Compounds and methods for the treatment of renal disease

Abstract

The present invention provides compounds and methods for the treatment and prophylaxis of renal disease and inflammation. In particular the invention provides methods for the treatment of kidney disease and failure through the administration of compounds which function as inhibitors of TLR2 function and expression.

1 . A method of reducing one or more biological activities of Toll like receptor 2 (TLR2) in a TLR2 expressing cell or tissue implicated in renal disease or inflammation, comprising:
 contacting the cell or tissue with an antibody which acts as an antagonist of TLR2 activity, in an amount sufficient to reduce one or more biological activities of TLR2 in the cell or tissue.   
     
     
         2 . The method as claimed in  claim 1 , wherein the TLR2 expressing cell is a cell selected from the group consisting of a renal tubular epithelial cell, an epithelial cell of the Bowman's capsule, a kidney glomerulus parietal cell, kidney glomerulus podocyte, kidney proximal tubule brush border cell, loop of henle thin segment cell, kidney distal tubule cell, kidney collecting duct cell. 
     
     
         3 . The method as claimed in  claim 1  wherein the contacting step occurs in a cell lysate, a reconstituted system or cells in culture. 
     
     
         4 . The method as claimed in  claim 1  wherein the contacting step occurs on cells or a tissue present in a subject. 
     
     
         5 . The method as claimed in  claim 4 , wherein the subject is a human patient having, or at risk of renal failure or a renal disorder. 
     
     
         6 . The method as claimed in  claim 1  wherein the TLR2 is human or murine TLR2. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method as claimed in  claim 1 , wherein the antibody has binding specificity to human TLR2. 
     
     
         10 . The method as claimed in  claim 1 , wherein the antibody is selected from the group consisting of a human, humanised, chimeric, synthetic, camelid, shark or in-vitro antibody which has binding specificity to TLR2, or a binding fragment derived from any of the same. 
     
     
         11 . The method as claimed in  claim 1 , wherein the antibody is an antibody binding fragment selected from the group consisting of a Fab, scFv, Fv, and dAb. 
     
     
         12 . The method as claimed in  claim 1 , wherein the antibody comprises two complete heavy chains, and two complete light chains, or an antigen-binding fragment thereof. 
     
     
         13 . The method as claimed in  claim 1  wherein the antibody binds to an epitope defined by the extracellular domain of human TLR2. 
     
     
         14 . The method as claimed in  claim 1  wherein the antibody binds to a non-continuous epitope comprising amino acid residues derived from the amino and carboxyl terminals of the amino acid sequence of human TLR2. 
     
     
         15 . The method as claimed in  claim 13 , wherein the antibody binds to an epitope on TLR2 comprising amino acid residues 19 to 39, or 538 to 549 of SEQ ID NO:2. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . A method for the treatment and/or prophylaxis of a renal disorder, the method comprising the steps of:
 providing a therapeutically effective amount of an antibody or a binding fragment thereof which is an agonist of the function of Toll-like Receptor 2, and   administering said compound to a subject in need of such treatment.   
     
     
         19 - 21 . (canceled) 
     
     
         22 . The method as claimed in  claim 18  wherein the antibody is selected from the group consisting of: a monoclonal antibody, a polyclonal antibody or a synthetic antibody. 
     
     
         23 . The method of  claim 18 , wherein the antibody is selected from the group comprising a human, humanised, camelid, in vitro generated antibody to human TLR2. 
     
     
         24 . The method as claimed in  claim 18  wherein the antibody is of an isotype selected from the group consisting of IgG, IgA, IgM, and IgE. 
     
     
         25 . The method as claimed in  claim 18  wherein the antibody binds to an inhibitory epitope present on TLR2 with a dissociation constant (Kd) of from about 10 −7 M to about 10 −11 M. 
     
     
         26 . The method of  claim 18 , wherein the antibody binds to an epitope defined by the extracellular domain of human TLR2. 
     
     
         27 . The method of  claim 18 , wherein the antibody binds to a non-continuous epitope comprising amino acid residues derived from the amino and carboxyl terminals of the amino acid sequence of human TLR2. 
     
     
         28 . The method of  claim 18 , wherein the antibody binds to an epitope on TLR2 comprising amino acid residues 19 to 39, or 538 to 549 of SEQ ID NO:1. 
     
     
         29 - 34 . (canceled) 
     
     
         35 . The method as claimed in  claim 18  wherein the antibody is administered to the subject in order to reduce or inhibit one or more TLR2 biological activities in a TLR2 expressing cell, wherein the cell is a cell selected from the group consisting of a renal tubular epithelial cell, an epithelial cell of the Bowman's capsule, a kidney glomerulus parietal cell, kidney glomerulus podocyte, kidney proximal tubule brush border cell, loop of henle thin segment cell, kidney distal tubule cell, kidney collecting duct cell. 
     
     
         36 . The method as claimed in  claim 18  wherein the renal disorder is selected from the group consisting of renal disease, chronic renal failure, acute renal failure heterologous nephrotoxic nephritis, glomerulonephritis, sclerosis of the glomerulus, systemic lupus erythematosus (SLE), diabetic nephropathy, and diabetic nephropathy. 
     
     
         37 . The method as claimed in  claim 18  wherein the renal disorder is selected from the group consisting of Immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, nonproliferative glomerulonephritis, membranous glomerulonephritis, minimal-change disease, primary focal segmental glomerulosclerosis, fibrillary glomerulonephritis, immunotactoid glomerulonephritis, proliferative glomerulonephritis, progressive glomerulonephritis, anti-GBM disease, kidney ischemia, delayed graft function, kidney vasculitis, including disease associated with anti-neutrophil cytoplasmic antibodies, lupus nephritis cryoglobulinemia-associated glomerulonephritis, bacterial endocarditis, Henoch-Schönlein purpura, postinfectious glomerulonephritis, Hepatitis C disease, diabetic nephropathy, myloidosis, hypertensive nephrosclerosis, light-chain disease from multiple myeloma, secondary focal glomerulosclerosis, and hypertensive nephrosclerosis. 
     
     
         38 . The method as claimed in  claim 18  wherein the TLR2 is human TLR2 or murine TLR2. 
     
     
         39 . The method as claimed in  claim 18  further comprising the step of administering a therapeutically effective amount of at least one secondary therapeutic compound, said secondary therapeutic compound being an immunosuppressant compound. 
     
     
         40 . The method as claimed in  claim 39  wherein the secondary therapeutic compound is selected from the group consisting of: a glucocorticoid, a cytostatic, an anti-metabolite, an anti-CD2 antibody or related binding fragment, an anti-CD20 antibody, an anti-TNF-alpha antibody, cyclosporine, tacrolimus, sirolimus or FTY720. 
     
     
         41 . The method as claimed in  claim 39  wherein the agent is administered simultaneously with the secondary therapeutic compound. 
     
     
         42 . The method as claimed in  claim 39  wherein the agent is administered sequentially to the administration of the secondary therapeutic compound. 
     
     
         43 . (canceled) 
     
     
         44 . A pharmaceutical composition for use in the treatment and prophylaxis of a renal disorder comprising an antibody which is an antagonist of the function of Toll-like Receptor 2 along with at least one pharmaceutically acceptable carrier, diluent, solubilizer, emulsifier, preservative and/or adjuvant. 
     
     
         45 . The pharmaceutical composition as claimed in  claim 44  wherein the antibody is selected from the group consisting of: a polyclonal antibody, a monoclonal antibody, a humanized antibody, a chimeric antibody or an antibody fragment. 
     
     
         46 - 47 . (canceled) 
     
     
         48 . The pharmaceutical composition as claimed in  claim 44  wherein the composition further comprises a secondary therapeutic compound. 
     
     
         49 . The pharmaceutical composition as claimed in  claim 48  wherein the secondary therapeutic compound is an immunosuppressant selected from the group consisting of: a glucocorticoid, a cytostatic, an anti-metabolite, an anti-CD2 antibody or related binding fragment, an anti-CD20 antibody, an anti-TNF-alpha antibody, cyclosporine, tacrolimus, sirolimus or FTY720. 
     
     
         50 - 78 . (canceled)