Ameliorating systemic sclerosis with death receptor agonists
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.
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.