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EP-4735039-A1 - METHOD OF TREATING OSTEOARTHRITIS

EP4735039A1EP 4735039 A1EP4735039 A1EP 4735039A1EP-4735039-A1

Abstract

The present disclosure provides compositions and methods of treating osteoarthritis such as osteoarthritis in a subject. The method comprises blocking the opening of Cx43 hemichannel in chondrocytes by, e.g ., using a composition comprising an anti-connexin 43 antibody.

Inventors

  • ZHANG, YANFENG

Assignees

  • Alamab Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject at least one dose of an anti-connexin 43 (Cx43) antibody, wherein the anti- Cx43 antibody comprises heavy chain CDR sequences and light chain CDR sequences as follows: HCDR1 : SEQ ID NO: 1; HCDR2: SEQ ID NO: 2; HCDR3: SEQ ID NO: 3; LCDR1 : SEQ ID NO: 4; LCDR2: SEQ ID NO: 5; and LCDR3: SEQ ID NO: 6.
  2. 2. The method of claim 1, comprising administering a first dose of the anti-Cx43 antibody at day 1, and a second dose at day 8.
  3. 3. The method of claim 2, further comprising administering a third dose of the anti-Cx43 antibody at day 15.
  4. 4. The method of claim 3, further comprising administering a fourth dose of the anti-Cx43 antibody at day 22.
  5. 5. The method of claim 4, further comprising administering subsequently doses weekly after the fourth dose.
  6. 6. The method of any one of claims 1-5, wherein the first, second, third, fourth and/or subsequent doses are about 0.01 mg/kg to about 100 mg/kg.
  7. 7. The method of any one of claims 1-6, wherein the first, second, third, fourth and/or subsequent doses are about 15 mg/kg.
  8. 8. The method of any one of claims 1-6, wherein the first, second, third, fourth and/or subsequent doses are about 25 mg/kg.
  9. 9. The method of any one of claims 1-6, wherein the first, second, third, fourth and/or subsequent doses are about 50 mg/kg.
  10. 10. The method of any one of claims 1-9, wherein the anti-Cx43 antibody administered intravenously.
  11. 11. The method of any one of claims 1-10, wherein at least one indicator of osteoarthritis severity is assessed at least one day to one week after each dose is administered.
  12. 12. The method of claim 11, wherein the at least one indicator of osteoarthritis severity comprises: (a) pain threshold of the arthritis, (b) gait score, or (c) weight bearing difference.
  13. 13. The method of any one of claims 1-12, wherein at least one indicator of osteoarthritis severity is improved after at least one dose of the anti-Cx43 antibody is administered.
  14. 14. The method of any one of claims 1-13, wherein the subject is a human.
  15. 15. The method of any one of claims 1-14, wherein the anti-Cx43 antibody comprises heavy chain variable sequence of SEQ ID NO: 7, and/or light chain variable sequence of SEQ ID NO: 8.
  16. 16. The method of any one of claims 1-15, wherein the anti-Cx43 antibody comprises heavy chain sequence of any one of SEQ ID NOs: 9 and 11-18, and/or light chain variable sequence of SEQ ID NO: 10.
  17. 17. The method of any one of claims 1-16, wherein the anti-Cx43 antibody comprises heavy chain sequence of SEQ ID NO: 9, and/or light chain variable sequence of SEQ ID NO: 10.
  18. 18. A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti- Cx43 antibody is administered according to the following dosage regimen: i) a first dose at day 1 ; ii) a second dose at day 8; iii) a third dose at day 15; and iv) a fourth dose at day 21.
  19. 19. The method of claim 18, further comprising administering subsequent doses of the anti- Cx43 antibody weekly after the fourth dose.
  20. 20. The method of claim 18 or claim 19, wherein the first, second, third, fourth and/or subsequent doses are about 0.01 mg/kg to about 100 mg/kg.

Description

METHOD OF TREATING OSTEOARTHRITIS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to U.S. Provisional Application No. 63/511,563, filed on June 30, 2023, the disclosure of which is hereby incorporated by reference in its entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING [0002] The Sequence Listing titled 172628-201003_PCT_SL.xml, which was created on June 19, 2024 and is 34,860 bytes in size, is hereby incorporated by reference in its entirety. BACKGROUND [0003] Osteoarthritis (OA) is a prevalent type of arthritis that affects approximately 20% of U.S. adults. Osteoarthritis causes the degeneration of joints including articular cartilage and subchondral bone, and is characterized by a loss of articular cartilage leading to narrowing of joint space, increased joint friction and potential structure remodeling. Current treatment includes exercise, lifestyle change and analgesics. If symptom becomes severe, joint replacement surgery is normally performed. However, most existing therapies fail to address the underlying cause of osteoarthritis (z.e., the deterioration of cartilage). [0004] Chondrocytes express connexin Cx43 hemichannels, and these channels mediate the passage of small molecules (less than 1.2 kDa) between inside/outside of the cell. Hemichannels are normally closed, but under certain conditions, such as mechanical stress and inflammatory conditions, they are activated and opened. Opened Cx43 hemichannels in chondrocytes promote inflammatory response with the release of pro-inflammatory factors, such as prostaglandin E2 (PGE2) and ATP. Inhibiting the opening of Cx43 hemichannels in chondrocytes (e.g., by chemical reagents, etc.), can suppress the inflammation and the development of osteoarthritis. [0005] Thus, there remains a need for therapies for effective treatment of osteoarthritis and other pathological conditions associated with increased hemichannel activity SUMMARY [0006] In some aspects of the disclosure, provided herein are methods for treating osteoarthritis in a subject in need thereof, comprising administering to the subject at least one dose of an anti-connexin 43 (Cx43) antibody. In some embodiments, the anti-Cx43 antibody comprises heavy chain CDR sequences and light chain CDR sequences as follows: HCDR1 : SEQ ID NO: 1; HCDR2: SEQ ID NO: 2; HCDR3: SEQ ID NO: 3; LCDR1 : SEQ ID NO: 4; LCDR2: SEQ ID NO: 5; and LCDR3: SEQ ID NO: 6. [0007] In some embodiments, the method comprises administering a first dose of the anti-Cx43 antibody at day 1, and a second dose at day 8. In some embodiments, the method further comprises administering a third dose of the anti-Cx43 antibody at day 15. In some embodiments, the method further comprises administering a fourth dose of the anti-Cx43 antibody at day 22. In some embodiments, the method further comprises administering subsequently doses weekly after the fourth dose. [0008] In other aspects of the disclosure, provided herein are methods for treating osteoarthritis in a subject in need thereof, comprising administering to the subject an effective amount of an anti-connexin 43 (Cx43) antibody, wherein the anti-Cx43 antibody is administered according to the following dosage regimen: i) a first dose at day 1 ; ii) a second dose at day 8; iii) a third dose at day 15; and iv) a fourth dose at day 21. [0009] In some embodiments, the method further comprises administering subsequent doses of the anti-Cx43 antibody weekly after the fourth dose. [0010] In some embodiments, the anti-Cx43 antibody comprises heavy chain CDR sequences and light chain sequences as follows: HCDR1 : SEQ ID NO: 1; HCDR2: SEQ ID NO: 2; HCDR3: SEQ ID NO: 3; LCDR1 : SEQ ID NO: 4; LCDR2: SEQ ID NO: 5; and LCDR3: SEQ ID NO: 6. [0011] In some embodiments of any of the methods of the disclosure, the first, second, third, fourth and/or subsequent doses are about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the first, second, third, fourth and/or subsequent doses are about 15 mg/kg. In some embodiments, the first, second, third, fourth and/or subsequent doses are about 25 mg/kg. In some embodiments, the first, second, third, fourth and/or subsequent doses are about 50 mg/kg. [0012] In some embodiments of any of the methods of the disclosure, the anti-Cx43 antibody administered intravenously. [0013] In some embodiments of any of the methods of the disclosure, at least one indicator of osteoarthritis severity is assessed at least one day to one week after each dose is administered. In some embodiments, the at least one indicator of osteoarthritis severity comprises: (a) pain threshold of the arthritis, (b) gait score, or (c) weight bearing difference. In some embodiments, at least one indicator of osteoarthritis severity is improved after at least one dose of the anti-Cx43 antibody is administered. [0014] In some embodiments of any of the methods of the disclosure, the anti-Cx43 antibody comprises heavy chain variable sequence of SEQ ID NO: 7,