(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 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