Methods for Treating Autoimmune Diseases in a Subject and In Vitro Diagnostic Assays

Abstract

The invention provides a method for treating an autoimmune disease in a subject by administering an interferon antagonist and a Flt3 ligand (Flt3L) antagonist. The invention also provides compositions containing one or more interferon antagonists, and one or more Flt3L antagonists, an in vitro assay for determining a subject's risk for developing an autoimmune disease, and kits for use, inter alia, with the assay.

1 . A method for treating an autoimmune disease in a subject, comprising administering to the subject an effective amount of (a) at least one interferon antagonist that reduces activity of a type I interferon, and (b) at least one Flt3 ligand (Flt3L) antagonist that reduces activity of a Flt3L, thereby treating the autoimmune disease. 
     
     
         2 . The method of  claim 1 , wherein the autoimmune disease is selected from the group consisting of acquired immune deficiency syndrome (AIDS), ankylosing spondylitis, arthritis, aplastic anemia, Bechet's disease, diabetes, graft-versus-host disease, Graves' disease, hemolytic anemia, hypogammaglobulinemia, hyper IgE syndrome, idiopathic thrombocytopenia purpura (ITP), multiple sclerosis (MS), Myasthenia gravis, psoriasis, lupus and any combination thereof. 
     
     
         3 . The method of  claim 2 , wherein the lupus is systemic lupus erythematosus (SLE), or drug-induced lupus. 
     
     
         4 . The method of  claim 2 , wherein the diabetes is diabetes mellitus, Type I diabetes, Type II diabetes, juvenile on-set diabetes or any combination thereof. 
     
     
         5 . The method of  claim 2 , wherein the arthritis is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis or any combination thereof. 
     
     
         6 . The method of  claim 1 , wherein the autoimmune disease is SLE. 
     
     
         7 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         8 . The method of  claim 7 , wherein the mammal is a human, a primate, a rat, a dog, a cat or a mouse. 
     
     
         9 . The method of  claim 1 , wherein the interferon antagonist is selected from the group consisting of an antibody, an antigen-binding fragment of an antibody, a polypeptide, a peptidomimetic, a nucleic acid encoding a peptide, an organic molecule and any combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the interferon antagonist comprises soluble receptor for IFN-α. 
     
     
         11 . The method of  claim 1 , wherein the interferon antagonist comprises an anti-IFN-α antibody or an antigen-binding fragment thereof. 
     
     
         12 . The method of  claim 1 , wherein the Flt3L antagonist is selected from the group consisting of an antibody, an antigen-binding fragment of an antibody, a polypeptide, a peptidomimetic, a nucleic acid encoding a polypeptide, an organic molecule and any combination thereof. 
     
     
         13 . The method of  claim 1 , wherein the Flt3L antagonist comprises a soluble Flt3 receptor. 
     
     
         14 . The method of  claim 1 , wherein the Flt3L antagonist comprises an anti-Flt3L antibody or an antigen-binding fragment thereof. 
     
     
         15 . The method of anyone of  claims 9 , wherein the antibody comprises a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, a primatized antibody and any combination thereof. 
     
     
         16 . The method of anyone of  claims 11 , wherein the antibody comprises a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, a primatized antibody and any combination thereof. 
     
     
         17 . The method of anyone of  claims 12 , wherein the antibody comprises a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, a primatized antibody and any combination thereof. 
     
     
         18 . The method of anyone of  claims 14 , wherein the antibody comprises a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, a primatized antibody and any combination thereof. 
     
     
         19 . The method of  claim 1 , wherein the interferon antagonist and the Flt3L antagonist are part of one molecule. 
     
     
         20 . The method of  claim 1 , wherein the effective amount of the interferon antagonist comprises from about 1 to about 10 fold molar excess of interferon. 
     
     
         21 . The method of  claim 1 , wherein the effective amount of the Flt3L antagonist comprises from about 1 to about 10 molar excess of Flt3L. 
     
     
         22 . The method of  claim 1 , wherein the administration of the composition is by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; or topical, nasal, oral, ocular or otic delivery. 
     
     
         23 . The method of  claim 1 , wherein the type I interferon is an interferon-α (IFN-α) or an IFN-β. 
     
     
         24 . The method of  claim 1 , wherein the interferon antagonist reduces one or more of the following: (i) binding of a type I interferon with its receptor; (ii) interferon-dependent signal transduction; (iii) interferon serum levels; (iv) interferon secretion from cells as measured by an interferon receptor binding assay; (v) bioavailability of interferon in serum as measured by an interferon receptor binding assay; or (vi) development of cells which produce type I interferon in the subject as measured by a monocyte differentiation assay. 
     
     
         25 . The method of  claim 1 , wherein the interferon antagonist is TNF. 
     
     
         26 . A therapeutic composition to inhibit monocyte differentiation into dendritic cells capable of antigen presentation which comprises:
 (a) at least one interferon antagonist that reduces activity of a type I interferon, and   (b) at least one FIt3 ligand (Flt3L) antagonist that reduces activity of Flt3L.   
     
     
         27 . The composition of  claim 26 , wherein the type I interferon is an interferon-α (IFN-α) or an IFN-β. 
     
     
         28 . The composition of  claim 26 , wherein the composition further comprises a carrier. 
     
     
         29 . The composition of  claim 26 , wherein the interferon antagonist is selected from the group consisting of an antibody, an antigen-binding fragment of an antibody, a polypeptide, a peptidomimetic, a nucleic acid encoding a polypeptide, an organic molecule and any combination thereof. 
     
     
         30 . The composition of  claim 26 , wherein the interferon antagonist comprises a soluble receptor for IFN-α. 
     
     
         31 . The composition of  claim 26 , wherein the interferon antagonist comprises an anti-IFN-α antibody or an antigen-binding fragment thereof. 
     
     
         32 . The composition of  claim 26 , wherein the interferon antagonist is TNF. 
     
     
         33 . The composition of  claim 26 , wherein the FIt3L antagonist is selected from the group consisting of an antibody, an antigen-binding fragment of an antibody, a peptide, a peptidomimetic, a nucleic acid encoding a peptide, an organic molecule and any combination thereof. 
     
     
         34 . The composition of  claim 26 , wherein the FIt3L antagonist comprises a soluble FIt3 receptor. 
     
     
         35 . The composition of  claim 26 , wherein the Flt3L antagonist comprises an anti-Flt3L antibody or an antigen-binding fragment thereof. 
     
     
         36 . The composition of anyone of  claims 29 , wherein the antibody is a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, or a primatized antibody. 
     
     
         37 . The composition of anyone of  claims 31 , wherein the antibody is a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, or a primatized antibody. 
     
     
         38 . The composition of anyone of  claims 33 , wherein the antibody is a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, or a primatized antibody. 
     
     
         39 . The composition of anyone of  claims 35 , wherein the antibody is a monoclonal antibody, a chimeric antibody, an anti-idiotypic antibody, a humanized antibody, or a primatized antibody. 
     
     
         40 . The composition of  claim 26 , wherein the interferon antagonist and the Flt3L antagonist are part of one molecule. 
     
     
         41 . The composition of  claim 26 , wherein the composition comprises two or more interferon antagonists and a Flt3L antagonist. 
     
     
         42 . The composition of  claim 41 , wherein one interferon antagonist is TNF. 
     
     
         43 . The composition of  claim 41 , wherein the composition comprises an anti-IFN-α antibody, an anti-Flt3L antibody and TNF. 
     
     
         44 . An in vitro assay for determining a subject's risk for developing an autoimmune disease, comprising:
 (a) obtaining a serum sample from the subject;   (b) quantifying IFN-α and Flt3 ligand (Flt3L) in the serum sample; and   (c) comparing the quantity of IFN-α and Flt3L with the quantities of IFN-α and Flt3L in serum from subjects with an autoimmune disease, thereby determining the subject's risk for developing an autoimmune disease.   
     
     
         45 . The method of  claim 44 , wherein a risk of developing an autoimmune disease occurs when the quantities of IFN-α and Flt3L are within about a 30% range of those quantities for subjects with an autoimmune disease. 
     
     
         46 . The method of  claim 45 , wherein said risk increases when said range is about 20%. 
     
     
         47 . The method of  claim 44 , wherein said comparison is made for age-matched subjects. 
     
     
         48 . A kit for determining a subject's risk for developing an autoimmune disease or for monitoring the status of an autoimmune disease in a subject which comprises a composition which specifically binds to Flt3L and to IFN-α in an amount effective to detect Flt3L and IFN-α in a biological sample of a subject. 
     
     
         49 . The kit of  claim 48 , wherein the biological sample is a blood sample or a serum sample. 
     
     
         50 . The kit of  claim 48 , wherein the composition comprises a monoclonal antibody that binds Flt3L and a monoclonal antibody that binds IFN-α. 
     
     
         51 . The kit of  claim 48 , wherein the kit further comprises one or more reagents for detecting amounts of the composition bound to one or more samples. 
     
     
         52 . The kit of  claim 48 , wherein the composition is labeled with a detectable marker. 
     
     
         53 . The kit of  claim 52 , wherein the detectable marker is selected from the group consisting of a fluorescent marker, a radioactive marker, an enzymatic marker, a colorimetric marker, a chemiluminescent marker and any combination thereof. 
     
     
         54 . A method for treating an autoimmune disease in a subject comprising administering to the subject an effective amount of a Flt3L antagonist that reduces monocyte differentiation into dendritic cells, thereby treating an autoimmune disease, wherein the Flt3L antagonist is selected from the group consisting of: an antibody which specifically binds Flt3L, an organic molecule, an antigen-binding fragment of an antibody, a nucleic acid and any combination thereof. 
     
     
         55 . The method of  claim 54 , wherein the Flt3L antagonist reduces hematopoietic stem cell differentiation into type I interferon producing cells. 
     
     
         56 . The method of  claim 55 , wherein the type I interferon producing cells comprise plasmacytoid dendritic cells. 
     
     
         57 . The method of  claim 54 , wherein the autoimmune disease is selected from the group consisting of acquired immune deficiency syndrome (AIDS), ankylosing spondylitis, arthritis, aplastic anemia, Bechet's disease, diabetes, graft-versus-host disease, Graves' disease, hemolytic anemia, hypoganmlaglobulinemia, hyper IgE syndrome, idiopathic thrombocytopenia purpura (ITP), multiple sclerosis (MS), Myasthenia gravis, psoriasis, lupus and any combination thereof. 
     
     
         58 . The method of  claim 54 , wherein the autoimmune disease comprises systemic lupus erythematosus (SLE) or drug-induced lupus or a combination thereof. 
     
     
         59 . The method of  claim 54 , wherein the autoimmune disease comprises diabetes mellitus, Type I diabetes, Type II diabetes, juvenile on-set diabetes or any combination thereof. 
     
     
         60 . The method of  claim 54 , wherein the autoimmune disease comprises rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis or any combination thereof. 
     
     
         61 . The method of  claim 54 , wherein the autoimmune disease comprises SLE. 
     
     
         62 . The method of  claim 54 , wherein the effective amount of the Flt3L antagonist comprises from about 1 to about 10 fold molar excess of Flt3L or Flt3L receptor.