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(12) Patent Application Publication (10) Pub. No.: US 2017/0137885 A1 Salomon Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0137885 A1 Salomon Et Al US 2017013 7885A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0137885 A1 Salomon et al. (43) Pub. Date: May 18, 2017 (54) GENE EXPRESSION PROFILES Sep. 9, 2014, which is a continuation-in-part of appli ASSOCATED WITH SUB-CLINICAL cation No. PCT/US2014/054735, filed on May 22, KIDNEY TRANSPLANT RELECTION 2014. (60) Provisional application No. 62/001.902, filed on May (71) Applicants: THE SCRIPPS RESEARCH 22, 2014, provisional application No. 62/001,909, INSTITUTE, LA JOLLA, CA (US); filed on May 22, 2014, provisional application No. NORTHWESTERN UNIVERSITY, 62/001.889, filed on May 22, 2014, provisional ap EVANSTON, IL (US) plication No. 62/029,038, filed on Jul. 25, 2014. (72) Inventors: Daniel R. Salomon, San Diego, CA (US); John Friedewald, Chicago, IL Publication Classification (US); Sunil Kurian, San Diego, CA (51) Int. C. (US); Michael M. Abecassis, Highland CI2O I/68 (2006.01) Park, IL (US); Steven Head, Lakeside, (52) U.S. C. CA (US); Phillip Ordoukhanian, San CPC ..... CI2O 1/6883 (2013.01); C12O 2600/158 Diego, CA (US) (2013.01); C12O 2600/118 (2013.01) (21) Appl. No.: 15/358,390 (57) ABSTRACT (22) Filed: Nov. 22, 2016 By a genome-wide gene analysis of expression profiles of over 50,000 known or putative gene sequences in peripheral Related U.S. Application Data blood, the present inventors have identified a consensus set (63) Continuation of application No. PCT/US2015/ of gene expression-based molecular biomarkers associated 032202, filed on May 22, 2015, which is a continu with subclinical acute rejection (subAR). These genes sets ation-in-part of application No. 14/481,167, filed on are useful for diagnosis, prognosis, monitoring of SubAR. Patent Application Publication May 18, 2017. Sheet 1 of 7 US 2017/O137885 A1 A schematic Overview of certain methods in the disclosure, 10. Obtain sample from a transplant recipient 120. Perform assay to determine gene expression level 130. Apply computer algorithm to the gene expression level 4. Classification Class A Class E Class C based on the results Patent Application Publication May 18, 2017. Sheet 2 of 7 US 2017/O137885 A1 A system for implementing the methods of the disclosure. 2. Transplant 22. 23, recipient Sample Assay 240. \ S 25,internet 29O. Other use -1 Patent Application Publication May 18, 2017. Sheet 3 of 7 US 2017/O137885 A1 WHSC 3 ZNF883 s US 37 C303 SC23A g 44242 g ARS3 S. 2 ZNF,75 ASRS S. ARHAP4 3 33 B 5 SKAP2 - 3 RAGEF5 8 . ERE C 5. r sxs : CR X e & 0.348 PLNS 3.: 10.7%f2 k s Cl4cras s SATA s TMEM22 Corf.32 R 3. A4 2 RLBP is SP3 f. Patent Application Publication May 18, 2017. Sheet 4 of 7 US 2017/O137885 A1 A system for implementing the methods of the disclosure. 435 45 4. Patent Application Publication May 18, 2017. Sheet 5 of 7 US 2017/O137885 A1 Correlation of fold-change between microarray and NGS analyses (68 common genes). Fold-Change, AR 8x vs. SCAR BX: wo -4 • Fold-Change ARBX vs. SCAR 8x: -8 -tier Fochange:ARBX s.33ARBX}} Fold-ChargetAR vs. TX8x} 2. * 2 R-r:- .888.8885 -4 • Fold-Change ARVs, TXBX: - - Linear Fel-Chenge:AR vs. TXBX. Fold-Change:SCAR vs. TXBX} 8 R* : 0.988 0 Fok-Change: Patent Application Publication May 18, 2017. Sheet 6 of 7 US 2017/O137885 A1 t & S & s & & - 3. Patent Application Publication May 18, 2017. Sheet 7 of 7 US 2017/O137885 A1 Correlation of fold-change between microarray and NGS analyses (ali expressed NGS 7.378 genes). Fold-Change{AR vs.TX. 8 R2 = 9.8053 6---------------------------------------------------------------------------------- (s • Fold-Change:ARys. X -4 Fold-Change(AR 8x vs.SCAR Bx R2 = 9.4855 8 8 wk • Fok-Charge AR 9x vs. 80AREx Fold-ChangeSCAR 8x vs.TX 3x) 6 4. 0 Fok-Change:SCARBX vs. TXBx US 2017/O 137885 A1 May 18, 2017 GENE EXPRESSION PROFILES (such as increased perforin, granzyme, c-Bet expression or ASSOCATED WITH SUB-CLINICAL macrophage markers), or by an increased ability of the KIDNEY TRANSPLANT REUECTION allograft to withstand immune injury (accommodation). SubAR or SCAR is often diagnosed only on biopsies taken CROSS-REFERENCE TO RELATED as per protocol at a fixed time after transplantation, rather APPLICATIONS than driven by clinical indication. Its diagnosis cannot rely 0001. This application claims the benefit of priority to on traditional kidney function measurements like serum International Application No. PCT/US2015/032202, filed creatinine and glomerular filtration rates. Predicting graft May 22, 2015; to U.S. application Ser. No. 14/481,167, filed outcomes strictly based on the kidney biopsy is difficult and Sep. 9, 2014; to International Application No. PCT/US2014/ this invasive procedure has significant costs and risks for 054735, filed Sep. 9, 2014; to U.S. Provisional Application patients. Organ biopsy results can also be inaccurate, par No. 62/029,038, filed Jul. 25, 2014; to U.S. Provisional ticularly if the area biopsied is not representative of the Application No. 62/001,889, filed May 22, 2014; to U.S. health of the organ as a whole (e.g., as a result of sampling error). There can be significant differences between indi Provisional Application No. 62/001,902, filed May 22, vidual observers when they read the same biopsies indepen 2014; and to U.S. Provisional Application No. 62/001,909, dently and these discrepancies are particularly an issue for filed May 22, 2014, each of which is incorporated by complex histologies that can be challenging for clinicians. In reference herein in their entirety. addition, the early detection of rejection of a transplant STATEMENT CONCERNING GOVERNMENT organ may require serial monitoring by obtaining multiple SUPPORT biopsies, thereby multiplying the risks to the patients, as well as the associated costs. 0002 This invention was made with government support 0008 Transplant rejection is a marker of ineffective under AIO63603 awarded by the National Institutes of immunosuppression and ultimately if it cannot be resolved, Health. government has certain rights in the invention. a failure of the chosen therapy. The fact that 50% of kidney transplant patients will lose their grafts by ten years post COPYRIGHT NOTIFICATION transplant reveals the difficulty of maintaining adequate and 0003 Pursuant to 37 C.F.R. S1.71(e), Applicants note effective long-term immunosuppression. Currently, there are that a portion of this disclosure contains material which is no other effective and reliable blood-based or any other tests Subject to copyright protection. The copyright owner has no for subAR or SCAR diagnosis. Thus, there is a pressing objection to the facsimile reproduction by anyone of the medical need to identify minimally invasive biomarkers that patent document or patent disclosure, as it appears in the are able to identify SubAR or SCAR at a time that changes Patent and Trademark Office patent file or records, but in therapy may alter outcomes. The present invention otherwise reserves all copyright rights whatsoever. addresses this and other unfulfilled needs in the art. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0004 Kidney transplantation offers a significant 0009. In one aspect, the disclosure provides methods of improvement in life expectancy and quality of life for detecting, prognosing, diagnosing or monitoring Subclinical patients with end stage renal disease. Unfortunately, graft acute rejection (subAR or SCAR). These methods typically losses due to allograft dysfunction or other uncertain etiolo entail obtaining nucleic acids of interest, and then (a) gies have greatly hampered the therapeutic potential of determining or detecting expression levels in a Subject of at kidney transplantation. Among various types of graft losses, least 5 genes (e.g., at least 10 genes, at least 20 genes, at least Subclinical acute 50 genes, at least 100 genes, at least 300 genes, at least 500 0005 rejection (subAR or SCAR) is histologically genes, etc.); and (b) detecting, prognosing, diagnosing or defined as acute rejection characterized by tubule-interstitial monitoring subAR or SCAR in the subject from the expres mononuclear infiltration identified from a biopsy specimen, sion levels. In some methods, the nucleic acids of interest but without concurrent functional deterioration (variably comprise mRNA extracted from a sample from the subject defined as a serum creatinine not exceeding 10%, 20% or or nucleic acids derived from the mRNA extracted from the 25% of baseline values). sample from the subject. The methods are particularly useful 0006. A critically important challenge for the future of for analysis of blood samples. molecular diagnostics in transplantation based on peripheral 0010 Some of the methods are directed to subjects who blood profiling is to predict a state of adequate immunosup have or are at risk of developing SubAR or SCAR or acute pression with immune mediated kidney injury before there rejection (AR), or have well-functioning normal transplant is a change in the serum creatinine. This is the challenge of (TX). In some of the methods, the subject has a serum identifying Subclinical acute rejection, which at this time is creatinine level of less than 3 mg/dL, less than 2.5 mg/dL, only occasionally and accidentally picked up by protocol less than 2.0 mg/dL, or less than 1.5 mg/dL. In some biopsies done at arbitrary time points. methods, the Subject has a normal serum creatinine level. In 0007. The terms subAR and SCAR are used interchange Some of the methods, for each of the at least five genes, step ably herein to refer to subclinical acute rejection. SubAR (or (b) involves comparing the expression level of the gene in SCAR) is distinct from clinical acute rejection, which is the subject to one or more reference expression levels of the characterized by acute functional renal impairment.
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