Compositions and methods for the diagnosis and treatment of immune disorders

Abstract

The present invention relates to methods and compositions for the treatment and diagnosis of immune disorders, especially T helper lymphocyte-related disorders. In particular, the invention describes a gene known in the art, alternatively, as ST2, T1 and Fit-1, and referred to herein as the 103 gene. The 103 gene is disclosed herein to be differentially expressed in TH2 cells and not in TH1 cells. Further, the 103 gene product is demonstrated herein to be an important modulator of TH2 and TH2-like immune response both in vitro and in vivo. Thus, the 103 gene, its gene products and antibodies that specifically bind thereto can be used diagnostically or as targets for therapeutic intervention in the treatment of a variety of immune disorders. In this regard, the invention provides methods for the identification and therapeutic use of compounds for treatments of immune disorders, especially TH cell subpopulation-related disorders and including TH2 and TH2-like disorders (i.e., disorders associated with a TH2 or TH2-like mediated immune response) such as atopic conditions (e.g., allergy and asthma). Additionally, methods are provided for the diagnostic evaluation and prognosis of TH cell subpopulation related disorders, for the identification of subjects exhibiting a predisposition to such conditions, for monitoring patients undergoing clinical evaluation for the treatment of such disorders and for monitoring the efficacy of compounds used in clinical trials.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule comprising a nucleotide sequence which encodes a polypeptide comprising the amino acid sequence in SEQ ID NO: 13.  
     
     
         2 . The isolated nucleic acid molecule of  claim 1  wherein the nucleic acid molecule comprises of the nucleotide sequence in SEQ ID NO:12.  
     
     
         3 . An isolated nucleic acid molecule comprising a nucleotide sequence which encodes a polypeptide comprising amino acid residues 19 to 158 in SEQ ID NO:13.  
     
     
         4 . An isolated nucleic acid molecule which encodes a polypeptide comprising amino acid residues 151 to 158 of SEQ ID NO: 13 and which hybridizes to the complement of a nucleic acid molecule that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 13 under hybridization conditions comprising 6×SSC at 45° C. and one or more washes in 0.2×SSC/0.1% SDS at 50°-65° C.  
     
     
         5 . The isolated nucleic acid molecule of  claim 4  wherein said nucleic acid molecule hybridizes to the complement of the nucleic acid molecule in SEQ ID NO: 12 under said stringent conditions.  
     
     
         6 . An isolated nucleic acid molecule which encodes a polypeptide comprising amino acid residues 151 to 158 of SEQ ID NO: 13 and which hybridizes to the complement of a nucleic acid molecule that encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 13 under hybridization conditions comprising 6×SSC at 45° C. and one or more washes in 0.1×SSC/0.2% SDS at 68° C.  
     
     
         7 . The isolated nucleic acid molecule of  claim 6  wherein said nucleic acid molecule hybridizes to the complement of the nucleic acid molecule in SEQ ID NO:12 under said stringent conditions.  
     
     
         8 . A vector comprising the nucleic acid molecule of  claim 1 ,  2  or  3 .  
     
     
         9 . The vector of  claim 8  further comprising a nucleic acid molecule which regulates the expression of a polypeptide encoded by the nucleic acid molecule.  
     
     
         10 . A host cell comprising the vector of  claim 8 .  
     
     
         11 . A host cell comprising the vector of  claim 9 .  
     
     
         12 . A host cell genetically engineered to express the nucleic acid molecule of  claim 1 ,  2  or  3 .  
     
     
         13 . The host cell of  claim 10  which is a mammalian host cell.  
     
     
         14 . The host cell of  claim 11  which is a mammalian host cell.  
     
     
         15 . The host cell of  claim 12  which is a mammalian host cell.  
     
     
         16 . A method of producing a polypeptide comprising: culturing the host cell of  claim 10  under conditions in which the nucleic acid molecule is expressed.  
     
     
         17 . A method of producing a polypeptide comprising: culturing the host cell of  claim 11  under conditions in which the nucleic acid molecule is expressed.  
     
     
         18 . An isolated polypeptide comprising of the amino acid sequence in SEQ ID NO:13.  
     
     
         19 . An isolated polypeptide comprising of the amino acid sequence of amino acid residues 19 to 158 of the amino acid sequence in SEQ ID NO:13.  
     
     
         20 . An isolated polypeptide comprising at least amino acid residues: 
 (a) 125 to 158 of SEQ ID NO: 13;    (b) 100 to 158 of SEQ ID NO:13;    (c) 75 to 158 of SEQ ID NO:13;    (d) 50 to 158 of SEQ ID NO:13; or    (e) 25 to 158 of SEQ ID NO:13.    
     
     
         21 . The isolated polypeptide of  claim 18  further comprising a heterologous polypeptide.  
     
     
         22 . The isolated polypeptide of  claim 21 , wherein the heterologous polypeptide is an Ig polypeptide.  
     
     
         23 . A monoclonal antibody produced by: 
 (a) hybridoma clone M15 3F7.3 (ATCC™ No. PTA-593);    (b) hybridoma clone M15 203.1 (ATCC™ No. PTA-591);    (c) hybridoma clone M15 10F7.1 (ATCC™ No. PTA-592);    (d) hybridoma clone M15 1B4.1 (ATCC™ No. PTA-588);    (e) hybridoma clone M15 9F11.1 (ATCC™ No. PTA-590);    (f) hybridoma clone M15 5A16.1 (ATTC™ No. PTA-587); or    an antigen binding fragment thereof.    
     
     
         24 . An isolated antibody that competes with the monoclonal antibody produced by hybridoma clone M15 3F7.3, M15 203.1, M15 10F7.1, M15 1B4.1, M15 9F11.1 or M15 5A16.1 for epitope binding.  
     
     
         25 . The isolated antibody of  claim 24 , wherein the antibody is a monoclonal antibody.  
     
     
         26 . The isolated antibody of  claim 24 , wherein the antibody is a humanized antibody.  
     
     
         27 . The isolated antibody of  claim 24 , wherein the antibody is a human antibody.  
     
     
         28 . The isolated antibody of  claim 24 , wherein the antibody is a single chain antibody.  
     
     
         29 . The monoclonal antibody of  claim 23  which is conjugated to a therapeutic moiety.  
     
     
         30 . The monoclonal antibody of  claim 29 , wherein the therapeutic moiety is a cytotoxic agent, therapeutic agent or cytokine.  
     
     
         31 . The monoclonal antibody of  claim 29 , wherein the cytotoxic factor is paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, or puromycin.  
     
     
         32 . The monoclonal antibody of  claim 29 , wherein the therapeutic agent is methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSSNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, orcis-dichlorodiamine platinum (II) (DDP) cisplatin.  
     
     
         33 . The monoclonal antibody of  claim 29 , wherein the cytokine IL-1, IL-2, IL-6, TNF-α, TNF-β, or IFN-γ.  
     
     
         34 . A pharmaceutical composition comprising the monoclonal antibody of  claim 23  or an antigen binding fragment thereof and a pharmaceutically acceptable calrier.  
     
     
         35 . A pharmaceutical composition comprising the monoclonal antibody of  claim 9  or an antigen binding fragment thereof and a pharmaceutically acceptable carrier.  
     
     
         36 . A method for treating or preventing an immune disorder in a mammal, comprising administering to the subject the pharmaceutical composition of  claim 34  or  35 .  
     
     
         37 . The method of  claim 35  or  36 , wherein the immune disorder is a TH2 or H2-like related immune disorder.  
     
     
         38 . The method of  claim 35  or  36 , wherein the immune disorder is asthma.  
     
     
         39 . The method of  claim 35  or  36 , wherein the immune disorder is an allergy.  
     
     
         40 . The method of  claim 35  or  36 , wherein the immune disorder is an IgE-mediated condition.  
     
     
         41 . The method of  claim 35  or  36 , wherein the immune disorder is an IL-4-mediated condition.  
     
     
         42 . The method of  claim 35  or  36 , wherein the mammal is a human.  
     
     
         43 . A method for detecting aberrant expression of a 103 polypeptide in a subject, comprising: 
 a) contacting a sample of cells or body fluid from said subject with an antibody of  claim 28  or antigen binding fragment thereof, or  claim 29  or antigen binding fragment thereof; and    b) measuring the level of the 103 polypeptide in said sample, wherein an increase or decrease in the 103 polypeptide level in said sample relative to a standard level of 103 polypeptide indicates aberrant expression of said 103 polypeptide in said subject.    
     
     
         44 . A method for detecting aberrant expression of a 103 polypeptide in a subject, comprising: 
 a) contacting a sample of cells or body fluid from said subject with an antibody of  claim 28  or antigen binding fragment thereof, or  claim 29  or antigen binding fragment thereof,    b) measuring the level of the 103 polypeptide in said sample; and    c) comparing the level of the103 polypeptide in said sample with a standard level of the 103 polypeptide,    wherein an increase or decrease in the 103 polypeptide level in said sample compared to the standard level indicates aberrant expression of said 103 polypeptide in said subject.    
     
     
         45 . The method of  claim 43 , wherein the antibody is conjugated to a detectable substance.  
     
     
         46 . The method of  claim 43 , wherein the detectable substance is horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase.  
     
     
         47 . The method of  claim 43 , wherein the detectable substance is fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, or phycoerythrin.  
     
     
         48 . The method of  claim 43 , wherein the detectable substance is  125 I,  131 I,  35 S  3 H or  99 Tc.  
     
     
         49 . The method of  claim 43 , wherein the subject is a human.  
     
     
         50 . A kit comprising the monoclonal antibody of  claim 23  or an antigen binding fragment thereof and a container.  
     
     
         51 . The kit of  claim 50 , wherein the monoclonal antibody is conjugated to a detectable substance.  
     
     
         52 . The kit of  claim 50 , wherein the detectable substance is horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase.  
     
     
         53 . The kit of  claim 50 , wherein the detectable substance is fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, or phycoerythrin.  
     
     
         54 . A kit comprising the antibody of  claim 24  or an antigen binding fragment thereof and a container.  
     
     
         55 . The kit of  claim 54 , wherein the monoclonal antibody is conjugated to a detectable substance.  
     
     
         56 . The kit of  claim 54 , wherein the detectable substance is horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase.  
     
     
         57 . The kit of  claim 54 , wherein the detectable substance is fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, or phycoerythrin.