Inflammation-regulating compositions and methods

Abstract

The various embodiments provide a composition that provides local control over inflammation. The composition localizes the activities of the cytokine-neutralizing antibodies to the site of inflammation through covalent attachment to hydrophilic matrices. The various embodiments including a hydrophilic polymer, a ligand binding moiety covalently attached to the polymer, and optionally, a cellular adhesion peptide covalently attached to the polymer. The hydrophilic polymer may be a glycosaminoglycan such as hyaluronan. The cellular adhesion peptide may be linear RGD peptide sequence covalently attached to the polymer. The ligand binding moiety may be a monoclonal antibody covalently attached to the polymer. The antibody may be selected from the group consisting of an anti-IL-1β, an anti-IL-6, an anti-TNF-α, and combinations thereof. The polymer functions as a substrate or matrix for cell migration and tissue regeneration. The RGD peptide functions to promote cellular proliferation, migration and attachment to the polymer. The monoclonal antibody functions to inhibit the inflammatory response.

What is claimed is: 
     
         1 . A composition comprising:
 a hydrophilic polymer; and   a ligand binding moiety covalently attached to the hydrophilic polymer.   
     
     
         2 . The composition of  claim 1 , further comprising a cellular adhesion peptide covalently attached to the polymer. 
     
     
         3 . The composition of  claim 1 , wherein the hydrophilic polymer is selected from the group consisting of hyaluronan, agarose, dextran, starch, methyl cellulose, poly(ethylene glycol), collagen, gelatin, fibrin, fibrinogen, fibronectin, vitronectin, polyhydroxyalkanoates, polyhydroxybutyrate, polyhydroxyvalerate, copolymers thereof, poly(glycolic acid), poly(lactic acid), polycaprolactone, polyanhydrides, poly(ortho esters), poly(amino acids), polyacrylates, and blends thereof. 
     
     
         4 . The composition of  claim 1 , wherein the ligand binding moiety is selected from the group consisting of, antibodies to a pro-inflammation mediators, antibodies to a pro-inflammatory cytokines, non-neutralizing antibodies, neutralizing antibodies, and combinations thereof. 
     
     
         5 . The composition of  claim 1 , wherein the ligand binding moiety is selected from the group consisting of IL-1, IL-6, IL-8, IL-12, IL-18, TNF, MCP-1, IFN-γ, histamine, bradykinin, anti-IL-1β, an anti-IL-6, an anti-TNF-α, anti-TGF-β, IL-6, TGF-β, and combinations thereof. 
     
     
         6 . The composition of  claim 1 , wherein the hydrophilic polymer comprises a blend of at least two hydrophilic polymers. 
     
     
         7 . The composition of  claim 6 , wherein each of the at least two hydrophilic polymer is functionalized with at least one ligand binding moiety. 
     
     
         8 . The composition of  claim 6 , wherein at least one of the at least two hydrophilic polymers is functionalized with at least one ligand binding moiety. 
     
     
         9 . The composition of  claim 6 , wherein the at least two hydrophilic polymers are selected from the group consisting of synthetic polymers, biopolymers, or a mixture of one or more synthetic and one or more biopolymers. 
     
     
         10 . The composition of  claim 1 , wherein the hydrophilic polymer is uncrosslinked. 
     
     
         11 . The composition of  claim 1 , wherein the hydrophilic polymer is crosslinked. 
     
     
         12 . The composition of  claim 1 , wherein the composition comprises a colloidal suspension dispersed in a plurality of beads. 
     
     
         13 . The composition of  claim 1 , wherein the composition is bound to a woven substrate. 
     
     
         14 . A composition comprising:
 a hyaluronan gel matrix; and   a monoclonal antibody selected from the group consisting of an anti-IL-1β, an anti-IL-6, an anti-TNF-α, and combinations thereof covalently attached to the hyaluronan gel matrix.   
     
     
         15 . The composition of  claim 14 , further comprising at least one linear RGD peptide sequence covalently attached to the hyaluronan matrix. 
     
     
         16 . The composition of  claim 14 , wherein the composition forms a colloidal suspension dispersed in a plurality of beads. 
     
     
         17 . The composition of  claim 14 , wherein the composition is bound to a woven substrate. 
     
     
         18 . A method of producing an anti-inflammatory composition comprising attaching a ligand binding moiety to the hydrophilic polymer. 
     
     
         19 . The method of  claim 14 , further comprising attaching an adhesion peptide to a hydrophilic polymer. 
     
     
         20 . A method of producing an anti-inflammatory composition comprising:
 forming a reaction mixture by dissolving hyaluronic acid in phosphate buffered saline;   adding EDC, sulfo-NHS, and 4-DMAP to the reaction mixture;   adding an antibody selected from the group consisting of an anti-IL-1β, an anti-IL-6, an anti-TNF-α, and combinations thereof to the reaction mixture; and   purifying the reaction mixture.   
     
     
         21 . The method of treatment of  claim 20 , further comprising attaching a glycine-arginine-glycine-aspardic acid-serine (GRGDS) peptide to the hyaluronic acid. 
     
     
         22 . A method of treatment comprising:
 administering a composition comprising:
 a hydrophilic polymer; and 
 a ligand binding moiety covalently attached to the polymer. 
   
     
     
         23 . The method of treatment of  claim 22 , wherein the composition further comprises a cellular adhesion peptide covalently attached to the polymer. 
     
     
         24 . The method of treatment of  claim 22 , wherein the composition is used to treat a condition selected from the group consisting of pressure ulcers, venous ulcers, diabetic ulcers, dermal wounds, inflammatory bowel disease, and rheumatoid arthritis. 
     
     
         25 . The method of treatment of  claim 22 , wherein administering comprises topically applying the composition. 
     
     
         26 . The method of treatment of  claim 22 , wherein administering comprises local hypodermic injection locally of the composition. 
     
     
         27 . A method of treatment comprising:
 administering to a wound site a composition comprising:
 hyaluronan; and 
 a monoclonal antibody selected from the group consisting of an anti-IL-1β, an anti-IL-6, an anti-TNF-α, and combinations thereof covalently attached to the hyaluronan. 
   
     
     
         28 . The method of treatment of  claim 27 , wherein the composition further comprises a linear arginine-glycine-aspartic acid (RGD) peptide covalently attached to the hyaluronan. 
     
     
         29 . The method of treatment of  claim 27 , wherein the hyaluronan is crosslinked to form a gel-like matrix. 
     
     
         30 . The method of treatment of  claim 27 , wherein the composition is a colloidal suspension dispersed in a plurality of beads when administered. 
     
     
         31 . The method of treatment of  claim 27 , wherein the composition is bound to a woven substrate when administered. 
     
     
         32 . A wound dressing comprising:
 a woven substrate having an inflammation regulating composition dispersed thereon, the composition comprising a hyaluronan gel matrix and a monoclonal antibody covalently attached to the hyaluronan matrix, wherein the antibody is selected from the group consisting of an anti-IL-1β, an anti-IL-6, an anti-TNF-α, and combinations thereof.   
     
     
         33 . The wound dressing of  claim 29 , wherein the composition further comprises a cellular adhesion peptide covalently attached to the hyaluronan gel matrix.