# US 2014/0155411 A1 · Tuberculosis Biomarkers and Uses Thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0155411 A1 - Document ID: US20140155411A1 - Status: Published application - Kind: A1 - Application number: 13/862,177 - Filed: 2013-04-12 - Published: 2014-06-05 - Earliest claimed: 2012-04-13 - Assignees: SomaLogic, Inc. - Inventors: Urs Ochsner; David G. Sterling; Nebojsa Janjic - Web page: https://patentgrep.com/patent/US20140155411A1 ## CPC - G01N 33/6893: {related to diseases not provided for elsewhere} - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - C12Q 1/6883: for diseases caused by alterations of genetic material - G01N 33/5695: {Mycobacteria} - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/158: Expression markers - G01N 2570/00: Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes - G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis - G01N 2800/60: Complex ways of combining multiple protein biomarkers for diagnosis - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - 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) - 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 ## Abstract The present application includes biomarkers, methods, devices, reagents, systems, and kits for the detection, treatment and diagnosis of tuberculosis (TB). In one aspect, the present application includes the identification of biomarkers that can be used alone or in various combinations for the detection of TB, including those set forth in Tables 1, 2, 4, 5, and 8 to 12. In another aspect, the application provides biomarkers that can be used alone or in various combinations to diagnose or prognose TB or follow treatment response. In another aspect, methods are provided for diagnosing TB in an individual, where the methods include detecting, in a biological sample from an individual, at least one biomarker value corresponding to at least one biomarker selected from the group of biomarkers provided in Tables 1, 2, 4, 5, and 8 to 12, wherein the individual is classified as having TB, or the likelihood of the individual having TB is determined, based on the at least one biomarker value. ## Claims ### Claim 1 A method of diagnosing an individual as having or not having the TB comprising: providing a biomarker panel comprising N of the biomarker proteins listed in Tables 1, 2, 4, 5 or 8 to 12; wherein N is an integer from 1 to 239 and detecting biomarker proteins, in a biological sample from an individual, to give biomarker values that each correspond to one of said N biomarker proteins in the panel, wherein said individual is classified as having or not having TB based on said biomarker values. ### Claim 2 (depends on 1) The method of claim 1, wherein detecting the biomarker values comprises performing an in vitro assay. ### Claim 3 (depends on 2) The method of claim 2, wherein said in vitro assay comprises at least one capture reagent corresponding to each of said biomarkers, and further comprising selecting said at least one capture reagent from the group consisting of aptamers, antibodies, and a nucleic acid probe. ### Claim 4 (depends on 3) The method of claim 3, wherein said at least one capture reagent is an aptamer. ### Claim 5 (depends on 2, 3, 4) The method according to any one of claims 2 to 4, wherein the in vitro assay is selected from the group consisting of an immunoassay, an aptamer-based assay, a histological or cytological assay, and an mRNA expression level assay. ### Claim 6 (depends on 1, 2, 3, 4, 5) The method according to any one of claims 1 to 5, wherein an individual is classified as having TB, or the likelihood of the individual having TB is determined, based on a classification score that deviates from a predetermined threshold. ### Claim 7 (depends on 1, 2, 3, 4, 5, 6) The method according to any one of claims 1 to 6, wherein the biological sample is sputum, urine, lung or other infected tissue and wherein the biomarker values derive from a histological or cytological analysis of said tissue. ### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7) The method according to any one of claims 1 to 7, wherein the biological sample is selected from the group consisting of sputum, whole blood, plasma, urine, body (e.g. pleural) fluid and serum. ### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7) The method according to any one of claims 1 to 7, wherein the biological sample is sputum. ### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The method according to any one of claims 1 to 9, wherein the individual is a human. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method according to any one of claims 1 to 10, wherein N=3 to 239. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method according to any one of claims 1 to 10, wherein N=4 to 239. ### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method according to any one of claims 1 to 10, wherein N=5 to 239. ### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method according to any one of claims 1 to 10, wherein N=10 to 239. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) The method according to any one of claims 1 to 10, wherein N=15 to 239. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) The method according to any one of claims 1 to 15 wherein at least one biomarker is selected from the group consisting of Table 1 and/or Table 4 and/or Table 5 and/or Tables 8 to 12. ### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The method according to any one of claims 1 to 16 wherein at least one biomarker is selected from the group consisting of TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, LBP, Coagulation factor V, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. ### Claim 18 A computer-implemented method for classifying an individual as either having a first evaluation of NED, or as having a second evaluation of EVD, said method comprising: a) retrieving on a computer biomarker information for an individual, wherein the biomarker information comprises a biomarker value that corresponds to at least one biomarker of Tables 1, 2, 4, 5 or 8 to 12; b) comparing said biomarker value of step a) to a biomarker value of a control population to determine if there is differential expression; and c) classifying the individual as having a first evaluation of NED when there is no differential expression in step b) of the biomarker value relative to said control population, and as having a second evaluation of EVD when there is differential expression of the biomarker value relative to the control population. ### Claim 19 (depends on 18) The method of claim 18, wherein said evaluation comprises a diagnosis, prognosis, determination of recurrence of TB, and/or a combination thereof. ### Claim 20 (depends on 19) The method of claim 19, wherein said evaluation of NED can be indicative of a diagnosis of no TB, a prognosis of an outcome of no TB at a selected future time point, a determination of no recurrence of TB, and/or a combination thereof. ### Claim 21 (depends on 19) The method of claim 19, wherein said evaluation of EVD can be indicative of a diagnosis of TB, a prognosis of an outcome of treatment for TB at a selected future time point, a determination of recurrence of TB, and/or a combination thereof. ### Claim 22 A computer program product comprising a computer readable medium embodying program code executable by a processor of a computing device or system, the program code comprising: a) code that retrieves data attributed to a biological sample from an individual, wherein the data comprises a biomarker value that corresponds to the at least one biomarker of Tables 1, 2, 4, 5 or 8 to 12; b) code for comparing the biomarker value of step a) to a biomarker value of a control population; and c) code that executes a classification method that indicates a first evaluation of NED when there is no differential expression of the individual's biomarker value in step b) relative to the control population, or second evaluation of EVD when there is differential expression of the individual's biomarker value relative to the control population. ### Claim 23 A method of evaluating an individual for tuberculosis (TB), wherein said evaluating comprises diagnosing the individual as having or not having TB, prognosing a future course of the TB, determining treatment response, recurrence or reactivation of TB in an individual who had been apparently cured of the TB, or any combination thereof the method comprising: providing a biomarker panel comprising N of the biomarker proteins listed in Table 1, 2, 4, 5 or 8 to 12; wherein N is an integer from 2 to 239 and detecting biomarker proteins, in a biological sample from an individual, to give values that each correspond to one of said N biomarker proteins in the panel, wherein said individual is classified as having or not having TB based on said biomarker values. ### Claim 24 (depends on 23) The method of claim 23, wherein detecting the biomarker values comprises performing an in vitro assay. ### Claim 25 (depends on 24) The method of claim 24, wherein said in vitro assay comprises at least one capture reagent corresponding to each of said biomarkers, and further comprising selecting said at least one capture reagent from the group consisting of aptamers, antibodies, and a nucleic acid probe. ### Claim 26 (depends on 25) The method of claim 25, wherein said at least one capture reagent is an aptamer. ### Claim 27 (depends on 24) The method of claim 24, wherein the in vitro assay is selected from the group consisting of an immunoassay, an aptamer-based assay, a histological or cytological assay, and an mRNA expression level assay. ### Claim 28 (depends on 23, 24, 25, 26, 27) The method according to any one of claims 23 to 27, wherein an individual is classified as having TB, or the likelihood of the individual having TB is determined, based on a classification score that deviates from a predetermined threshold. ### Claim 29 (depends on 23, 24, 25, 26, 27, 28) The method according to any one of claims 23 to 28, wherein the biological sample is lung, sputum, urine or other infected tissue and wherein the biomarker values derive from a histological or cytological analysis of said sample. ### Claim 30 (depends on 23, 24, 25, 26, 27, 28) The method of claims 23 to 28, wherein the biological sample is selected from the group consisting of sputum, whole blood, plasma, other infected tissue or fluids and serum. ### Claim 31 (depends on 23, 24, 25, 26, 27, 28) The method according to any one of claims 23 to 28, wherein the biological sample is sputum. ### Claim 32 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31) The method according to any one of claims 23 to 31, wherein the individual is a human. ### Claim 33 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method according to any one of claims 23 to 32, wherein N=3 to 239. ### Claim 34 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method according to any one of claims 23 to 32, wherein N=4 to 239. ### Claim 35 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method according to any one of claims 23 to 32, wherein N=5 to 239. ### Claim 36 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method according to any one of claims 23 to 32, wherein N=10 to 239. ### Claim 37 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method according to any one of claims 23 to 32, wherein N=15 to 239. ### Claim 38 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) The method according to any one of claims 23 to 37 wherein at least one biomarker is selected from the group consisting of Table 1 and/or Table 4 and/or Table 5 and/or Tables 8 to 12. ### Claim 39 (depends on 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38) The method according to any one of claims 23 to 38 wherein at least one biomarker is selected from the group consisting of TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, LBP, Coagulation factor V, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. ### Claim 40 A method for treating tuberculosis infection in an individual, comprising: diagnosing tuberculosis infection by causing to be determined a biomarker value corresponding N biomarker(s) of Tables 1, 2, 4, 5, or 8 to 12 in a biological sample of the individual, wherein said determination comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the presence of tuberculosis infection in the individual, wherein N is at least one; and administering treatment for tuberculosis infection to the individual thereby diagnosed with tuberculosis infection. ### Claim 41 (depends on 40) The method claim 40, wherein the biological sample is sputum, urine, lung or other infected tissue and wherein the biomarker values derive from a histological or cytological analysis of said tissue. ### Claim 42 (depends on 40) The method of claim 40, wherein the biological sample is selected from the group consisting of sputum, whole blood, plasma, urine, body (e.g. pleural) fluid and serum. ### Claim 43 (depends on 40) The method of claim 40, wherein the biological sample is sputum. ### Claim 44 (depends on 40, 41, 42, 43) The method according to any of claims 40 to 43, wherein the individual is a human. ### Claim 45 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=2 to 239. ### Claim 46 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=3 to 239. ### Claim 47 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=4 to 239. ### Claim 48 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=5 to 239. ### Claim 49 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=10 to 239. ### Claim 50 (depends on 40, 41, 42, 43, 44) The method according to any one of claims 40 to 44, wherein N=15 to 239. ### Claim 51 (depends on 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) The method according to any one of claims 40 to 50, wherein at least one biomarker is selected from the group consisting of Table 1 and/or Table 4 and/or Table 5 and/or Tables 8 to 12. ### Claim 52 (depends on 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51) The method according to any one of claims 40 to 51 wherein at least one biomarker is selected from the group consisting of TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, LBP, Coagulation factor V, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. ### Claim 53 An assay for diagnosing tuberculosis infection in an individual, comprising: causing to be determined a biomarker value corresponding to N biomarker(s) of Tables 1, 2, 4, 5, or 8 to 12 in a biological sample of the individual, wherein said determining comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the presence of tuberculosis infection in the individual, wherein N is at least one and diagnosing an individual to have tuberculosis infection based on said differential expression of the biomarker. ### Claim 54 (depends on 53) The method of claim 53, wherein the biological sample is selected from the group consisting of sputum, whole blood, plasma, urine, body (e.g. pleural) fluid, serum. ### Claim 55 (depends on 53) The method claim 53, wherein the biological sample is infected tissue and said biomarker value derives from a histological or cytological analysis of said tissue. ### Claim 56 (depends on 53) The method of claim 53, wherein the biological sample is sputum. ### Claim 57 (depends on 53, 54, 55, 56) The method according to any one of claims 53 to 56, wherein the individual is a human. ### Claim 58 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=2 to 239. ### Claim 59 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=3 to 239. ### Claim 60 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=4 to 239. ### Claim 61 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=5 to 239. ### Claim 62 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=10 to 239. ### Claim 63 (depends on 53, 54, 55, 56, 57) The method according to any one of claims 53 to 57, wherein N=15 to 239. ### Claim 64 (depends on 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63) The method according to any one of claims 53 to 63, wherein at least one biomarker is selected from the group consisting of Table 1 and/or Table 4 and/or Table 5 and/or Tables 8 to 12. ### Claim 65 (depends on 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64) The method according to any one of claims 53 to 64, wherein at least one biomarker is selected from the group consisting of TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, LBP, Coagulation factor V, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. ### Claim 66 A method for determining whether treatment for tuberculosis infection should be administered to a patient, comprising: a) causing an assay to be conducted for determining a biomarker value corresponding N biomarker(s) of Tables 1, 2, 4, 5, or 8 to 12 in a biological sample of the individual, wherein said determining comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the presence of tuberculosis infection in the individual, wherein N is at least one b) diagnosing an individual to have tuberculosis infection based on said differential expression of the biomarker; and c) administering treatment for tuberculosis infection. ### Claim 67 A method for determining whether treatment for tuberculosis infection should be administered to a patient, comprising: a) obtaining a biological sample from said patient b) causing an assay to be conducted for determining a biomarker value corresponding to N biomarker(s) of Tables 1, 2, 4, 5, or 8 to 12 in said biological sample of the individual, wherein said determining comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the presence of tuberculosis infection in the individual, wherein N is at least one; c) diagnosing an individual to have tuberculosis infection based on said differential expression of the biomarker; and d) administering treatment for tuberculosis infection. ### Claim 68 A method for treating recurrence or reactivation of tuberculosis infection in an individual, comprising: diagnosing recurrence or reactivation of tuberculosis infection by causing to be determined a biomarker value corresponding to N biomarker(s) of Tables 1, 2, 4, 5, or 8 to 12 in a biological sample of the individual, wherein said determination comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the recurrence or reactivation of tuberculosis infection in the individual, and administering treatment for recurrence or reactivation of tuberculosis infection to the individual thereby diagnosed with recurrent or reactivated tuberculosis infection. ### Claim 69 A method for modifying treatment of tuberculosis infection in an individual, comprising evaluating the status of tuberculosis infection by causing to be determined a biomarker value corresponding to N biomarker(s) of Tables 8 to 12 in a biological sample of the individual, wherein said evaluation comprises comparing the biomarker value of the individual to the biomarker value in a control population for differential expression of the biomarker, wherein differential expression of the biomarker indicates the need to intensify treatment of tuberculosis infection in the individual, and modifying treatment for tuberculosis infection to the individual thereby evaluated as in need of modified treatment of tuberculosis infection.