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WO 2017/136709 A2 10 August 2017 (10.08.2017) P O P C T (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 WO 2017/136709 A2 10 August 2017 (10.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, PCT/US20 17/0 16482 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 3 February 2017 (03.02.2017) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (25) Filing Language: English NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (26) Publication Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW. 62/290,657 3 February 2016 (03.02.2016) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: THE SCRIPPS RESEARCH INSITUTE kind of regional protection available): ARIPO (BW, GH, [US/US]; 10550 North Torrey Pines Road, La Jolla, CA GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 92037 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: SALOMON, Daniel, R.; 4728 Reedley Ter DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, race, San Diego, CA 92130 (US). KURIAN, Sunil, M.; LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 10963 Tobago Road, San Diego, CA 92126 (US). MOD- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, ENA, Brian, D.; 645 Front Street, Unit 710, San Deigo, GW, KM, ML, MR, NE, SN, TD, TG). CA 92101 (US). Published: (74) Agents: FITTING, Thomas et al; The Scripps Research Institute, 10550 North Torrey Pines Road, TPC-8, La Jolla, — without international search report and to be republished CA 92037 (US). upon receipt of that report (Rule 48.2(g)) (54) Title: MOLECULAR ASSAYS FOR REGULATING IMMUNOSUPPRESSION, AVERTING IMMUNE-MEDIATED RE JECTION AND INCREASING GRAFT SURVIVAL (57) Abstract: Disclosed herein are methods of detecting, predicting or monitoring im mune-mediated rejection, immunosuppres provide sample from transplant recipient on - 101 sion, or risk of graft loss in a transplant recip immunosuppressant regimen ient undergoing an immunosuppression regi men. These methods may be useful even In patients with kidney damage not thought to - 105 (optional) pre-process sample result from ongoing immune activation. Also provided are molecular profiles that more sensitively detect ongoing immune-mediated injury and are a better indicator of later graft measure gene expression levels - 110 loss than standard microscopic biopsy exam of panel ination. add or discontinue therapeutic - 115 agent in regimen MOLECULAR ASSAYS FOR REGULATING IMMUNOSUPPRESSION, AVERTING IMMUNE-MEDIATED REJECTION AND INCREASING GRAFF SURVIVAL CROSS-REFERENCE TO RELATED APPLICATIONS δθ ] This application claims the benefit of U.S. Provisional Patent Application No. 62/290,657. filed February 3, 2 , which is c rp ral d by reference in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under U AI063603 (DRS SMK, TG, TSM, SRH) arid CTSA L2 T ! (BM) awarded by National Institutes of Health (N ). The government has certain rights in the invention. BACKGROUND [0003 Kidney transplant recipients routinely take immunosuppressant dings in order to reduce the risk of acute or chronic rejection of the allograft. The health of the transplanted organ is usually closely monitored using blood tests for kidney function (such as creatinine levels) and kidney biopsies, which are then evaluated histologically for pathological evidence of rejection. Medical decisions regarding the course of treatment thus often hinge on histological characterization of biopsies, which include findings of pathological changes associated with acute rejection, chronic rejection or interstitial fibrosis and/or tubular atrophy (IFTA). Acute rejection and chronic rejection a e immune-mediated events associated with abnormal kidney function and lead to eventual graft loss, IFTA describes a common histological abnormality seen i kidney transplant biopsies in which norma! cortical structures are replaced by interstitial fibrosis as result of tissue injury and subsequent scarring, IFTA, when accompanied by histological evidence of inflammation, may correlate with decreased graft survival IFTA is evident histologically in 25% or more of 1-year surveillance biopsies despite concomitant stable renal function. Our new results indicate that at the molecular level, IFTA can be the histological manifestation of chronic immune-mediated rejection, [0004] The 10-year graft survival rates for kidney transplant recipients have not improved in the last decade despite the widespread use of effective immunosuppressive drugs. There is thus a dire need in the field for improved management of immunosuppression regimens, for tests that provide early detection of graft rejection even in the absence of definitive histological findings and tests that are objective and non-biased in contrast to the current practice of histology-based pathology tha is largely subjective and can vary significantly with only about 70% inter- observer concordance from different pathologists in the same transplant center and/or different between transplant centers. SUMMARY 5 n some aspects, a method of administering immunosuppressant drugs is provided herein comprising: (a) obtaining a biological sample comprising nucleic acids, wherein the biological sample is obtained from a kidney transplant recipient on an immunosuppression drug regimen and wherein the nucleic acids comprise expression products from a panel of genes; (b) diagnosing immune-mediated rejection or inadequate immunosuppression n the kidney transplant recipient based on levels of the expression products from the panel of genes, wherei the panel of genes is specifically selected to detect immune-mediated rejection or inadequate immunosuppression n a kidney transplant subject irrespective of histological findings; and (e) adjusting the immunosuppression drug regimen administered to the kidney transplant recipient based on the levels of the expression products from the panel of genes specifically selected to detect immune-mediated rejection or inadequate immunosuppression in a kidney transplant subject irrespective of histological findings. [00061 some aspects, provided herein is a method of managing an immunosuppression regimen in a kidney transplant recipient comprising: (a) obtaining a biological sample comprising nucleic acids, wherein the biological sample is obtained from a kidney transplant recipient on an immunosuppression drug regimen and wherein the nucleic acids comprise gene expression products from a panel of genes; (b) diagnosing immune-mediated rejection or inadequate immunosuppression in the kidney transplant recipient using levels of the expression products from the panel of genes , wherein the panel of genes comprises: (i) twenty or more genes listed in Table 37, ( ) twenty or more genes iisted in Table 38, (iii) twenty or more genes listed in Table 39, (iv) twenty or more genes listed in Table 40, (v) twenty o more genes iisted in Table 4 , (vi) twenty or more genes listed in Table 42 (vii) twenty or more genes Iisted in Table 45, (viii) twenty or ore genes listed in Table 4 , (ix) twenty or more genes listed in Table ; (x) twenty or more genes listed in Table 23, or (xi) twenty or more genes listed in Table 48; and (c) adjusting the Immunosuppression drug regimen administered to the kidney transplant recipient based on the levels of the expression products from the panel of genes comprising (i) twenty or more genes iisted in Table 37, (ii) twenty or more genes listed in Table , (iii) twenty or more genes Iisted in Table 39, (iv) twenty or more genes listed in Table 40, (v) twenty or more genes Iisted in Table 41, (vi) twenty or more genes listed in Table 42, (vii) twenty or more genes listed in Table 45, (viii) twenty or more genes listed in Table 47, (ix) twenty or more genes listed in Table ; x) twenty or more genes listed in Table 23, or (xi) twenty or more genes listed in Table 48. [0007] In some embodiments, the diagnosing of any of the foregoing methods comprises diagnosing immune-mediated rejection without distinguishing between acute and chronic rejection, Θ ] In some aspects, provided herein is a method of administering immunosuppressant drugs to a kidney transplant recipient comprising: (a) obtaining a biological sample comprising nucleic acids, wherein the biological sample is obtained fro a kidney transplant recipient on an immunosuppression drug regimen and the nucleic acids comprise expression products from a panel of genes that are commonly regulated in acute and chronic rejection; (b) detecting presence or absence of immune-mediated rejection in the kidney transplant recipient without distinguishing between acute and chronic rejection, wherein the detecting is based on levels of the expression products from the panel of genes commonly regulated in acute and chronic rejection; and (c) adjusting the immunosuppression drug regimen of the kidney transplant
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