Methods for treating heterotopic ossification

Patent metadata

Field	Value
Publication number	US-12364736-B2
Application number	US-201916967922-A
Country	US
Kind code	B2
Filing date	Feb 8, 2019
Priority date	Feb 9, 2018
Publication date	Jul 22, 2025
Grant date	Jul 22, 2025

Abstract

In part, the present disclosure relates methods for treating heterotopic ossification or one or more complications of heterotopic ossification. In particular, the disclosure provided methods for treating heterotopic ossification by administering to a patient in need thereof one or more TGFβ antagonists, optionally in combination with one or more additional active agents or supportive therapies for treating heterotopic ossification. For example, in some embodiments, the disclosure provided methods for treating heterotopic ossifications by administering to a patient in need thereof an effective amount of a TβRII polypeptide.

First claim

We claim:

1. A method for treating heterotopic ossification (HO) in a patient in need thereof, comprising administering to the patient an effective amount of a Transforming Growth Factor-β (TGFβ) antagonist, wherein the TGFB antagonist is a fusion polypeptide comprising:
a Transforming Growth Factor-β Receptor II (TβRII) polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 18;
a linker domain comprising (GGGGS) n (SEQ ID NO: 19), wherein n≠>5; and
an Fc domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 49,
wherein the linker domain connects the TBRII polypeptide and Fc domain; and
wherein the TβRII polypeptide (1) binds to TGFβ1 and/or TGFβ3, and (2) inhibits TGFβ1 and/or TGFβ3 signaling.

2. The method of claim 1 , wherein the TβRII polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 18.

3. The method of claim 1 , wherein the TβRII polypeptide comprises the amino acid sequence of SEQ ID NO: 18.

4. The method of claim 1 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 49.

5. The method of claim 1 , wherein the linker
is between 10 and 25 amino acids in length.

6. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of (GGGGS)n (SEQ ID NO: 19), wherein n≥2.

7. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of (GGGGS)n (SEQ ID NO: 19), wherein n≥3.

8. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of (GGGGS)n (SEQ ID NO: 19), wherein n≥4.

9. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of (GGGGS)n (SEQ ID NO: 19), wherein n=2-4.

10. The method of claim 1 , wherein the linker domain comprises the amino acid sequence of any one of SEQ ID NOs: 4-6, 21 and 25.

11. The method of claim 1 , wherein the fusion polypeptide comprises:
a TβRII polypeptide comprising the amino acid sequence of SEQ ID NO: 18;
a linker portion comprising the amino acid sequence of SEQ ID NO: 6; and
an Fc domain comprising the amino acid sequence of SEQ ID NO: 49.

12. The method of claim 1 , wherein the fusion polypeptide consists of:
a TβRII polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 18 and no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 additional amino acids;
a linker domain comprising (GGGGS) n (SEQ ID NO: 19), wherein n≠>5, and no more than 5, 4, 3, 2 or 1 additional amino acids; and
an Fc domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 49 and no more than 25, 20, 15, 10, 5, 4, 3, 2 or 1 additional amino acids.

13. The method of claim 1 , wherein the fusion polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 11, 13, 15, 65 or 68.

14. The method of claim 1 , wherein the fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 48.

15. The method of claim 1 , wherein the fusion polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety.

16. The method of claim 1 , wherein the fusion polypeptide is a homodimer.

17. The method of claim 1 , wherein the heterotopic ossification is associated with one or more disorders or conditions selected from the group consisting of: spinal cord injury, trauma, brain injuries, burns, fractures, muscle contusion, joint arthroplasty/replacement, hip surgery/replacement, acetabular surgery/replacement, elbow fracture, fracture of the long bones of the lower leg, combat-related trauma, amputation, neuromuscular blockade used to manage adult respiratory distress syndrome, and non-traumatic myelopathies.

18. The method of claim 1 , wherein the heterotopic ossification occurs in one or more tissues selected from the group consisting of: bone, skin, subcutaneous tissue, skeletal muscle, fibrosis tissue adjacent to joints, walls of blood vessels, and ligaments.

19. The method of claim 1 , wherein the fusion polypeptide prevents or reduces the severity or duration of heterotopic ossification in the patient, or prevents or reduces one or more complications of heterotopic ossification selected from the group consisting of: joint contracture, ankylosis, pain, spasticity, swelling fever, neurovascular compression, and pressure ulcers.

20. The method of claim 1 , wherein the fusion polypeptide is administered in combination with an additional active agent or supportive therapy for treating heterotopic ossification, fibrodysplasia ossificans progressiva (FOP), progressive osseous heteroplasia (POH), or fibrous dysplasia,
said additional active agent or supportive therapy being selected from the group consisting of: isotretinoin, etidronate with oral corticosteroids, perhexiline maleate, ALK2 small molecule inhibitors, palovarotene, retinoic acid receptor gamma agonists, retinoic acid receptor alpha agonists, activin antibodies, ALK2 allele-specific RNA interference, bisphosphonates, radiation therapy, anti-inflammatory agents, conservative treatments, passive range of motion exercises, and mobilization techniques.

Assignees

• Acceleron Pharma Inc
• Univ Michigan Regents

Inventors

• Levi Benjamin
• Kumar Ravindra
• Agarwal Shailesh

Classifications

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07K14/71

  for growth factors; for growth regulators · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title