# US 2014/0154247 A1 · Biological Markers and Methods for Predicting Response to B-Cell Antagonists > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0154247 A1 - Document ID: US20140154247A1 - Status: Published application - Kind: A1 - Application number: 13/974,817 - Filed: 2013-08-23 - Published: 2014-06-05 - Earliest claimed: 2011-02-28 - Assignees: Genentech, Inc. - Applicants: Genentech, Inc. - Inventors: Timothy W. Behrens; Kasia Owczarczyk; Michael J. Townsend - Web page: https://patentgrep.com/patent/US20140154247A1 ## CPC - C12Q 1/6883: for diseases caused by alterations of genetic material - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 25/00: Drugs for disorders of the nervous system - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - C07K 14/70521: {CD28, CD152} - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/158: Expression markers - C12Q 2600/16: Primer sets for multiplex assays - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## 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. ## Claims ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) The biomarker of claim 1, wherein the biological sample is whole blood. ### Claim 4 (depends on 1) The biomarker of claim 1, wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis. ### Claim 5 (depends on 1) 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. ### Claim 6 (depends on 5) The biomarker of claim 5, wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 7 (depends on 1) 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. ### Claim 8 (depends on 7) The biomarker of claim 7, wherein the B-cell antagonist is an anti-CD20 antibody. ### Claim 9 (depends on 8) The biomarker of claim 8, wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. ### Claim 10 (depends on 9) The biomarker of claim 9, wherein the anti-CD20 antibody is rituximab. ### Claim 11 (depends on 9) The biomarker of claim 9, wherein the anti-CD20 antibody is ocrelizumab. ### Claim 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. ### Claim 13 (depends on 12) 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. ### Claim 14 (depends on 12) The biomarker of claim 12, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 15 (depends on 13) The biomarker of claim 13, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 16 (depends on 13) The biomarker of claim 13, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 17 (depends on 13) The biomarker of claim 13, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 18 (depends on 13) 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. ### Claim 19 (depends on 12) The biomarker of claim 12, wherein the biomarker comprises mRNA. ### Claim 20 (depends on 12) The biomarker of claim 12, wherein the biological sample is whole blood. ### Claim 21 (depends on 12) The biomarker of claim 12, wherein the patient is sufferering from, or is suspected of suffering from, rheumatoid arthritis. ### Claim 22 (depends on 12) 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. ### Claim 23 (depends on 22) The biomarker of claim 22, wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 24 (depends on 12) 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. ### Claim 25 (depends on 24) The biomarker of claim 24, wherein the B-cell antagonist is an anti-CD20 antibody. ### Claim 26 (depends on 25) The biomarker of claim 25, wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. ### Claim 27 (depends on 26) The biomarker of claim 26, wherein the anti-CD20 antibody is rituximab. ### Claim 28 (depends on 26) The biomarker of claim 26, wherein the anti-CD20 antibody is ocrelizumab. ### Claim 29 (depends on 17) 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. ### Claim 30 (depends on 17) 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. ### Claim 31 (depends on 30) The biomarker of claim 30, wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 32 (depends on 1, 12) The biomarker of claim 1 or claim 12, wherein the predicted response is non-response. ### Claim 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. ### Claim 34 (depends on 33) 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. ### Claim 35 (depends on 33) The method of claim 33, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 36 (depends on 34) The method of claim 34, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 37 (depends on 34) The method of claim 34, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 38 (depends on 34) The method of claim 34, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 39 (depends on 34) 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. ### Claim 40 (depends on 33) The method of claim 33, wherein measuring the expression of at least one gene comprises measuring mRNA. ### Claim 41 (depends on 40) The method of claim 40, wherein measuring mRNA comprises a PCR method or a microarray chip. ### Claim 42 (depends on 33) The method of claim 33, wherein the biological sample comprises whole blood. ### Claim 43 (depends on 33) The method of claim 33, wherein the patient is suffering from, or is suspected of suffering from, rheumatoid arthritis. ### Claim 44 (depends on 33) 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. ### Claim 45 (depends on 44) The method of claim 44, wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 46 (depends on 33) 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. ### Claim 47 (depends on 46) The method of claim 46, wherein the B-cell antagonist is an anti-CD20 antibody. ### Claim 48 (depends on 47) The method of claim 47, wherein the anti-CD20 antibody is selected from rituximab, ibritumomab tiuxetan, tositumomab, ocrelizumab, 1F5, 2H7, and A20. ### Claim 49 (depends on 48) The method of claim 48, wherein the anti-CD20 antibody is rituximab. ### Claim 50 (depends on 48) The method of claim 48, wherein the anti-CD20 antibody is ocrelizumab. ### Claim 51 (depends on 38) 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. ### Claim 52 (depends on 38) 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. ### Claim 53 (depends on 52) The method of claim 52, wherein the multiple sclerosis is selected from replasing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 54 (depends on 39) 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. ### Claim 55 (depends on 39) 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. ### Claim 56 (depends on 55) The method of claim 55, wherein the multiple sclerosis is selected from replasing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 57 (depends on 33) The method of claim 33, wherein the predicted response is non-response. ### Claim 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. ### Claim 59 (depends on 58) 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. ### Claim 60 (depends on 58) The method of claim 58, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 61 (depends on 59) The method of claim 59, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 62 (depends on 59) The method of claim 59, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 63 (depends on 59) The method of claim 59, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 64 (depends on 59) 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. ### Claim 65 (depends on 58) The method of claim 58, wherein the biological sample comprises whole blood. ### Claim 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. ### Claim 67 (depends on 66) 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. ### Claim 68 (depends on 66) The method of claim 66, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 69 (depends on 67) The method of claim 67, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 70 (depends on 67) The method of claim 67, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 71 (depends on 67) The method of claim 67, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 72 (depends on 67) 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. ### Claim 73 (depends on 66) The method of claim 66, wherein the biological sample comprises whole blood. ### Claim 74 (depends on 66) The method of claim 66, wherein the multiple sclerosis is selected from relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. ### Claim 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. ### Claim 76 (depends on 75) 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. ### Claim 77 (depends on 75) The method of claim 75, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 78 (depends on 76) The method of claim 76, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 79 (depends on 76) The method of claim 76, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 80 (depends on 76) The method of claim 76, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 81 (depends on 76) 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. ### Claim 82 (depends on 75) The method of claim 75, wherein the biological sample comprises whole blood. ### Claim 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. ### Claim 84 (depends on 83) 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. ### Claim 85 (depends on 83) The method of claim 83, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 86 (depends on 84) The method of claim 84, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 87 (depends on 84) The method of claim 84, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 88 (depends on 84) The method of claim 84, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 89 (depends on 84) 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. ### Claim 90 (depends on 83) The method of claim 83, wherein the biological sample comprises whole blood. ### Claim 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. ### Claim 92 (depends on 91) 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. ### Claim 93 (depends on 91) The method of claim 91, wherein the plasma/plasmablast cell-enriched gene is IgJ. ### Claim 94 (depends on 92) The method of claim 92, wherein the naïve/mature B cell-enriched gene is FCRL5. ### Claim 95 (depends on 92) The method of claim 92, wherein the naïve/mature B cell-enriched gene is CD19. ### Claim 96 (depends on 92) The method of claim 92, wherein the plasma/plasmablast cell-enriched gene is IgJ and the naïve/mature B cell-enriched gene is FCRL5. ### Claim 97 (depends on 92) 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. ### Claim 98 (depends on 91) The method of claim 91, wherein measuring the expression of at least one gene comprises measuring mRNA. ### Claim 99 (depends on 98) The method of claim 98, wherein measuring mRNA comprises a PCR method or a microarray chip. ### Claim 100 (depends on 91) The method of claim 91, wherein the biological sample comprises whole blood. ### Claim 101 (depends on 91) 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.