Treatment of renal disease
Inventors
Heffernan, Mark • O'Neill, Luke • Mcguirk, Peter • Keogh, Brian • Locher, Christopher
Assignees
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Publication Number
US-9234046-B2
Publication Date
2016-01-12
Expiration Date
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.
Core Innovation
The invention concerns treating and preventing kidney inflammation and renal disorders by antagonizing Toll-like receptor 2 (TLR2) function and/or expression. The approach is based on administering a therapeutically effective amount of an antibody or an antigen binding fragment with binding specificity for TLR2 that antagonizes TLR2 activity, particularly in kidney cells and tissues involved in glomerulonephritis and renal failure.
The documented rationale is that TLR2 blockade reduces kidney inflammation markers, including neutrophil accumulation and associated inflammatory readouts, and also reduces albuminuria and thrombosis in the kidney. The described TLR2 intracellular signaling context is linked to TLR2 ligand binding and TLR2 intracellular signaling pathways such as MyD88/MAL/TIRAP and NF-κB, with the overall goal of diminishing TLR2-mediated inflammatory responses in renal tissues.
The document further describes TLR2-modulating agent formats including antibodies and antigen binding fragments that bind an inhibitory epitope on TLR2, as well as other TLR2 antagonist/modulator agents such as inhibitory nucleic acids, soluble TLR2, and aptamers. Combination regimens are described through adding a secondary therapeutic compound, including immunosuppressants, in conjunction with TLR2 antagonism to treat renal disorders.
Claims Coverage
The provided claim set centers on treatment of a renal disorder by administering a TLR2-antagonist antibody or antigen binding fragment. The inventive features include TLR2-specific antagonism, binding to an inhibitory epitope with a defined Kd range, reduction or inhibition of TLR2 biological activities in specified TLR2-expressing renal cell types, limitation to ischemia reperfusion injury including kidney organ transplantation, and optional use of a secondary therapeutic compound.
Administering a therapeutically effective TLR2-antagonist antibody or antigen binding fragment
A method for the treatment of a renal disorder comprising administering a therapeutically effective amount of an antibody or an antigen binding fragment thereof that has binding specificity for Toll-like Receptor 2 and is an antagonist of the function of Toll-like Receptor 2, to a subject in need of such treatment, where said subject has not been administered said antibody or antigen binding fragment prior to the onset of the renal disorder.
Binding an inhibitory epitope on TLR2 with a defined Kd range
The method includes that the antibody or an antigen binding fragment thereof binds to an inhibitory epitope on TLR2 with a dissociation constant (Kd) between about 10^-7 M and about 10^-11 M.
Reducing or inhibiting TLR2 biological activities in specified TLR2-expressing renal epithelial cells
The method reduces or inhibits one or more TLR2 biological activities in a TLR2-expressing kidney cell selected from renal tubular epithelial cell and specified kidney glomerulus and tubule cell types including epithelial cells of the Bowman's capsule, kidney glomerulus parietal cell, kidney glomerulus podocyte, kidney proximal tubule brush border cell, loop of henle thin segment cell, kidney distal tubule cell, and kidney collecting duct cell.
Treating ischemia reperfusion injury as the renal disorder indication
The method is for treating a renal disorder identified as ischemia reperfusion injury.
Ischemia reperfusion injury resulting from kidney organ transplantation
The ischemia-reperfusion injury results from kidney organ transplantation.
Adding an optional secondary immunosuppressant or therapeutic compound
The method includes selecting the secondary therapeutic compound from a group of drug and antibody options including glucocorticoid, cytostatic, anti-metabolite, anti-CD2 antibody and related binding fragment, anti-CD20 antibody, anti-Tumor Necrosis Factor-alpha (TNF-alpha) antibody, cyclosporine, tacrolimus, sirolimus, and Fingolimod (FTY720).
The core claim is a renal-disorder treatment method using a therapeutically effective TLR2-specific antagonist antibody or antigen binding fragment administered to a subject not previously treated with the same antibody or fragment. Dependent features further narrow binding to an inhibitory epitope with a defined Kd range, restrict the functional effect to specified TLR2-expressing renal epithelial cell types, limit indications to ischemia reperfusion injury including cases from kidney organ transplantation, and allow an optional secondary therapeutic compound.
Stated Advantages
Reduces or inhibits kidney inflammation by antagonizing TLR2 function and/or expression.
Reduces neutrophil accumulation and other kidney inflammation markers.
Reduces albuminuria.
Reduces thrombosis.
Provides protective effects in renal inflammatory readouts in warm renal ischemia/reperfusion models.
Documented Applications
Treating renal disorders associated with kidney inflammation, including glomerulonephritis and renal failure.
Treating ischemia reperfusion injury, including when ischemia-reperfusion injury results from kidney organ transplantation.
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