one of claims 21 to 39, wherein the subject achieves complete or partial remission from treatment with the anti-Cx43 antibody or its antigen-binding fragment.

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