Methods and compositions for diagnosis and treatment of autoimmune disease secondary to multiple sclerosis

Abstract

The invention provides methods of diagnosing and treating multiple sclerosis (MS) patients, including methods of identifying and treating multiple sclerosis patients who are at increased risk of developing a secondary autoimmune disease following lymphocyte depletion, caused, e.g., by treatment with an anti-CD52 antibody. Also embraced are methods of selecting treatment regimens for MS patients, and reagents useful in the above methods.

1 - 80 . (canceled) 
     
     
         81 . A method for treating a multiple sclerosis (MS) patient, comprising the steps of:
 selecting an MS patient who has been diagnosed as being in need of heightened monitoring for development of a secondary autoimmune disease after lymphocyte depleting therapy, wherein the need has been diagnosed by
 (i) measuring IL-21 in a blood sample from the patient, or 
 (ii) determining the presence or absence of one or more genotypes of single nucleotide polymorphisms (SNPs) selected from the group consisting of: A/A at SNP rs13151961, G/G at SNP rs6822844, and C/C at SNP rs6840978, 
 wherein elevated IL-21 in said patient compared to a subject without an autoimmune disease or the presence of one or more of said SNPs indicates that the patient is in need of heightened monitoring for development of a secondary autoimmune disease after lymphocyte depleting therapy, compared to MS patients without elevated IL-21 or without said SNPs; 
   administering a therapeutic agent that targets CD52-bearing cells to said patient; and   monitoring said patient for development of a secondary autoimmune disease.   
     
     
         82 . The method of  claim 81 , further comprising administering an IL-21 antagonist to the patient. 
     
     
         83 . The method of  claim 81 , wherein the measuring is of serum IL-21. 
     
     
         84 . The method of  claim 81 , wherein the secondary autoimmune disease is selected from the group consisting of: immune thrombocytopenic purpura (ITP), Graves' disease, Goodpasture's disease, autoimmune thyroid disease, autoimmune hemolytic anemia, autoimmune neutropenia, and autoimmune lymphopenia. 
     
     
         85 . The method of  claim 81 , wherein the blood sample is obtained from the patient prior to the lymphocyte depleting therapy. 
     
     
         86 . The method of  claim 81 , wherein the multiple sclerosis is relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis. 
     
     
         87 . The method of  claim 81 , wherein the therapeutic agent that targets CD52-bearing cells is an anti-CD52 antibody or an antigen-binding portion thereof. 
     
     
         88 . The method of  claim 81 , wherein the therapeutic agent that targets CD52-bearing cells is alemtuzumab. 
     
     
         89 . A method for reducing the occurrence or severity of a secondary autoimmune disease in a multiple sclerosis patient who has been or will be treated with a lymphocyte depleting therapy according to the method of  claim 81 , wherein the secondary autoimmune disease occurs after treatment with the lymphocyte depleting therapy, comprising the step of administering an IL-21 antagonist. 
     
     
         90 . The method of  claim 89 , wherein the IL-21 antagonist is an antibody or an antigen-binding portion thereof. 
     
     
         91 . A method for treating a multiple sclerosis (MS) patient, comprising the steps of:
 selecting a patient who has been diagnosed as not being at increased risk of developing a secondary autoimmune disease after lymphocyte depletion therapy, wherein the risk has been diagnosed by
 (i) measuring IL-21 in a blood sample from the patient, or 
 (ii) determining the presence or absence of one or more genotypes of single-nucleotide polymorphisms (SNPs) selected from the group consisting of: A/A at SNP rs13151961, G/G at SNP rs6822844 G/G, and C/C at SNP rs6840978, 
 wherein a normal IL-21 level compared to a subject without an autoimmune disease or the absence of said SNPs indicates that the patient is not at increased risk of developing a secondary autoimmune disease after lymphocyte depletion therapy, compared to MS patients without elevated IL-21 or without said SNPs; and 
   administering a therapeutic agent that targets CD52-bearing cells to said patient.   
     
     
         92 . The method of  claim 91 , wherein the measuring is of serum IL-21. 
     
     
         93 . The method of  claim 91 , wherein the secondary autoimmune disease is selected from the group consisting of: immune thrombocytopenic purpura (ITP), Graves' disease, Goodpasture's disease, autoimmune thyroid disease, autoimmune hemolytic anemia, autoimmune neutropenia, and autoimmune lymphopenia. 
     
     
         94 . The method of  claim 91 , wherein the blood sample is obtained from the patient prior to a lymphocyte depleting therapy. 
     
     
         95 . The method of  claim 91 , wherein the multiple sclerosis is relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis. 
     
     
         96 . The method of  claim 91 , wherein the therapeutic agent that targets CD52-bearing cells is an anti-CD52 antibody or an antigen-binding portion thereof. 
     
     
         97 . The method of  claim 91 , wherein the therapeutic agent that targets CD52-bearing cells is alemtuzumab. 
     
     
         98 . A method for assessing T cell responsiveness to treatment with a lymphocyte depleting therapy in a multiple sclerosis patient, comprising:
 measuring caspase-3 in T cells obtained from said patient after said therapy,   wherein an increase in caspase-3 in said T cells compared to T cells from an MS patient not receiving said therapy is indicative of T cell responsiveness to said therapy.   
     
     
         99 . A kit for performing the method of  claim 81 , comprising:
 an anti-interleukin-21 (IL-21) antibody and one or more reagents for detecting the binding of said antibody to IL-21 in a blood sample from the MS patient; and/or one or more reagents suitable for identifying the genotype of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: SNP rs13151961, SNP rs6822844, and SNP rs6840978, in a sample obtained from an individual; and   a therapeutic agent that targets CD52-bearing cells.   
     
     
         100 . A kit for performing the method of  claim 91 , comprising:
 an anti-interleukin-21 (IL-21) antibody and one or more reagents for detecting the binding of said antibody to IL-21 in a blood sample from the MS patient; and/or one or more reagents suitable for identifying the genotype of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: SNP rs13151961, SNP rs6822844, and SNP rs6840978, in a sample obtained from an individual; and   a therapeutic agent that targets CD52-bearing cells.