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2011/109440 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . 9 September 2011 (09.09.2011) 2011/109440 Al (51) International Patent Classification: [CH/CH]; Chemin Des Chevreuils 1, 1188 Gimel (CH). C12Q 1/68 (2006.01) G01N 33/53 (2006.01) HOLTERMAN, Daniel [US/US]; 14465 North 14th St., Phoenix, AZ 85022 (US). (21) International Application Number: PCT/US201 1/026750 (74) Agent: AKHAVAN, Ramin; Caris Life Sciences, Inc., 6655 N. MacArthur Blvd., Irving, TX 75039 (US). (22) International Filing Date: 1 March 201 1 (01 .03.201 1) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, English (25) Filing Language: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (26) Publication Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 61/274,124 1 March 2010 (01 .03.2010) US KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 61/357,5 17 22 June 2010 (22.06.2010) US ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/364,785 15 July 2010 (15.07.2010) us NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (71) Applicant (for all designated States except US): CARIS SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, LIFE SCIENCES LUXEMBOURG HOLDINGS [LU/ TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. LU]; 102 Rue De Maraichers, Luxembourg, L2124 (84) Designated States (unless otherwise indicated, for every Grand-duche De Luxembourg (LU). kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (75) Inventors/ Applicants (for US only): HALBERT, David, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, D. [US/US]; 3103 Carisbrooke C , Colleyville, TX TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 76034 (US). KUSLICH, Christine [US/US]; 401 1 E. EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Claremont St., Paradise Valley, AZ 85253 (US). POSTE, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, George [US/US]; PO Box 387, Cave Creek, AZ 85327 GW, ML, MR, NE, SN, TD, TG). (US). KLASS, Michael [US/US]; 11554 N Verch Way, Oro Valley, AZ 85737 (US). SPETZLER, David Published: [US/US]; 13539 N. 95th Way, Scottsdale, AZ 85260 — with international search report (Art. 21(3)) (US). PAWLOWSKI, Traci [US/US]; 2014 N Milkweed Loop, Phoenix, AZ 85037 (US). TASINATO, Andrea © © (54) Title: BIOMARKERS FOR THERANOSTICS (57) Abstract: Biomarkers can be assessed for diagnostic, therapy-related or prognostic methods to identify phenotypes, such as a condition or disease, or the stage or progression of a disease. Circulating biomarkers from a bodily fluid can be used in profiling of physiological states or determining phenotypes. These include nucleic acids, protein, and circulating structures such as vesicles. Biomarkers can be used for theranostic purposes to select candidate treatment regimens for diseases, conditions, disease stages, ¾ and stages of a condition, and can also be used to determine treatment efficacy. The biomarkers can be circulating biomarkers, in- eluding vesicles and microRNA. BIOMARKERS FOR THERANOSTICS BACKGROUND [0001] Biomarkers for conditions and diseases such as cancer include biological molecules such as proteins, peptides, lipids, RNAs, DNA and variations and modifications thereof. [0002] The identification of specific biomarkers, such as DNA, RNA and proteins, can provide biosignatures that are used for the diagnosis, prognosis, or theranosis of conditions or diseases. Biomarkers can be detected in bodily fluids, including circulating DNA, RNA, proteins, and vesicles. Circulating biomarkers include proteins such as PSA and CA125, and nucleic acids such as SEPT9 DNA and PCA3 messenger RNA (mRNA). Circulating biomarkers also include circulating vesicles. Vesicles are membrane encapsulated structures that are shed from cells and have been found in a number of bodily fluids, including blood, plasma, serum, breast milk, ascites, bronchoalveolar lavage fluid and urine. Vesicles can take part in the communication between cells as transport vehicles for proteins, RNAs, DNAs, viruses, and prions. MicroRNAs are short RNAs that regulate the transcription and degradation of messenger RNAs. MicroRNAs have been found in bodily fluids and have been observed as a component within vesicles shed from tumor cells. The analysis of circulating biomarkers associated with diseases, including vesicles and/or microRNA, can aid in detection of disease or severity thereof, determining predisposition to a disease, as well as making treatment decisions. [0003] Vesicles present in a biological sample provide a source of biomarkers, e.g., the markers are present within a vesicle (vesicle payload), or are present on the surface of a vesicle. Characteristics of vesicles (e.g., size, surface antigens, determination of cell-of-origin, payload) can also provide a diagnostic, prognostic or theranostic readout. There remains a need to identify biomarkers that can be used to detect and treat disease. microRNA and other biomarkers associated with vesicles as well as the characteristics of a vesicle can provide a diagnosis, prognosis, or theranosis. [0004] The present invention provides methods and systems for characterizing a phenotype by detecting biomarkers that are indicative of disease or disease progress. The biomarkers can be circulating biomarkers including vesicles and microRNA. SUMMARY [0005] Disclosed herein are methods and compositions for characterizing a phenotype by analyzing a vesicle, such as a vesicle present in a biological sample derived from a subject's cell. Characterizing a phenotype for a subject or individual may include, but is not limited to, the diagnosis of a disease or condition, the prognosis of a disease or condition, the determination of a disease stage or a condition stage, a drug efficacy, a physiological condition, organ distress or organ rejection, disease or condition progression, therapy-related association to a disease or condition, or a specific physiological or biological state. [0006] In an aspect, the invention provides a method of theranosing a disease or disorder in a subject in need thereof, comprising: identifying a biosignature of a vesicle population in a sample from the subject, wherein the biosignature comprises a presence or level of one or more cell-specific biomarker and/or a presence or level of one or more one or more disease-specific biomarker, and a presence or level of one or more general vesicle biomarker; and comparing the biosignature to a reference, wherein the comparison is indicative of whether the subject is a responder or non-responder to a therapeutic agent, thereby theranosing the disease or disorder. In some embodiments, the subject has not been exposed to the therapeutic agent previously. In other -1- Docket No. 37901-706.602 embodiments, the theranosis comprises determining a treatment efficacy. The methods provided herein can be performed in vitro, wherein the biomarkers are assessed in an in vitro setting. [0007] In some embodiments, the subject is not currently being treated for the disease or disorder. In other embodiments, the subject is on an existing treatment for the disease or disorder. The method can further comprise administering the therapeutic agent to the subject. [0008] The methods of identifying a biosignature can be performed in a single assay. For example, a number of biomarkers can be assessed using a multiplexed approach. In some embodiments, all markers in the biosignature are assessed in a multiplexed assay. In other embodiments, some of the biomarkers are assessed in a single assay and one or more other biomarker is assessed in a different assay, which can also be a multiplexed assay. As an example, multiple vesicle surface biomarkers can be assessed in a first multiplex assay, and multiple microRNAs can be assessed in a second multiplex assay. The results of the first and second multiplex assays can be combined to identify a biosignature comprising the vesicle surface biomarkers and the microRNAs. [0009] In some embodiments, the sample that is assessed comprises a bodily fluid. The bodily fluid can comprise any appropriate bodily fluid, including without limitation peripheral blood, sera, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper's fluid or pre-ejaculatory fluid, female ejaculate, sweat, fecal matter, hair, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, or umbilical cord blood. In some embodiments, the bodily fluid comprises serum or plasma. [0010] The vesicle population comprises any useful population of vesicles. In some embodiments, the vesicle population has a diameter between 20 nm and 1500 nm. In other embodiments, the vesicle population comprises vesicles with a diameter between 20 nm and 800 nm. In other embodiments, the vesicle population comprises vesicles with a diameter between 20 nm and 200 nm. [0011] The vesicle population can be subjected to size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, affinity capture, immunoassay, microfluidic separation, or combinations thereof. These methods can be performed on the sample to isolate or capture the desired vesicles. The vesicle population can also be assessed without first performing a technique to isolate or capture the vesicle population. [0012] The one or more cell-specific biomarker, one or more disease-specific biomarker, and one or more general vesicle biomarker can comprise proteins.
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