AU2015258345A1 - Inflammatory bowel disease prognostics - Google Patents

Inflammatory bowel disease prognostics Download PDF

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AU2015258345A1
AU2015258345A1 AU2015258345A AU2015258345A AU2015258345A1 AU 2015258345 A1 AU2015258345 A1 AU 2015258345A1 AU 2015258345 A AU2015258345 A AU 2015258345A AU 2015258345 A AU2015258345 A AU 2015258345A AU 2015258345 A1 AU2015258345 A1 AU 2015258345A1
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antibody
group
marker
individual
markers
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AU2015258345A
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Derren Barken
Leonard Eggleston
Fred Princen
Sharat Singh
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Nestec SA
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Nestec SA
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Priority claimed from AU2010236568A external-priority patent/AU2010236568B2/en
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Abandoned legal-status Critical Current

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Abstract

The methods and systems of the present invention are useful in the diagnosis of inflammatory bowel disease (IBD) and in the prognosis of IBD progression and disease complications. With the present invention, it is possible to predict outcome of disease 5 and patients who will have a particular risk of disease complications and/or progression to surgery.

Description

INFLAMMATORY BOWEL DISEASE PROGNOSTICS CROSS-REFERENCE TO RELATED APPLICATIONS [0000] The present application is a divisional application of Australian Application No. 2010236568, which is incorporated in its entirety herein by reference. 5 [0001] This application claims priority to US Provisional Application No 61/169,230, filed April 14, 2009, US Provisional Application No 61/178,454, filed May 14, 2009, US Provisional Application No 61/220,453, filed June 25, 2009, US Provisional Application No 61/255,066, filed October 26, 2009, US Provisional Application No 61/262,903, filed November 19, 2009, US Provisional Application No 10 61/265,324, filed November 30, 2009, US Provisional Application No 61/265,723, filed December 1, 2009, US Provisional Application No 61/286,356, filed December 14, 2009, US Provisional Application No 61/300,787, filed February 2, 2010, and US Provisional Application No 61/302,066, filed February 5, 2010, all of which are hereby incorporated by reference in their entirety for all purposes. 15 BACKGROUND OF THE INVENTION [0002] Inflammatory bowel disease (IBD), which occurs world wide and afflicts millions of people, is the collective term used to describe three gastrointestinal disorders of unknown etiology Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) IBD, together with irritable bowel syndrome (IBS), will affect one-half of all 20 Americans during their lifetime, at a cost of greater than $26 billion dollars for IBD and greater than $8 billion dollars for IBS. A primary determinant of these high medical costs is the difficulty of diagnosing digestive diseases and how these diseases will progress. The cost of IBD and IBS is compounded by lost productivity, with people suffering from these disorders missing at least 8 more days of work annually than the 25 national average. [0003] Inflammatory bowel disease has many symptoms in common with irritable bowel syndrome, including abdominal pain, chronic diarrhea, weight loss, and cramping, making definitive diagnosis extremely difficult. Of the 5 million people suspected of suffering from IBD in the United States, only 1 million are diagnosed as having IBD. 30 The difficulty in differentially diagnosing IBD and determining its outcome hampers early and effective treatment of these diseases. Thus, there is a need for rapid and sensitive testing methods for prognosticating the severity of IBD. [0004] Although progress has been made in precisely diagnosing clinical subtypes of IBD, current methods for determining its prognosis are non existent. 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N' 5 3831 1ming no N to *Jr & th'a fiVumi',tstee a I ar gAha p a "dn a33Th uan -'tv-io-ake mentem-e"<'ra s (SQBh ins 5omb inao h 'whaphtisng' esi deemdna9ion' of thecotU of the di\"-Se 1$ -?spo"se to,'V<A' nw ex'mpk rWPm To tsigure shows a' serie of draw - gaimi (43)13 a tieC t ce-i a s ratmet. Th grap «F him: -313 he pah<"'s history a" nn'-tdon orasead prov '"-~ide osim-Ia leA- o a ' p3)-Fnt treN)Atmeic ge-ng3iv away fr the s-' 'Agle 7()apsher .f mos cere 1testing EurNo#p3 8, E Ckoftribiki 'tu s-nA BD DiagStk1(U A igorithm,3 {o 3'S41 ''--ckhon af <-27"sample" dhe c0nabatory-$ eiffect. af 1%Fkd ecrs ation v<633s evase in~ a smrtA -- <ihm bZ:~ Q his <SIeA coAr-Iso lAdom Forest. -3N algorrthmser mas~rke-' n. nt.e ss Aa \ASCA IgA, ASC-A IgG, NS C h Op C,-Ad pANCA See, IS. 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0 2032t (1$'00033)"~s'~t-'so s c sict'' st5>3>5 3'.\3-bi>"-6ASOk ' ;c 0 4s. --- -- N " -e s~i pata 3s-t'-) 3-053n5 (3 -53503343 :- 1 1kon vunn an ma t d m AannyaJ' in CA." 4 'a g 5 ~lhs 41tHc~'p 4 &"" , cc to , 1:t1 w o " wP' Ch1u op'iu 'J. W. 1S AJA re ;s 7Mason on -W 1: n Q vi rS o (4'a96 ssn-ua M tH $45 r onu td auest X4 cra iSe eAC 4 AS A O enha sr gasAN Aa 14d 'n1 e o nisadSdid'a9 Vi4lsa 141 Cja l I o 411 af11 j6 hey tugos i s sidi - R au3l5 34dicated 11hm3 tepe centageW rf ptier who had Gl sugeyw wg e grup wi h v i-ghnQS , 04 -wiin1A, S* rap\, ne: " of m$3 iAt Dy 3<3W mNre vai.3 ue"' (ASCA - A * eoie Ann nw BD nmam pi ro stanh mboevh Patoeis ho ha uey" (N=D): y a V nOmO n wne n ANLm W W ' boo 1 &D M s ' Vol "e pans, g n i t~v&..3o On & y. o Any 1o03 1 4 0 0 W& to a -n NY '-<I> 33<'eti<') I tt <'3"'C'(E 1 \tn 4 neomo 001 No ONO PQA nrag 0"n <l'-o o su 'we tAtk ed dpoe Ax o"4 inn w syn O y e eg 0i0< s t ihme 3'30' 03003"'0 r''> ($Wv4Iy th*o ha5 C 3'33) oe'ni high.wQS. we< (4 r"<' ed a e Ifd 0030)o0ry I4<'E ,44 0$ oe-ife diagr 1<9% to. p..A I'( v43) h 2i 4433tNeOr' 2 (hptt up3 14 S-< 0"N 0<a N3I4 (3 03 < t4'tga ' ' * '51'o 3t3E t 3&r33 o'e' 11 Yd rnwad Te de at "A o upm t i an An, 24 e)st 'de idts asl pisin ck wa gnhe te Rxina nM- " mnA" S d4 . a ,?tet.e&at, A 1519 N41 \V iT1c'o '~tvi A 1 t;'41a4 a apend ess Oww"nnQ 1m d c mt almost nawky VAM OVOws ami awyka 1um. of s ova; sde w msae studied (tta VoN;Wm; O qw 1 mot A- .................... .. & I2ZiRA~oh~iteflta- -s -------- - -- O ---- ------- -~Nt 'aeinpt aaaI I ~ ~C te-uvek.s Protin -AA -S rs.n A.rv A......... V A % atc 1 Ceid-ll4 A h;a oeca vte n rs206 I SNP2- --- G9-- (0}42Z} bnt se amplA 1nv2 sIaampies fimsmulupr rinsam'ut'" were Audied Each pfaK~ hiad >' caeatriandaal<ms The prognis proeco compreniised scrological psuacs :ss4 g*tyicrnay ~ais t Al "swsyw" for ntvkmpC, ami i ASC.A Ma'gG, i~ ASCA t'A C 'ilaid NANC A werel pieTfoied t tw ~'o diluio\ of serali I '108 Istd L200 A'subd le"vels we"e determitved ada the resilke presa as KiSA\v'~" utres'a~i;:a vih e native't NsJi4 Id 8t~ isx deied from is poul f pan sen- w'ri-h wel -charatered ises [M4)Th la I't th am"yt n the scmkcrwn sarcXles w 1 dIesul"tni'i\a the at le '425 ' Th'i' e geeoypin trsdys incinein tes; NODC ARI'itl m sd piymorphisms (NPsil er/432:s SKP13 - 402insC I rarC6t585SNP12 - A39t5Jt e nd rs2'06'64\3~ (n'- XVW) 04261 Figure I6 hisrtLesa iexempiky a ibration 'a or t2. tFcsen' IA 1Jhaasesan eemples cairai entve fo h2 with stadcda. Figure 48 shows\ tred of sitadd L u 451ngc acnmna -- alibrat'in curv't 4)in eema aspects, baase- In e numbher s4f evated maIkat eachn ptuent risw. e<angisi.eavieri an 'ageryt s it s:St44 In certam spet a -i e of4a bioa'er lgy gena;e ;md" prinh bhemrsca) ite meaee S'ud i'i anLyed latn emb'sitieW twA"' bomgt~vs-,xs m us and adelCt (s , t test iy,1 a&t nm te ci least fons at least 'sin at 2 lta't cc>: at5 leas> seven, at leat an~t' at lea. ma, ,ma C.ess i a"t 'a vN. 0r 'a es tl ma 1 k sl- ---- d la one tspct ee" bor"C ri3s con"id elvmd it i---s ae med...-n Jr n- 172 wrh Own Am!PWi q= 4 $.. . in n ,A'4 mmm( -T---- ' -v TTT ;& TA -TO sem a Y I a [ S. 4 p ____p a T~k e sh4, b' \P' '' V3dN's R "4)N>~ A~t co1X8 Ifl tw> anda"'t '4 t&4 ' '4 &~k n *&fo. .' . ..... ... ---- -- -- -- ' ---~ -i --- '-- -
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Claims (11)

  1. 6. The method of claim 3, wherein said antimicrobiantibody is selected 2 from the group consisting of an antiouter membrane protein C ntiempC) antibody an 3 antid2 anibod, anti-fiagellin antibod and a combination thereof.
  2. 7. The method of claim 1, wherein saidserolgical marker is selected 2 from the group consisting of ASCA-IgAASC.gG. anti 0mpC antibody antiCBiir 3 antibody, antiI2 antibody, pA-\NCA and a combination thereof. 190 8 The method of claim , wherein the presence or level of said 2 SCrlogical markei detected with a hybridization n ampilion-based assay, 3 inamnoas0ay1o immunohisochemical assay, 1 9, The method of ciam 1. wherein said genetic narker is at least one of 2 the genes set forth in Tables IA-- IE 1 10. The method of claim 1 wherein the genotype of said genetic marker is detected by genotyping for the presence otabsence of a sngle nucleotide polymorphism 3 (SNPin said genetic. marker, 1 11. The method of claim 1.0, wherein said SNPP is at least one of the SNPs 2 set forth in Tables 1B:- l. 12, The method of claim 10, wherein said genetic marker is NOD2 and 2 said SNP is selected from the group consiting of SNP8, SNP12. SNP13. and a combination 3 thereof. S131 The method of claim 1, wherein said marker profie is determined by 2 detecting the presence, level, or genotye of at least two, three, four, five, six, seven, eight, 3 nine, or ten markers. t14 The method of claim , wherein said sample is selected from the group 2 insisting of seru plasna whole blood, and stool.
  3. 15. The method of claim 1, wherein said statistical analysis is a quartile 2 analysis; 1 16, The method of claim 15, wherein said quartile analysis converts the 2 presence, level or genotype of said one or more markers into a quartile score. 1 17. The method of clain 161 wherein said prognostic protie a quartile 2 s( re QSS) for said individual obtained by summing saiu 3 one or more markers S18, he method of claim 17, wherein said prognostic model is established 2 using aretrospective cohort with known outcomes of a clinical subtype of IBD, 191
  4. 19. The method of claim 18, wherein said prognostic model is selected 2 fom the group consisting ot a serological model. a serogenetic mode, and a comoination 3 thereof. S20. The method of claim 19, wherein said serological model is derived by 2 applyn aogisicregression anal ysis to the presence or level of one or more- serogical 3 markers determined in said retrospective cohort
  5. 21. The method of dlaim 19, wherein said sero-genetic model is derived by 2 applying logistic regression analysis to the presence or level of one or more 3 markers and the genotype of one or more genetic markers determined in said retrospective 4 cohort. 1 221 The method of claim 19.wherein said prognosc. model comprises a 2 lookAtup table or graph 23, The method of clann 22 wherein said ookZp table or graph provides 2 a cunulative probability of said individua developing or not developing i CD complications 3 over ine,
  6. 24. The method of caim 23,wherin said CD compication is selected 2 from the group consisting of internal stricturimg sease, internal penetrating disease, and a 3 conshination there-ni.
  7. 25. The method of claim 19, wherein said QSS for said individnais 2 compared to said serokagical models
  8. 26. The method of claim 25.wherein said serological model is depicted in 2 Figure 38a. 1 27. The method of claim 19 wherein said QS for said idividual is 2 compared said serogene-ic model 28, The method of claim 27, wherein saidsero genetic modei is depicted 2 in Figure 38b. 1 29. The method of claim 22. wherein said look-up table or graph provides 2 a cunuative pro ability of said individual needing surgery or not needing surgery over time, 192 S30 The method of claim 29 wherein said surgery is small bowel sutery 1 31. The method of daim 1 further comprising recommending a course of 2 therapy for said indi vidual based upon said comparison of said prOgnOStiCoprofile toami 3 prognostic model' 1 32. A method for predicting the likelihood that an individual diagnosed 2 wih inflammatory bowel disease IBD) will respond to an [BDterapeutic agentaid 3 method comprising 4 (a) analyzing a sample obtained from said individual to determine the 5 presence level or genotype of one or more markers selected from the group consisting of a 6 serolgical marker, a genetic marker, and a combination thereof in said sample to obtain a markerr profile; 8 (b) applying a statistical analysis to said marker profile to obtain a therapeutic 9 profile for said individuals and 10 (c) comparing said therapeutic profile for said individual to a therapeutic 1 model to aid in the prediction of the likelihood that an. individual diagnosed with IUD will 12 respond to an lBD therapeutic agent 1 33 The method of claim 32, wherein said 1BD therapeutic agent is a 2 biologic agent a conventional drugor a coribination thereof. 1 34. The method of clan 33, wherein said biologic agent i a member 2 selected from the group consisting of iflximab, CDP57, PECyltaed CDP8Y, adalimmab 3 etanercept, onerceptA, kinase inhibitors, and a combination thereof. 35 The method of claii 32, wherein said individual is diagnosed with 2 Crohn's Disease (CD),ucerative colitis (UCt or indeterminate colttis (IC) 1 36, The method of claim 32, wherein said serological marker isa member 2 seete6 fron the group consisting of an anti-netrophil antibody, anti-Sccharomycc i cerevisiae antibody, an antimicrobial antibody an acute phase protein, an apolipoprotina, a 4 defensin, a growth factor, a cytokne a cadherin, and a combination thereof. 1 37. The method of clim 36, wherein said anti-neuttophil antibody is a 2 m from the group consisting of an antineutrphil cytoplasmic antibody 193 (ANCA), pearntidear anti-neutrophil cytopismic antibody (pANCA) and a combination 4 thereof,. 381 The method o claim 36 wherein said ant -$c chcumyces nrcreeae 2 antibody is a member selected frthe group consisting otantiaSaccharo yces cereisiae 3 linmtoglobin A.(ASCA-igAr anti -- Saccharomyces eradSae iunagobuiin Gk ASCA 4 IgG% and a cobinaton thereof.
  9. 39. The method of clain 36 wherein said antimicrobial antibody is a 2 member selected fror the group consisting of an ant-outer membrane proein C (anti--OmpC) 3 antibodyan and2 antibody, an antifiagellin antibody, and a combination thereof. I 4k The method of claim 32 wherein said stroogical marker is selected 2 fronlthe group consisting of ASCAgA, ASCA-IgO anti-OmpC anybody anti-fi I 3 antibody, anti-2 antibody, pANCA, and a combination thereof 1 41 The method of clain 32, wherein the presence or level of said 2 serological marier is detected wih a hybridization assay.unpohfcadon-based assay 3 immunoassay, or xmmunohstochemcal assay. 1 42 The method of daim 32., wherein said genetic marker is at least one of 2 the genes set forth in Tables I A-1EI 1 43. The method of cdain 32, herein the genotype of said genetic masrer 2 is detected by genotypirng for the presence or absence of a single nnceotide polymorphsrn 3 (SNP) in said genicrk 1 44, The method of claim 43, wherein said SNP is at least one of the SNPs 2 set forth in Tables l1-IK
  10. 45. The method of claim 43, wherein said genetic marker is NOD2 and 2 said SNP is seleAted from the group consisting of SNP8 SNPI 2, SN? . "and a combination 3 thereof. 146 The method of claim 32, herein said marker profile is determined by 2 detecting the presence, level or genotype of at least two, three fourfive, s seveneight 3 nine or ten markers. i 194. 147 The method of claim 32, whein said sample is selected from the 2 group consisting of serum pasma whole blood and st 48, The method of claim 32 wherein said statistical analysis predicts that 2 said individual has a high likelihood of responding or not responding tosad RD therapeutic agent.
  11. 49. The method of caum 32 wherein said statistiCal analysis predicts that 2 said individual has a low likelihood of responding or not responding to said IBD therapeutic 3 agent 1 50. The method of claim 32, wherein said statistical analyis is a quartile 2 analysis. I5L The method of claim 50, wherensanid quarter analysis converts the 2 presence, level or genotype of said one or more markers into a quartile score. 1 52 The method of claim 5, wherein said herapeic profile is a quartile 2 sum scote QSS) for said individual obtained bysurmig said quatile score for each of said 3 one or more markers S53. The method of claim 52, wherein said QSS for said individual is 2 compared to said therapeutic model. 195
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US61/265,324 2009-11-30
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US61/300,787 2010-02-02
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