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

Abstract

The invention provides methods of diagnosing multiple sclerosis (MS) patients, including methods of identifying 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 . A method for identifying a multiple sclerosis (MS) patient who has elevated interleukin-21 (IL-21) compared to IL-21 in a subject without an autoimmune disease, comprising the step of:
 measuring IL-21 in a blood sample from the MS patient, thereby identifying an MS patient having elevated IL-21 compared to said subject.   
     
     
         2 . A method for identifying a multiple sclerosis patient who is likely to have elevated interleukin-21 (IL-21) compared to a subject without an autoimmune disease, comprising the step of genotyping the patient to detect 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 the presence of one or more of said genotypes is associated with elevated IL-21. 
     
     
         3 . A method for identifying a multiple sclerosis (MS) patient who is at increased risk of developing a secondary autoimmune disease following lymphocyte depletion, comprising the step of:
 measuring interleukin-21 (IL-21) in a blood sample from the MS patient, wherein elevated IL-21 compared to a subject without an autoimmune disease indicates that the patient is at increased risk of developing a secondary autoimmune disease compared to MS patients without elevated IL-21; and   informing the patient of said increased risk.   
     
     
         4 . A method for identifying a multiple sclerosis patient who is at increased risk of developing a secondary autoimmune disease following lymphocyte depletion, comprising the step of:
 genotyping the patient to detect the presence or absence in the patient 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 the presence of one or more of said genotypes is associated with an increased risk of developing a secondary autoimmune disease compared to MS patients without said one or more genotypes; and   informing the patient of said increased risk.   
     
     
         5 . The method of  claim 3 , wherein said lymphocyte depletion is induced by a treatment that targets CD52. 
     
     
         6 . The method of  claim 5 , wherein the treatment that targets CD52 comprises treatment with an anti-CD52 antibody or an antigen-binding portion thereof. 
     
     
         7 . The method of  claim 6 , wherein the anti-CD52 antibody is alemtuzumab or a biologically similar agent. 
     
     
         8 . The method of  claim 4 , wherein said lymphocyte depletion is induced by a treatment that targets CD52. 
     
     
         9 . The method of  claim 8 , wherein the treatment that targets CD52 comprises treatment with an anti-CD52 antibody or an antigen-binding portion thereof. 
     
     
         10 . The method of  claim 9 , wherein the anti-CD52 antibody is alemtuzumab or a biologically similar agent. 
     
     
         11 . A method for selecting a multiple sclerosis (MS) patient in need of heightened monitoring for development of a secondary autoimmune disease after lymphocyte depleting therapy, comprising the step of:
 measuring IL-21 in a blood sample from the MS patient, wherein elevated IL-21 in said patient compared to a subject without an autoimmune disease indicates that the patient is in need of heightened monitoring for development of a secondary autoimmune disease compared to MS patients without elevated IL-21.   
     
     
         12 . A method for selecting a multiple sclerosis patient in need of heightened monitoring for development of a secondary autoimmune disease after lymphocyte depleting therapy, comprising the step of:
 genotyping the patient to detect 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 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 compared to MS patients without said one or more genotypes.   
     
     
         13 . A method for informing a treatment decision for a multiple sclerosis patient, comprising the steps of:
 measuring IL-21 in a blood sample from said patient; and   selecting a treatment regimen appropriate for the IL-21 measurement.   
     
     
         14 . A method for informing a treatment decision for a multiple sclerosis patient, comprising the steps of:
 genotyping the patient for the presence or absence of one or more genotypes of single polynucleotide polymorphisms (SNPs) selected from the group consisting of: A/A at SNP rs13151961, G/G at SNP rs6822844, and C/C at SNP rs6840978; and   selecting a treatment regimen appropriate for the patient's genotype.   
     
     
         15 . A method for treating multiple sclerosis in a patient known to be in need thereof, comprising the steps of:
 obtaining information on (i) IL-21 in a blood sample from the patient; or (ii) 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; and   administering a therapeutic agent for multiple sclerosis to said patient.   
     
     
         16 . The method of  claim 15 , further comprising, after the administering step, monitoring said patient for development of a secondary autoimmune disease. 
     
     
         17 - 28 . (canceled) 
     
     
         29 . 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, wherein the secondary autoimmune disease occurs after treatment with the lymphocyte depleting therapy, comprising the step of administering an IL-21 antagonist. 
     
     
         30 - 34 . (canceled) 
     
     
         35 . A therapeutic regimen for treating multiple sclerosis in a patient known to be in need thereof, said regimen comprising:
 measuring IL-21 in a blood sample from the patient and/or genotyping the patient to detect 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; and   administering a therapeutic agent for multiple sclerosis to said patient.   
     
     
         36 - 37 . (canceled) 
     
     
         38 . An enzyme-linked immunosorbent assay (ELISA) kit for detecting serum IL-21 level in a subject, comprising an antibody that binds IL-21, or an antigen-binding portion of said antibody, or a soluble IL-21 receptor, and an instruction directing a user to take a blood sample from the subject. 
     
     
         39 - 58 . (canceled) 
     
     
         59 . 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.   
     
     
         60 - 63 . (canceled) 
     
     
         64 . A method for identifying an individual who is likely to have elevated interleukin-21 (IL-21) compared to a subject without any known inflammatory condition, comprising the step of genotyping the individual to detect 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 the presence of one or more of said genotypes is associated with elevated IL-21. 
     
     
         65 . A method for informing an MS patient of an increased risk of developing a secondary autoimmune disease following lymphocyte depletion, comprising the steps of:
 obtaining information on interleukin-21 (IL-21) in a blood sample from the MS patient, wherein elevated IL-21 compared to a subject without an autoimmune disease indicates that the patient is at increased risk of developing a secondary autoimmune disease compared to MS patients without elevated IL-21; and   informing the patient of said increased risk or lack thereof.   
     
     
         66 . A method for informing an MS patient of an increased risk of developing a secondary autoimmune disease following lymphocyte depletion, comprising the steps of:
 obtaining information on 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 the presence of one or more of said genotypes is associated with an increased risk of developing a secondary autoimmune disease compared to MS patients without said one or more genotypes; and   informing the patient of said increased risk or lack thereof.   
     
     
         67 . A method for informing an MS patient of a need for heightened monitoring for development of a secondary autoimmune disease following lymphocyte depleting therapy, comprising the steps of:
 obtaining information on IL-21 in a blood sample from the MS patient, wherein elevated IL-21 in said patient compared to a subject without an autoimmune disease indicates that the patient is in need of heightened monitoring for development of a secondary autoimmune disease compared to MS patients without elevated IL-21; and   informing the patient of said need or lack thereof.   
     
     
         68 . A method for informing an MS patient of a need for heightened monitoring for development of a secondary autoimmune disease following lymphocyte depleting therapy, comprising the step of:
 obtaining information on 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 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 compared to MS patients without said one or more genotypes; and   informing the patient of said need or lack thereof.   
     
     
         69 . A method for informing a regimen for monitoring an MS patient following lymphocyte depleting therapy, comprising the steps of:
 obtaining information on (i) IL-21 in a blood sample from the patient; or (ii) 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; and   selecting a monitoring regimen appropriate for the patient based on the information.   
     
     
         70 - 71 . (canceled) 
     
     
         72 . A method for distributing a lymphocyte depleting drug to a patient for treating multiple sclerosis, comprising the steps of:
 counseling the patient on the increased risk of developing a secondary autoimmune disease following treatment with said drug, wherein the increased risk is associated with (i) elevated IL-21; or (ii) the presence 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; and   providing the drug to the patient after said counseling.   
     
     
         73 - 75 . (canceled) 
     
     
         76 . A kit for treating multiple sclerosis, comprising:
 a lymphocyte depleting therapeutic agent; and   a written instruction for informing a health care provider or a patient of the potential for an increased risk of developing a secondary autoimmune disease following treatment with said agent, wherein said increased risk is associated with (i) elevated IL-21, or (ii) the presence 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.   
     
     
         77 - 78 . (canceled) 
     
     
         79 . A kit for identifying a multiple sclerosis (MS) patient who is at increased risk of developing a secondary autoimmune disease following lymphocyte depletion, 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. 
     
     
         80 . A kit for identifying a multiple sclerosis patient who is at increased risk of developing a secondary autoimmune disease following lymphocyte depletion, comprising: 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.