Methods and non-immunogenic compositions for treating inflammatory disorders

Abstract

Methods for making non-immunogenic anti-inflammatory cytokine compositions, comprising (a) obtaining a liquid comprising cytokine producing cells from a mammalian donor; (b) contacting the liquid with a solid extraction material to generate a composition rich in interleukin-1 receptor antagonist; and performing one or both of (i) removing cells from the composition and (ii) freezing the composition. The compositions comprise two or more of IL1-ra, sTNF-R1, sTNF-RII, IGF-I, EGF, HGF, PDGF-AB, PDGF-BB, VEGF, TGF-β1, and sIL-1RII. Compositions may also contain white blood cells and platelets.

1 .- 16 . (canceled) 
     
     
         17 . A method of treating an inflammatory disorder in a mammalian subject, comprising administering a non-immunogenic anti-inflammatory composition to the subject, the method comprising:
 obtaining a freeze-dried preparation comprising (i) interleukin-1 receptor antagonist (IL-1ra) and (ii) at least one of soluble tumor necrosis factor-receptor I (sTNF-RI), soluble tumor necrosis factor-receptor II (sTNF-RII), and soluble interleukin-1 receptor II (sIL-1RII), wherein (i), (ii) or both are isolated from non-autologous blood, bone marrow, adipose tissue, urine, or a combination of the foregoing;   forming a therapeutic solution from the freeze-dried preparation: and   administering the therapeutic solution to the subject.   
     
     
         18 . A method according to  claim 17 , wherein the therapeutic solution further comprises whole blood, a blood fraction or blood fraction concentrate, bone marrow aspirate or bone marrow concentrate, or a combination of any of the foregoing, obtained from the subject. 
     
     
         19 . The method according to  claim 17 , wherein the disorder is arthritis, osteolysis, tendonitis, synovitis, pain, traumatic injury, muscle strain, peripheral vascular disease, or an inflammatory respiratory disease. 
     
     
         20 . The method according to  claim 17 , further comprising administering to the subject a pharmaceutical active ingredient selected from the group consisting of steroids, analgesics, and combinations thereof. 
     
     
         21 .- 22 . (canceled) 
     
     
         23 . An anti-inflammatory composition comprising a lyophilized activated plasma composition, wherein:
 (a) the plasma is obtained from a plurality of mammalian subjects;   (b) the plasma is activated by contacting the plasma with a solid extraction material; and   (c) the plasma is substantially free of white blood cells.   
     
     
         24 . The anti-inflammatory cytokine composition according to  claim 23 , comprising:
 (i) interleukin-1 receptor antagonist (IL-1ra) at a concentration of at least about 10,000 pg/ml;   soluble tumor necrosis factor receptor I (sTNF-RI) at a concentration of at least about 1,2000 pg/ml; and   (iii) a protein selected from the group consisting of soluble tumor necrosis factor receptor II (sTNF-RII), insulin-like growth factor 1 (IGW-1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor AB (PDGF-AB), platelet-derived growth factor BB (PDGF-BB), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and soluble interleukin-1 receptor II (sIL-1RII), and mixtures thereof, wherein the concentration of the protein in the composition is greater than the concentration of the protein in normal blood.   
     
     
         25 .- 27 . (canceled) 
     
     
         28 . The method according to  claim 23 , wherein the solid extraction material is selected from the group consisting of corundum, quartz, titanium, dextran, agarose, polyacrylamide, polystyrene, polyethylene, polyvinyl chloride, polypropylene, and combinations thereof. 
     
     
         29 . The method according to  claim 17 , wherein the therapeutic solution has a concentration of at least 10,000 pg/ml IL-1ra and a concentration of at least 1,200 pg/ml sTNF-RI. 
     
     
         30 . The method according to  claim 17 , wherein the therapeutic solution has a concentration of at least 10,000 pg/m1 IL-1ra and a concentration of at least about 3,000 pg/ml sTNF-RII. 
     
     
         31 . The method according to  claim 17 , wherein the therapeutic solution has a concentration of at least 10,000 pg/ml IL-1ra and a concentration of at least about 11,800 pg/ml sIL-1RII. 
     
     
         32 . The method according to  claim 17 , wherein the therapeutic solution has a concentration of at least 10,000 pg/ml IL-1ra, a concentration of at least 3,000 pg/ml sTNF-RII, and at least about 11,800 pg/ml sIL-1RII. 
     
     
         33 . A method of making a non-immunogenic anti-inflammatory cytokine composition, comprising:
 obtaining a suspension comprising white blood cells from a plurality of mammalian donors;   contacting the suspension with a material configured to form a composition enriched in interleukin-1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor I (sTNF-RI); and   separating the white blood cells and the material from the composition; and   freezing the composition.   
     
     
         34 . The method according to  claim 33 , wherein the white blood cells are obtained from whole blood, a fraction of whole blood, bone marrow aspirate, adipose tissue, urine, or a combination of any of the foregoing. 
     
     
         35 . The method according to  claim 33 , wherein the solid extraction material is selected from the group consisting of corundum, quartz, titanium, dextran, agarose, polyacrylamide, polystyrene, polyethylene, polyvinyl chloride, polypropylene, and a combination of any of the foregoing. 
     
     
         36 . The method according to  claim 33 , wherein the solid extraction material comprises a bead, a fiber, a powder, a porous material, or a combination of any of the foregoing. 
     
     
         37 . The method according to  claim 33 , wherein the material activates white blood cells to generate IL-1ra, concentrates the suspension, or both. 
     
     
         38 . The method according to  claim 33 , wherein composition further comprises soluble tumor necrosis factor receptor II (sTNF-RII), insulin-like growth factor -1 (IGF-I), epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor-AB (PDGF-AB), platelet-derived growth factor BB (PDGF-BB), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and soluble interleukine-1 receptor (((sIL-1RII), or a combination of any of the foregoing. 
     
     
         39 . The method according to  claim 33 , wherein the composition comprises IL-1ra at a concentration of at least 10,000 pg/ml and at least 1,200 pg/ml sTNF-RI before freezing. 
     
     
         40 . The method according to  claim 33 , wherein the solution comprises at least about 15,000 white blood cells/μl.