Ameliorating systemic sclerosis with death receptor agonists

Patent metadata

Field	Value
Publication number	US-11007251-B2
Application number	US-201616063592-A
Country	US
Kind code	B2
Filing date	Dec 16, 2016
Priority date	Dec 17, 2015
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

The present disclosure relates to methods and compositions for treating and/or preventing autoimmune fibrosis, such as systemic sclerosis (SSc; scleroderma). The method includes administering to a subject in need thereof an effective amount of a death receptor agonist. Suitable death receptor agonists include tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), agonistic death receptor antibodies, and variants, analogues, or derivatives thereof. The administration of the death receptor agonist blocks fibroblast or profibrogenic cell activation, and/or reduces or depletes myofibroblasts, thereby reducing or preventing systemic sclerosis.

First claim

What is claimed is:

1. A method for treating systemic sclerosis (SSc) in a mammalian subject, the method comprising:
administering to the subject in need thereof a death receptor 4 (DR4) or DR5 agonist in an amount effective to block activation of fibroblasts or deplete activated myofibroblasts induced by transforming growth factor (TGF)-beta, and reduce collagen deposition to normal levels.

2. The method of claim 1 , wherein the SSc is limited scleroderma or diffuse scleroderma.

3. The method of claim 1 , wherein the death receptor agonist comprises a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a TRAIL analogue, a death receptor agonistic antibody, or a derivative thereof.

4. The method of claim 1 , wherein the death receptor agonist comprises human recombinant TRAIL, a human TRAIL analogue, or a derivative thereof.

5. The method of claim 1 , wherein the death receptor agonist comprises native TRAIL, a native TRAIL analogue, or a derivative thereof.

6. The method of claim 1 , wherein the death receptor agonist comprises a DR5 agonist selected from the group consisting of Lexatumumab, Tigatuzumab, Conatumumab, Drozitumab, HGSTR2J/KMTRS, and LBY-135.

7. The method of claim 1 , wherein the death receptor agonist comprises a multivalent DR agonist selected from the group consisting of TAS266 and scTRAIL-RBDs.

8. The method of claim 1 , wherein the death receptor agonist comprises human recombinant TRAIL, a human TRAIL analogue, or a derivative thereof selectively attached at its N-terminus to a polymer.

9. The method of claim 8 , wherein the polymer comprises polyethylene glycol (PEG), or derivative thereof.

10. The method of claim 9 , wherein the PEG or PEG derivative is selected from the group consisting of methoxypolyethylene glycol succinimidyl propionate, methoxypolyethylene glycol succinate N-hydroxysuccinimide, methoxypolyethylene glycol propionaldehyde, methoxypolyethylene glycol maleimide, and multiple-branched polyethylene glycol.

11. The method of claim 9 , wherein the PEG or derivative thereof has a molecular weight of between 1,000 Da and 100,000 Da.

12. The method of claim 9 , wherein the PEG or derivative thereof has a molecular weight of between 5,000 Da and 50,000 Da.

13. The method of claim 1 , wherein the death receptor agonist is administered systemically.

14. The method of claim 1 , wherein the death receptor agonist is administered locally.

15. The method of claim 1 , wherein the death receptor agonist is administered subcutaneously.

16. The method of claim 1 , wherein the fibrosis is treated or prevented in the subject, as compared to an appropriate control.

17. The method of claim 1 , wherein the death receptor agonist is administered by injection at a dosage of between 0.001 mg/kg and 50 mg/kg to the subject.

18. The method of claim 1 , wherein the death receptor agonist is administered by injection at a dosage of between 0.5 mg/kg and 50 mg/kg to the subject.

19. The method of claim 1 , wherein the effective amount of the death receptor agonist is administered to the subject over a period of one or more days.

20. The method of claim 1 , wherein the subject is human.

21. The method of claim 1 , wherein the administering of the effective amount of a death receptor agonist reduces dermal thickness, skin collagen levels, TGF-β, PDGFR, PDGF, IL-6 levels, and/or reduces α-SMA + fibroblastic cells as compared to an appropriate control.

22. The method of claim 21 , wherein the effective amount of the death receptor agonist is administered in one or more dosages.

23. The method of claim 1 , wherein the death receptor agonist is in an effective amount to reduce dermal thickness to normal levels.

24. The method of claim 1 , wherein the administering of the effective amount of a death receptor agonist restores normal wound healing of the skin.

Assignees

• Univ Johns Hopkins

Inventors

• Lee Seulki
• Pomper Martin G
• Park Jong-Sung
• Oh Yumin
• Scully Magdalena
• Horton Maureen

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• A61K39/39541

  against normal tissues, cells · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C07K16/2878

  against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 · CPC title