Method and composition for treating immune complex associated disorders

Abstract

The present invention provides methods and compositions for treating immune complex associated diseases (ICAD), such as SLE, rheumatoid arthritis, and hepatitis-C related immune complex disease (e.g., cryoglobulinemia) in a subject having an ICAD or at risk for developing ICAD. The invention is based upon the surprising finding that chromatin-containing immune complexes activate autoreactive B cells and dendritic cells by a dual receptor engagement process which, in both cell types, involves a Toll-like receptor (TLR). The methods of treating ICAD comprise administering a compound to an individual in need thereof that either 1) inhibits formation of the immune complex either by preventing formation and/or binding to the TLR, or 2) interferes with binding of an autoantigen-containing immune complex (or the antigenic component thereof) to the TLR, or 3) inhibits signaling pathways initiated by dual engagement of BCR and TLR (in B cells) or FcR and TLR (in dendritic cells) via immune complexed or uncomplexed autoantigens.

1 . A method of treating a patient having or at risk of having an Immune Complex Associated Disease (ICAD) or a systemic autoimmune disease, comprising
 administering to a patient having or at risk of having an ICAD or a systemic autoimmune disease an effective amount of a compound that inhibits immune complexes or autoantigens from binding to or activating a Toll-like receptor (TLR), wherein the Toll-like receptor is chosen from Toll-like receptor 9 (TLR9) and Toll-like receptor 3 (TLR3) and wherein said immune complex comprises an autoantibody and an autoantigen bound to a cell receptor, to treat the ICAD or systemic autoimmune disease.   
     
     
         2 . The method of  claim 1 , wherein the ICAD is systemic lupus erythematosus. 
     
     
         3 . The method of  claim 1 , wherein the ICAD is rheumatoid arthritis. 
     
     
         4 . The method of  claim 1 , wherein the ICAD is hepatitis-C related immune complex disease. 
     
     
         5 . The method of  claim 1  wherein the Toll-like receptor is TLR9. 
     
     
         6 . The method of  claim 1  wherein the Toll-like receptor is TLR3. 
     
     
         7 . The method of  claim 1 , wherein the compound is selected from the group consisting of
 (a) compounds that bind components of the immune complex and prevent its formation or binding to the Toll-like receptor;   (b) Toll-like receptor decoys;   (c) compounds that inhibit the activity of MyD88 or other components of a TLR-initiated signaling cascade;   (d) compounds that inhibit production of immune complex components; and   (e) Toll-like receptor antagonists.   
     
     
         8 . The method of  claim 7 , wherein the Toll-like receptor antagonist is an inhibitory oligonucleotide. 
     
     
         9 . The method of  claim 7 , wherein the Toll-like receptor antagonist is a dominant negative Toll-like receptor. 
     
     
         10 . The method of  claim 1 , wherein the compound is an antibody that binds a Toll-like receptor. 
     
     
         11 . The method of  claim 10 , wherein the antibody is a single chain antibody. 
     
     
         12 . The method of  claim 1 , wherein the compound comprises a cocktail of compounds that inhibit binding to a combination of at least two of Toll-like receptor 2 (TLR2), TLR3, and TLR9. 
     
     
         13 . A method for screening for compounds that inhibit immune complex formation or binding to a Toll-like receptor, comprising contacting immune complex components with a compound being screened and with a TLR chosen from Toll-like receptor 3 (TLR3) and Toll-like receptor 9 (TLR9);
 measuring binding of an antigenic fragment of an immune complex to the TLR, wherein said immune complex comprises an autoantibody and an autoantigen; and   identifying the compound being screened as an inhibitor of immune complex formation or of binding to a Toll-like receptor when the binding with the compound is reduced compared to binding without the compound.   
     
     
         14 . The method of  claim 13 , wherein the TLR is TLR9. 
     
     
         15 . The method of  claim 13 , wherein the binding with the compound is reduced at least 50 percent compared to binding without the compound. 
     
     
         16 . A method for screening for compounds that inhibit immune complex formation or binding to a Toll-like receptor, comprising
 contacting immune complex components with a compound being screened and with a dendritic cell that expresses a TLR chosen from Toll-like receptor 3 (TLR3) and Toll-like receptor 9 (TLR9);   measuring activation of the dendritic cell; and   identifying the compound being screened as an inhibitor of immune complex formation or of binding to a Toll-like receptor when activation of the dendritic cell with the compound is reduced compared to activation of the dendritic cell without the compound.   
     
     
         17 . The method of  claim 16 , wherein the TLR is TLR9. 
     
     
         18 . The method of  claim 16 , wherein the measuring activation of the dendritic cell comprises measuring production of a cytokine chosen from TNF-α, interferon-α, and BAFF. 
     
     
         19 . The method of  claim 16 , wherein the measuring activation of the dendritic cell comprises measuring upregulated expression on the dendritic cell of a costimulatory molecule chosen from CD80, CD86, and MHC class II. 
     
     
         20 . The method of  claim 16 , wherein the activation of the dendritic cell with the compound is reduced at least 50 percent compared to activation of the dendritic cell without the compound. 
     
     
         21 . The method of  claim 16 , wherein the immune complex components comprise an autoantibody and an autoantigen. 
     
     
         22 . A method for screening for compounds that inhibit immune complex formation or binding to a Toll-like receptor, comprising
 contacting immune complex components with a compound being screened and with a B cell that expresses a TLR chosen from Toll-like receptor 3 (TLR3) and Toll-like receptor 9 (TLR9);   measuring activation and/or proliferation of the B cell; and   identifying the compound being screened as an inhibitor of immune complex formation or of binding to a Toll-like receptor when activation and/or proliferation of the B cell with the compound is reduced compared to activation and/or proliferation of the B cell without the compound.   
     
     
         23 . The method of  claim 22 , wherein the TLR is TLR9. 
     
     
         24 . The method of  claim 22 , wherein the measuring activation of the B cell comprises measuring upregulated expression on the B cell of a costimulatory molecule chosen from CD80, CD86, and MHC class II. 
     
     
         25 . The method of  claim 22 , wherein the activation and/or proliferation of the B cell with the compound is reduced at least 50 percent compared to activation and/or proliferation of the B cell without the compound. 
     
     
         26 . The method of  claim 22 , wherein the immune complex components comprise an autoantibody and an autoantigen.