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(12) Patent Application Publication (10) Pub. No.: US 2011/0189680 A1 Keown Et Al US 201101.89680A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0189680 A1 KeoWn et al. (43) Pub. Date: Aug. 4, 2011 (54) METHODS OF DIAGNOSING REJECTION OF Related U.S. Application Data A KIDNEY ALLOGRAFT USING GENOMIC (60) Provisional application No. 61/129,022, filed on May OR PROTEOMC EXPRESSION PROFILNG 30, 2008. Publication Classification (75) Inventors: Paul Keown, Delta (CA); Andreas (51) Int. Cl. Scherer, Kontiolahti (FI): Oliver CI2O I/68 (2006.01) Gunther, Vancouver (CA); Robert GOIN 33/53 (2006.01) Balshaw, Vancouver (CA); GOIN 33/68 (2006.01) Raymond Ng, Vancouver (CA); CI2O 1/48 (2006.01) Alice Mui, Burnaby (CA); Robert CI2O I/00 (2006.01) McMaster, Vancouver (CA); Bruce CI2O I/37 (2006.01) McManus, Vancouver (CA); GOIN 33/573 (2006.01) Gabriela Cohen Freue, Vancouver HOIJ 49/26 (2006.01) (CA); Anna Meredith, Vancouver (52) U.S. Cl. ............ 435/6.12: 436/94; 436/86; 436/501; (CA) 435/7.92; 435/15; 435/4; 435/23: 435/7.4: 250/282 (73) Assignee: The University of British (57) ABSTRACT Columbia, Vancouver, BC (CA) A method of determining the acute allograft rejection status of a subject, the method comprising the steps of determining (21) Appl. No.: 12/991,922 the nucleic acid expression profile of one or more than one nucleic acid markers, or one or more than one proteomic markers in a biological sample from the Subject; comparing (22) PCT Filed: May 29, 2009 the expression profile of the one or more than one nucleic acid markers to a control profile; and determining whether the (86). PCT No.: PCTACA2O09/OOOT44 expression level of the one or more than one nucleic acid markers is increased relative to the control profile, wherein S371 (c)(1), the increase of the one or more than one nucleic acid markers (2), (4) Date: Mar. 15, 2011 is indicative of the acute rejection status of the subject. Patent Application Publication Aug. 4, 2011 Sheet 1 of 31 US 2011/0189680 A1 Figure 1A w O -O- BCAR - C - Controls cy) o - c\ O v c t d -- C -200 -100 O 1OO 200 300 400 Linear Discriminant SCOre Figure 1B w cs I, : -o- BCAR - C - Controls ; : - NS : dw | st raiso, H. mains a -222 -218 -214 -210 426 430 434 438 Linear Discriminant Score Linear Discriminant Score Patent Application Publication Aug. 4, 2011 Sheet 2 of 31 US 2011/O189680 A1 Figure 1C 5 fore 5 i 300-200-100 0 100 200 300 400 500 Discriminant war. 1 Patent Application Publication Aug. 4, 2011 Sheet 3 of 31 US 2011/O189680 A1 Figure 2 N 5 www. S 2.5 O 8 0. 0. O O -2.5 {0 -5 --- -3 -1 1 3 Discriminant War. 1 0 Acute Rejection O No Rejection Patent Application Publication Aug. 4, 2011 Sheet 4 of 31 US 2011/O189680 A1 Figure 3 Og foid-change Patent Application Publication Aug. 4, 2011 Sheet 5 of 31 US 2011/O189680 A1 Figure 4 10 -10 -28 -24 -20 - 16 -12 -8 56% 8 12 16 20 24, 28 Patent Application Publication Aug. 4, 2011 Sheet 6 of 31 US 2011/O189680 A1 Figure 5A actin cytoskeletor organization and biogenesis cytoskeleton organization and biogenesis actr; filarret-based process irrirrture systern process positive regulation of irrtune system process ce activation eukocyte activation response to bacterium regulation of protein retabolic process | protein kinase cascade positive regulation of response to stirrus actin filament organization cell motility localization of ce. regulation of irrirune systern process : regulation of cellular protein retabolic process signal transduction regation of response to simulus regulation of epiderral growth factor receptor activity regulation af receptor activity is i Figure 5B Cytoskeeter. Atif farerts Cytoskeleton_Regulation of cytoskeleton. infarrirration jak-SA Pathway it rephagocytosis riarratior Enterferor sigraig 3 8 Ce adhesioi etcote citerrotaxis Cell adhesior Gircoconjugates reproduction feedirig and era horrores sigFairg 8 : Celadhesior Arryloid proteins : : Proliferatior y rr photcyte proferation : exeoprent terror oiesis, Erythropoietir pathway : irtfar ratif -2 signerg : irrurie Phagosore in antiger presentation : Celadhesio regrin prinrirg : rarsatioregatio of iritiation Signal trarseiuctioS2 pathway Sigrial trarsdiction ESri-rticlear pathway Ce adhesior integrif-prediated ceil-rratrix acresion Cardiac developresert FGF Era sigrating ap optosis beath sorrain recepters & aspases if... Patent Application Publication Aug. 4, 2011 Sheet 7 of 31 US 2011/O189680 A1 Figure 6A 3 - | 5: g/ -- I - - I I I : : t Figure 6B 5 O 5 O Linear Discriminant Score Figure 6C : - BCAR K - or - no BCAR W 2 N - / \ s \ } : f : - - - d o Ho-3. ... 3 3- r : -T T I I B. W1 W2. W3 WA W2 Patent Application Publication Aug. 4, 2011 Sheet 8 of 31 US 2011/O189680 A1 Figure 7 KP3: 11 ARVS 21 NR O w - cyd - an O 9. (s > O) O 8 o 86°GO 0 O - t -0.4 -0.2 0.0 0.2 0.4 Log mean fold-change Patent Application Publication Aug. 4, 2011 Sheet 9 of 31 US 2011/O189680 A1 Figure 8 ---- BPAR Controls S3 s Linear Discriminant Wariable Figure 9 c - - - - - - - - - - - - - - - w 8 S. S START 111 224 23 18 100 116 38 135 125 PGC US 2011/O 189680 A1 Aug. 4, 2011 METHODS OF DAGNOSING REUECTION OF ~6-12 months of the subject receiving the allograft. Rejection A KIDNEY ALLOGRAFT USING GENOMIC or acute rejection may be characterized by cellular and OR PROTEOMC EXPRESSION PROFILNG humoral insults on the donor tissue, leading to rapid graft dysfunction and failure of the tissue or organ. Rejection of a tissue or organ allograft beyond 6-12 months is generally 0001. This application claims priority benefit of U.S. Pro considered to be chronic rejection, and may occur several visional application 61/129,022, filed May 30, 2008, the con years after receiving the allograft. Such late or chronic rejec tents of which is herein incorporated by reference. tion may be the result of sub-clinical or not fully resolved acute rejection episodes. Later-onset or chronic rejection may FIELD OF INVENTION be characterized by progressive tissue remodeling triggered 0002 The present invention relates to methods of diagnos by the alloimmune response may lead to gradual neointimal ing rejection of a kidney allograft using genomic expression formation within arteries, contributing to obliterative vascu profiling or proteomic expression profiling. lopathy, parenchymal fibrosis and consequently, failure and loss of the graft. Depending on the nature and severity of the BACKGROUND OF THE INVENTION rejection, there may be overlap in the indicators or clinical variables observed in a Subject undergoing, or Suspected of 0003 Transplantation is considered the primary therapy undergoing, allograft rejection—either chronic or acute. for patients with end-stage vital organ failure. While the avail 0008. The scientific and patent literature is blessed with ability of immunosuppressants such as cyclosporine and tac reports of this marker or that being important for identifica rolimus has improved allograft recipient survival and wellbe tion/diagnosis/prediction/treatment of every medical condi ing, identification of rejection of the allograft as early and as tion that can be named. Even within the field of allograft accurately as possible, and effective monitoring and adjusting rejection, a myriad of markers are recited (frequently singly), immunosuppressive medication doses is still of primary and conflicting results may be presented. This conflict in the importance to the continuing Survival of the allograft recipi literature, added to the complexity of the genome (estimates ent. range upwards of 30,000 transcriptional units), the variety of 0004 Rejection of an allograft results from a recipient's cell types (estimates range upwards of 200), organs and tis immune response to nonself antigens expressed by the donor Sues, and expressed proteins or polypeptides (estimates range tissues, and may occur with hours or days of receiving the upwards of 80,000) in the human body, renders the number of allograft, or months to years later. Renal allograft rejection is possible nucleic acid sequences, genes, proteins, metabolites characterized by features comprising oliguria, rapid deterio or combinations thereof useful for diagnosing acute organ ration of renal function and mild proteinuria. Renal allograft rejection is staggering. Variation between individuals pre rejection can lead to nephropathy and kidney failure. sents additional obstacles, as well as the dynamic range of 0005. At present, invasive biopsies (e.g. endomyocardial, protein concentration in plasma (ranging from 10 to 10 liver core, and renal fine-needle aspiration) are regarded as ug/mL) with many of the proteins of potential interest exist the gold standard for the Surveillance and diagnosis of ing at very low concentrations) and the overwhelming quan allograft rejections, but are invasive procedures which carry tities of the few, most abundant plasma proteins (constituting risks of their own (e.g. Mehra MR, et al. Curr. Opin. Cardiol. ~99% of the total protein mass. 2002 March; 17(2): 131-136.). Biopsy results may also be 0009 PCT Publication WO 2006/125301 discloses Subject to reproducibility and interpretation issues due to nucleic acids that are differentially expressed in transplanted sampling errors and inter-observer variabilities, despite the tissue, and methods and materials for detecting kidney tissue availability of international guidelines such as the Banff rejection. schema for grading kidney and liver allograft rejection (Solez et al 2008 Am J Transplant 8: 753: Table 1) An allograft (0010 U.S. Pat. No. 7,235,258 discloses methods of diag recipient may be exposed to the biopsy procedure multiple nosing or monitoring transplant rejection, including kidney times in the first year following the transplant. Noninvasive transplant rejection in a Subject, by detecting the expression Surveillance techniques are currently used (the increase in level of one or more genes in the Subject.
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