PROTEINS, NUCLEIC ACIDS AND MEDICAMENTS

• US 20090105146A1
• Filed: 03/12/2007
• Published: 04/23/2009
• Est. Priority Date: 03/11/2006
• Status: Active Grant

• Current Assignee: Renovo Ltd. (Bentley Park Ltd.)
• Original Assignee: Renovo Ltd. (Bentley Park Ltd.)
• Inventors: Mellor, Phillip, Ferguson, Mark William James, Occleston, Nick, Atkinson, Emma, O'Kane, Sharon, Laverty, Hugh Gerard
• Granted Patent: US 7,947,264 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/495 Transforming growth factor [TGF]

Abstract

The invention provides TGF-β3s, or fragments or derivatives thereof, wherein the alpha-helix-forming domain between amino acid residues (58) and (67) of full-length wild type TGF-β3 comprises at least one alpha-helix-stabilising substitution. The invention also provides TGF-β3s, or fragments or derivatives thereof, wherein the Glycine residue at position (63) of full-length wild type TGF-β3 is replaced with Proline. Further still, the invention provides TGF-β3s, or fragments or derivatives thereof, comprising a substitution of the Glutamic acid residue at position (12) of full-length wild type TGF-β3 and/or the Arginine residue at position (52) of full-length wild type TGF-β3. The invention also provides medicaments and methods of treatment using such TGF-β3s.

Claims

1. An isolated TGF-β

3 protein, or a fragment or derivative thereof, wherein an alpha-helix-forming domain between amino acid residues 58 and 67 of full-length wild type TGF-β

3 comprises at least one alpha-helix-stabilising substitution.

2. An isolated TGF-β

3 protein, or fragment or derivative thereof, according to claim 1, wherein a glycine residue at position 63 of full-length wild type TGF-β

3 is replaced with an alpha-helix-stabilising amino acid residue.

3. An isolated TGF-β

3 protein, or fragment or derivative thereof, according to claim 1, wherein the alpha-helix-stabilising substitution comprises introduction of a residue selected from the group consisting of an Alanine, a Serine, a Threonine, a Valine, a Leucine, an Isoleucine, a Methionine and a Phenylalanine residue.

4. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 2, wherein the Glycine residue at position 63 of full-length wild type TGF-β

3 is replaced with an alanine residue.

5. An isolated TGF-β

3 protein, according to claim 4 comprising Sequence ID No. 3, or a fragment or derivative thereof.

6. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 1, which does not comprise a substitution of a Valine residue at position 61 of full-length wild type TGF-β

3.

14. A monomeric TGF-β

33, or a fragment or derivative thereof, according to claim 1.

15. A dimeric TGF-β

3, or a fragment or derivative thereof, according to claim 1.

25. An isolated nucleic acid encoding a TGF-β

3, or fragment or derivative thereof, according to claim 1.

26. A method of accelerating wound healing, or preventing reducing or inhibiting scarring, the method comprising administering a therapeutically effective amount of a TGF-β

3, or a fragment or derivative thereof, according to claim 1, to a patient in need thereof.

27. A method of preventing or treating a fibrotic disorder, the method comprising administering a therapeutically effective amount of a TGF-β

3, or a fragment or derivative thereof, according to claim 1, to a patient in need thereof.

28. A method according to claim 26, wherein the TGF-β

3, or fragment or derivative thereof, is administered on the skin of the patient in need thereof.

29. A method according to claim 26, wherein the TGF-β

3, or fragment or derivative thereof, is administered to the eye of the patient in need thereof.

30. A method according to claim 27, wherein the fibrotic disorder is selected from the group consisting of lung fibrosis, liver fibrosis, scleroderma, skin fibrosis, muscle fibrosis, radiation fibrosis, kidney fibrosis, proliferative vitreoretinopathy, and uterine fibrosis.

31. A method of promoting epithelial regeneration, the method comprising administering a therapeutically effective amount of a TGF-β

3, or a fragment or derivative thereof, according to claim 1, to a patient in need thereof.

32. A method of treating a disorder or condition, the method comprising:

administering a therapeutically effective amount of a TGF-β

3, or a fragment or derivative thereof, according to claim 1, to a patient in need thereof, and

wherein the disorder or condition is selected from the group consisting of angiogenic disorders, restenosis, adhesions, endometriosis, ischemic disease, oral mucositis, renal disease, bone and cartilage induction, and in vitro fertilisation.

33. A composition comprising a TGF-β

3, or a fragment or derivative thereof, according to claim 1, and a pharmaceutically acceptable vehicle.

7. An isolated TGF-β

3 protein, or a fragment or derivative thereof, wherein a Glycine residue at position 63 of full-length wild type TGF-β

3 is replaced with a Proline residue.

8. An isolated TGF-β

3 protein according to claim 7 comprising Sequence ID No. 5, or a fragment or derivative thereof.

34. A composition comprising a TGF-β

3, or a fragment or derivative thereof, according to claim 7, and a pharmaceutically acceptable vehicle.

9. An isolated TGF-β

3 protein, or a fragment or derivative thereof, comprising a substitution of a Glutamic acid residue at position 12 of full-length wild type TGF-β

3, a substitution of an Arginine residue at position 52 of full-length wild type TGF-β

3, or substitutions at both a glutamic acid residue at position 12 and an arginine residue at position of 52 of full-length wild type TGF-β

3.

10. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 9, wherein the substitution, or substitutions, is with an amino acid residue selected from the group consisting of;

a Serine;

an Alanine;

a Threonine;

a Valine;

an Isoleucine;

a Methionine;

a Phenylalanine; and

a Leucine residue.

11. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 9, wherein the Glutamic acid residue at position 12 of full-length wild type TGF-β

3 is substituted by a Serine residue.

12. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 9, wherein the Arginine residue at position 52 of full-length wild type TGF-β

3 is substituted by a Serine residue.

13. An isolated TGF-β

3 protein, or a fragment or derivative thereof, according to claim 9, wherein the TGF-β

3 is selected from the group consisting of Sequence ID. No. 7, Sequence ID. No. 9 and Sequence ID. No. 11.

35. A composition comprising a TGF-β

3, or a fragment or derivative thereof, according to claim 9, and a pharmaceutically acceptable vehicle.

16-24. -24. (canceled)