Biological Markers and Methods for Predicting Response to B-Cell Antagonists

Abstract

Biological markers that predict patient responsiveness to B-cell antagonists are provided. Also provided are methods of using such biological markers. In addition, methods for identifying patients suffering from an autoimmune disease, e.g., rheumatoid arthritis, who are not likely to respond to B-cell antagonists are provided, as are methods of treating such patients. Methods for selecting therapeutic agents to treat such patients are also provided.

1 . A biomarker for predicting the response of a patient to a therapeutic agent comprising a B-cell antagonist, wherein the biomarker comprises elevated total plasma/plasmablast cell mRNA in a biological sample obtained from the patient compared to the level of total plasma/plasmablast cell mRNA in a biological sample obtained from a control subject or compared to a threshold value for total plasma/plasmablast cell mRNA. 
     
     
         2 . The biomarker of  claim 1 , further comprising a low level of total naïve/mature B cell mRNA in the patient's biological sample compared to the level of total naïve/mature B cell mRNA in the control subject's biological sample or compared to a threshold value for total naïve/mature B cell mRNA. 
     
     
         3 . The biomarker of  claim 1 , wherein the biological sample is whole blood. 
     
     
         4 . The biomarker of  claim 1 , wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis. 
     
     
         5 . The biomarker of  claim 1 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis. 
     
     
         6 . The biomarker of  claim 5 , wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         7 . The biomarker of  claim 1 , wherein the B-cell antagonist is selected from an anti-CD22 antibody, an anti-CD20 antibody, an anti-BR3 antibody, and a BR3-Fc immunoadhesin. 
     
     
         8 . The biomarker of  claim 7 , wherein the B-cell antagonist is an anti-CD20 antibody. 
     
     
         9 . The biomarker of  claim 8 , wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. 
     
     
         10 . The biomarker of  claim 9 , wherein the anti-CD20 antibody is rituximab. 
     
     
         11 . The biomarker of  claim 9 , wherein the anti-CD20 antibody is ocrelizumab. 
     
     
         12 . A biomarker for predicting the response of a patient to a therapeutic agent comprising a B-cell antagonist, wherein the biomarker comprises an elevated expression level of a plasma/plasmablast cell-enriched gene in a biological sample obtained from the patient compared to the expression level of the plasma/plasmablast cell-enriched gene in a biological sample obtained from a control subject or compared to a threshold value for the plasma/plasmablast cell-enriched gene. 
     
     
         13 . The biomarker of  claim 12 , further comprising a low expression level of a naïve/mature B cell-enriched gene in the patient's biological sample compared to the expression level of the naïve/mature B cell-enriched gene in the control subject's biological sample or compared to a threshold value for the naïve/mature B cell-enriched gene. 
     
     
         14 . The biomarker of  claim 12 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         15 . The biomarker of  claim 13 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         16 . The biomarker of  claim 13 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         17 . The biomarker of  claim 13 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         18 . The biomarker of  claim 13 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         19 . The biomarker of  claim 12 , wherein the biomarker comprises mRNA. 
     
     
         20 . The biomarker of  claim 12 , wherein the biological sample is whole blood. 
     
     
         21 . The biomarker of  claim 12 , wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis. 
     
     
         22 . The biomarker of  claim 12 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis. 
     
     
         23 . The biomarker of  claim 22 , wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         24 . The biomarker of  claim 12 , wherein the B-cell antagonist is selected from an anti-CD22 antibody, an anti-CD20 antibody, an anti-BR3 antibody, and a BR3-Fc immunoadhesin. 
     
     
         25 . The biomarker of  claim 24 , wherein the B-cell antagonist is an anti-CD20 antibody. 
     
     
         26 . The biomarker of  claim 25 , wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. 
     
     
         27 . The biomarker of  claim 26 , wherein the anti-CD20 antibody is rituximab. 
     
     
         28 . The biomarker of  claim 26 , wherein the anti-CD20 antibody is ocrelizumab. 
     
     
         29 . The biomarker of  claim 17 , wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         30 . The biomarker of  claim 17 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         31 . The biomarker of  claim 30 , wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         32 . The biomarker of  claim 1  or  claim 12 , wherein the predicted response is non-response. 
     
     
         33 . A method of predicting the response of a patient to a therapy comprising a B-cell antagonist, the method comprising:
 measuring in a biological sample obtained from the patient the expression of at least one gene enriched in plasma/plasmablast cells and   comparing the expression of the at least one gene in the patient's biological sample to the expression of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the at least one plasma/plasmablast cell-enriched gene,   
       wherein elevated expression of the at least one gene in the patient's biological sample compared to the expression in the control subject's biological sample or to the threshold value is predictive of response of the patient to the therapy comprising the B-cell antagonist. 
     
     
         34 . The method of  claim 33 , further comprising:
 measuring in the biological sample obtained from the patient the expression of at least one gene enriched in naïve/mature B cells and   comparing the expression of the at least one naïve/mature B cell-enriched gene in the patient's biological sample to the expression of the same at least one naïve/mature B cell-enriched gene in the biological sample obtained from the control subject or to a threshold value for the naïve/mature B cell-enriched gene,   
       wherein a low level of expression of the at least one naïve/mature B cell-enriched gene in the patient's biological sample compared to the expression of the same at least one naïve/mature B cell-enriched gene in the control subject's biological sample or to the threshold value for the naïve/mature B cell-enriched gene is predictive of response of the patient to the therapy comprising the B-cell antagonist. 
     
     
         35 . The method of  claim 33 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         36 . The method of  claim 34 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         37 . The method of  claim 34 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         38 . The method of  claim 34 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         39 . The method of  claim 34 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         40 . The method of  claim 33 , wherein measuring the expression of at least one gene comprises measuring mRNA. 
     
     
         41 . The method of  claim 40 , wherein measuring mRNA comprises a PCR method or a microarray chip. 
     
     
         42 . The method of  claim 33 , wherein the biological sample comprises whole blood. 
     
     
         43 . The method of  claim 33 , wherein the patient is suffering from, or is suspected of suffering from, rheumatoid arthritis. 
     
     
         44 . The method of  claim 33 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis. 
     
     
         45 . The method of  claim 44 , wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         46 . The method of  claim 33 , wherein the B-cell antagonist is selected from an anti-CD22 antibody, an anti-CD20 antibody, an anti-BR3 antibody, and a BR3-Fc immunoadhesin. 
     
     
         47 . The method of  claim 46 , wherein the B-cell antagonist is an anti-CD20 antibody. 
     
     
         48 . The method of  claim 47 , wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. 
     
     
         49 . The method of  claim 48 , wherein the anti-CD20 antibody is rituximab. 
     
     
         50 . The method of  claim 48 , wherein the anti-CD20 antibody is ocrelizumab. 
     
     
         51 . The method of  claim 38 , wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         52 . The method of  claim 38 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         53 . The method of  claim 52 , wherein the multiple sclerosis is selected from replasing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         54 . The method of  claim 39 , wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         55 . The method of  claim 39 , wherein the patient is suffering from, or is suspected of suffering from, an autoimmune disease selected from multiple sclerosis, lupus, and ANCA-vasculitis, and wherein the B-cell antagonist is selected from rituximab and ocrelizumab. 
     
     
         56 . The method of  claim 55 , wherein the multiple sclerosis is selected from replasing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         57 . The method of  claim 33 , wherein the predicted response is non-response. 
     
     
         58 . A method of treating rheumatoid arthritis in a patient comprising administering a therapeutically effective amount of a therapeutic agent other than a B-cell antagonist to the patient to treat the rheumatoid arthritis, provided that a biological sample obtained from the patient has been shown to possess elevated expression of at least one gene enriched in plasma/plasmablast cells compared to the expression level of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the plasma/plasmablast cell-enriched gene. 
     
     
         59 . The method of  claim 58 , wherein the biological sample has in addition been shown to possess a low level of expression of at least one gene enriched in naïve/mature B cells compared to the expression level of the same at least one gene enriched in naïve/mature B cells in the biological sample obtained from the control subject or to a threshold value for the naïve/mature B cell-enriched gene. 
     
     
         60 . The method of  claim 58 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         61 . The method of  claim 59 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         62 . The method of  claim 59 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         63 . The method of  claim 59 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         64 . The method of  claim 59 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         65 . The method of  claim 58 , wherein the biological sample comprises whole blood. 
     
     
         66 . A method of treating multiple sclerosis in a patient comprising administering a therapeutically effective amount of a therapeutic agent other than a B-cell antagonist to the patient to treat the multiple sclerosis, provided that a biological sample obtained from the patient has been shown to possess elevated expression of at least one gene enriched in plasma/plasmablast cells compared to the expression level of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the plasma/plasmablast cell-enriched gene. 
     
     
         67 . The method of  claim 66 , wherein the biological sample has in addition been shown to possess a low level of expression of at least one gene enriched in naïve/mature B cells compared to the expression level of the same at least one gene enriched in naïve/mature B cells in a biological sample obtained from a control subject or to a threshold value for the naïve/mature B cell-enriched gene. 
     
     
         68 . The method of  claim 66 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         69 . The method of  claim 67 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         70 . The method of  claim 67 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         71 . The method of  claim 67 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         72 . The method of  claim 67 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         73 . The method of  claim 66 , wherein the biological sample comprises whole blood. 
     
     
         74 . The method of  claim 66 , wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. 
     
     
         75 . A method of treating ANCA-vasculitis in a patient comprising administering a therapeutically effective amount of a therapeutic agent other than a B-cell antagonist to the patient to treat the ANCA-vasculitis, provided that a biological sample obtained from the patient has been shown to possess elevated expression of at least one gene enriched in plasma/plasmablast cells compared to the expression level of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the plasma/plasmablast cell-enriched gene. 
     
     
         76 . The method of  claim 75 , wherein the biological sample has in addition been shown to possess a low level of expression of at least one gene enriched in naïve/mature B cells compared to the expression level of the same at least one gene enriched in naïve/mature B cells in a biological sample obtained from a control subject or to a threshold value for the naïve/mature B cell-enriched gene. 
     
     
         77 . The method of  claim 75 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         78 . The method of  claim 76 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         79 . The method of  claim 76 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         80 . The method of  claim 76 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         81 . The method of  claim 76 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         82 . The method of  claim 75 , wherein the biological sample comprises whole blood. 
     
     
         83 . A method of treating lupus in a patient comprising administering a therapeutically effective amount of a therapeutic agent other than a B-cell antagonist to the patient to treat the lupus, provided that a biological sample obtained from the patient has been shown to possess elevated expression of at least one gene enriched in plasma/plasmablast cells compared to the expression level of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the plasma/plasmablast cell-enriched gene. 
     
     
         84 . The method of  claim 83  wherein the biological sample has in addition been shown to possess a low level of expression of at least one gene enriched in naïve/mature B cells compared to the expression level of the same at least one gene enriched in naïve/mature B cells in a biological sample obtained from a control subject or to a threshold value for the naïve/mature B cell-enriched gene. 
     
     
         85 . The method of  claim 83 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         86 . The method of  claim 84 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         87 . The method of  claim 84 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         88 . The method of  claim 84 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         89 . The method of  claim 84 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         90 . The method of  claim 83 , wherein the biological sample comprises whole blood. 
     
     
         91 . A method of selecting a therapeutic agent for treatment of a patient suffering from an autoimmune disease comprising:
 obtaining a biological sample from the patient;   measuring in the biological sample obtained from the patient the expression of at least one gene enriched in plasma/plasmablast cells;   comparing the expression of the at least one gene in the patient's biological sample to the expression of the same at least one gene in a biological sample obtained from a control subject or to a threshold value for the at least one plasma/plasmablast cell-enriched gene;   determining whether the expression of the at least one gene in the patient's biological sample is elevated compared to the expression in the control subject's biological sample or to the threshold value; and   selecting a therapeutic agent other than a B-cell antagonist provided the expression of the at least one gene in the patient's biological sample is elevated.   
     
     
         92 . The method of  claim 91 , further comprising:
 measuring in the biological sample obtained from the patient the expression of at least one gene enriched in naïve/mature B cells;   comparing the expression of the at least one naïve/mature B cell-enriched gene in the patient's biological sample to the expression of the same at least one naïve/mature B cell-enriched gene in the biological sample obtained from the control subject or to a threshold value for the naïve/mature B cell-enriched gene;   determining whether the expression of the at least one naïve/mature B cell-enriched gene in the patient's biological sample is low compared to the expression in the same at least one naïve/mature B cell-enriched gene in the control subject's biological sample or to the threshold value for the naïve/mature B cell-enriched gene; and   selecting a therapeutic agent other than a B-cell antagonist provided the expression of the at least one naïve/mature B cell-enriched gene is low.   
     
     
         93 . The method of  claim 91 , wherein the plasma/plasmablast cell-enriched gene is IgJ. 
     
     
         94 . The method of  claim 92 , wherein the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         95 . The method of  claim 92 , wherein the naïve/mature B cell-enriched gene is CD19. 
     
     
         96 . The method of  claim 92 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. 
     
     
         97 . The method of  claim 92 , wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is CD 19. 
     
     
         98 . The method of  claim 91 , wherein measuring the expression of at least one gene comprises measuring mRNA. 
     
     
         99 . The method of  claim 98 , wherein measuring mRNA comprises a PCR method or a microarray chip. 
     
     
         100 . The method of  claim 91 , wherein the biological sample comprises whole blood. 
     
     
         101 . The method of  claim 91 , wherein the autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, lupus, and ANCA-vasculitis.