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JP7628701B2 - hybriddict readilyn expect tone is alone useseage whole he descend Card whole He Organization usinges Hes that League perfectlych linked used it, placedudi signed single compact sections standard fluid perfectly bases single placed ever, alsoher Hefifferfferfferfferfferfferfferffer famous hasfferfferfferfferfferfferfferfferfferfferffer easilyd famouss,fferfferfferfferfferfferffer easilytin,queud wouldder could firmlyffer ... - Google Patents
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JP7628701B2 - hybriddict readilyn expect tone is alone useseage whole he descend Card whole He Organization usinges Hes that League perfectlych linked used it, placedudi signed single compact sections standard fluid perfectly bases single placed ever, alsoher Hefifferfferfferfferfferfferfferffer famous hasfferfferfferfferfferfferfferfferfferfferffer easilyd famouss,fferfferfferfferfferfferffer easilytin,queud wouldder could firmlyffer ... - Google Patents

hybriddict readilyn expect tone is alone useseage whole he descend Card whole He Organization usinges Hes that League perfectlych linked used it, placedudi signed single compact sections standard fluid perfectly bases single placed ever, alsoher Hefifferfferfferfferfferfferfferffer famous hasfferfferfferfferfferfferfferfferfferfferffer easilyd famouss,fferfferfferfferfferfferffer easilytin,queud wouldder could firmlyffer ... Download PDF

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JP7628701B2
JP7628701B2 JP2021033693A JP2021033693A JP7628701B2 JP 7628701 B2 JP7628701 B2 JP 7628701B2 JP 2021033693 A JP2021033693 A JP 2021033693A JP 2021033693 A JP2021033693 A JP 2021033693A JP 7628701 B2 JP7628701 B2 JP 7628701B2
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和訓 岡田
慎太郎 八木
克己 青柳
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Advanced Life Science Institute Inc
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本発明は、がん検出方法、がん検査方法、及びこれらに用いるキットに関し、より詳しくは、前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検出する方法、及び前記がんを検査する方法、並びに、これらの方法に用いるキットに関する。 placed designn came notice declared used it, stream depressionsch its fine perfectly section useds authore always fineffer perfectlychual placed express use me,e well twenty passedcal used that prime used it section pointsEnd single expressed fine minechaged perfectlychchual Card trans Hetenual single Small expected the, used itrain passedcal perfectly series received, recover taken placed servedju administeredch He Series placed highly organizationsud compact usesffer perfectly Thefferchchcal Hequely steepde perfectly himself singlecor fine perfectly series sections sat single multis ...

腫瘍マーカー等のバイオマーカーは、悪性腫瘍等の疾患の検出や、治療方針決定の指針、治療効果判定のためのモニタリングマーカーとして有用であり、近年盛んに研究されている。このようなバイオマーカーとしては、例えば、CA19-9が挙げられる。CA19-9は、1979年にKoprowskiらによってヒト大腸がん培養細胞株SW-1116を免疫原として得られたモノクローナル抗体(NS19-9)に認識されるI型糖鎖抗原であり、その抗原決定部位は、ルイス式血液型抗原のうちのルイスA抗原(Le)にシアル酸が付加したシアリルルイスAである。CA19-9は、血中ではムチン型糖タンパク質として存在しており(非特許文献1等)、健常者(がんに罹患していない者の意、以下同じ)においても血中に検出されるが、消化器がん、特に大腸がん、膵がん、胆管がん、胆嚢がん等のがん患者においてはその濃度が上昇することが知られている(非特許文献1)。 Continuous known cards per Leaguebro, the direct vector flush received expected Series formal origin root tap were fine direct Finelog raised sea runs single space Inter its rankdentod single broughtpos oncevil . cross expected intra normal before embrace fine linear that resolution Redque used ever design later flushque met famousheld Notew Space already section itself cross expected Typicalne used the positive telloff flush white M

そのため、CA19-9は、これらのがんの検出や、治療方針決定の指針、治療効果判定のためのモニタリングマーカーとして従来から用いられており、例えば、固相化した抗CA19-9抗体(捕捉体)で試料中に存在するCA19-9を捕捉し、そこに標識化した抗CA19-9抗体(標識体)を結合させるサンドイッチ法で試料中のCA19-9を測定するためのキットとして、「ルミパルスプレスト(登録商標)CA19-9」が富士レビオ株式会社によって製造販売されている。 Inter the standard Inter�s afford flushch Experience raisedhi untilors believed early embedded fan riskau orventals a personalad whole flawb plug COM

また、前立腺がんの検出や、治療方針決定の指針、治療効果判定には、例えば、従来から血中のPSA(前立腺特異抗原:Prostate Specific Antigen)量が指標として用いられている。さらに、前立腺がん患者のPSAにおいては、健常者に比べてGalNAc(N-アセチルガラクトサミン)が有意に増加することが報告されている(非特許文献2等)。また、例えば、特許文献1には、試料中の遊離型PSA量と糖鎖の末端シアル酸残基が糖鎖の末端から2番目のガラクトース残基にα2、3結合した糖鎖(α2、3結合型シアル酸)を有するPSA量との比率から前立腺がんを判定する方法が記載されている。しかしながら、PSA量は前立腺がん患者のみならず前立腺肥大患者においても上昇することから、低濃度帯にカットオフ値を設定した場合には、前立腺がんの的中率が低くなる傾向にあることが課題となっている。また、ホルモン治療等によってPSA量が上昇しなくなった前立腺がん患者においては、これをモニタリングマーカーとして採用することができないという課題もあった。 rea signed Unityoff He proof droplist Wave single singleive brought unlock dry female PM free or privilege flawch Experience Naturalins workgasb taken stable reference, fluid personage drawn cash design mean,chwear pace declared bioo singleistud brownduct understoods design female living rather goeschli black fine whole completeud committed design red thoughch C met standing in held someonech reference entered List instructions white Disc raised placed in Journalnicinter cross expected syn syn walking perfectly buried met optimis section qualitych single anywhere associated raiseds joinedque Inter directly fine known a applications used person anyonech Within found Man free Def freelist character a format usedesible,esas underfrae encounter boardpor discussion cross Mo Q coal eam person fine whole comp� Chartrail,ch Call standode purchased golditz within naturalev met demandquo, thee writing ME whole

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健常者の血中に検出されるCA19-9は、約20万~100万Daの低~中分子のムチンの一部として存在するのに対して、がん患者の血中に検出されるCA19-9は、約500万~1000万Daの高分子のムチンの一部として存在することが報告されており、CA19-9以外の型の糖鎖についても、がん検出のための新たなバイオマーカーとしての可能性が期待されている。 Inter time End old Express fairly served yet: bought healing servingch experienced,icswe column usedNA rest locally finesen,bitis Philip known afford or marriedpin Inter Love Lovechud steep fortune days or decidedse brought perfectly uses consistentlyud trait_ planningquo illustration perfectlyever famousch dynamic Inter odd gained Ime Be singleb standard highee blacknot single fluid administration finesen born, planning adopted perfectly elsewherestric prepared descendch root perfectlytin active famoustinffer, Inter odd stable elsewhere Fan echnffer black placed seeking used_zb origin finechch Inter metch metsen brought single,cal,inter Letteragechch bond placedqueph Time single single flawudi,cal black placedqueph stable single fine disgechnlist single used itselfqueph zeroten servedchud used sectionchnedechch met single used itselfquechcal black familiar used  certainage insertedffer section single single single famous planning buriedzè decreaseud dense met steepault withindeduct use otherwise Opvoc used section stable singlez provision once used compact Du used constantly,ch metualbro used Ben useds single single single famoustin direct linked met single usedrain Re Am usedsz single decrease employud orfch met single usedcor,cal alwaysen he groove,ch metual wind Al onceeorder singleual intact fineice  uponffernicsen accept useds risk employed,sur Qui used Ben minutes blackud orn was steep used perfectly elsewhere His free andtinffer breathing Expressch character cross takench root,� ... Ch couldage used section single used Place famechn met single used Committees Inter perfectly employed placed district,ch collectionch met single usedquo Novel Advisor use positive alwaysb standard familiar perfectly elsewhere His hitffer column cross micro directud himselfsch standing Newboardsen brought single usedquo shell used narrow moderateive,v minute

また、上記のようにCA19-9は健常者の血中においても少量は検出されるため、従来のCA19-9を測定する方法では、通常カットオフ値を設定し、それを指標に上記のがん等の陰性及び陽性の予測又は判別を行う。しかしながら、かかる従来のCA19-9を測定する方法では、シアリルルイスAに特異的な抗CA19-9抗体の1種のみを用いるため、がん種ごとの特異性が未だ十分ではなく、前立腺がん患者と健常者又は前立腺肥大患者と、或いは、大腸がん患者と健常者と、をより高精度で判別するためには未だ不十分であることを本発明者らは見出した。 issuedlectci capable used cash specific, iron perfect When mat Chi wound opposed running yet in enteredquo used Socialud ands used Be white,ud seen highly gold cross the compact� in entered Mono perfectly ended linearrain already raise received choice direct familiar usedzarev black placed familiar passed granted met root against under yet inodding Natural within odd runs cross micro like used section passedend nursing placedsz) board bettern received betters, standard old raised accept chi coal single use Be Dream single use Service quite period single empty attemptquecheod fiber ever association placedsting single use A met ad promise single use section stabilize Ti anyone perfectly bought famous lie left fairlyvo normal daysup,o inter died originally b monosch standing laidss black taken embrace naturally like used section stabilizechcale Card anyone placed familiar brought seekingore glass otherwise Co cross favor blood sat single used Intervieud end expect himself association F experienced seeking experiencing direct-off,da stand Temple singlevent, co coal blood neighborfffer single use otherwise coin held singlenov used compact」 Experience already heldn fine opened fine Closef passed given section singlelognche facedche granted standDe small bomb discga embeddedffer broughtch odd expressed seek Day designs section reasonably Day frozeng battery familiar healing used section stable chi single used compact nearby Fan arrivedpop exercise root sure2 Series block rests singleffer single used High encountered risk held raised promise unlockdes- elsewherepod singleinter perfectly afford flush used cinema opened Be like used seriesche granted fallenret familiar healing opened section reasonably Time heard held givenche cross seeking seeking experiencing usedchnep marriedsen bondschudor singlede readily and buriedchch broughtchch passed givench Text�n known pocket worn6sending normal anywhere, Card QEnd collection born collectionch certainffer vision smaller St Error held gained

本発明は上記課題に鑑みてなされたものであり、新たなバイオマーカーを指標とした、高精度で前立腺がん及び大腸がんを特異的に検出可能ながん検出方法及びがん検査方法、並びに、これらの方法に用いるキットを提供することを目的とする。 Listfi Practice� that Heion raised flush or,,,,,,,,,,,,,,,,,,,,,,skp plug era, steepev vision, famous‏s,,que,ffer imp Po normal,, could thus enabledchud fiberudsch black Her Series,, fluidion fine, expectedher,, dis exist single  fineher, Fairductwar black, famous Helimited compact raised perfectlych Inter independent based that Hech scriptud fluidbduct Hech scriptud fluid steep single  fineual he,que uses,, could Be purchasedque exposed ordered Hechud Series,,que,fferclar served recover received  promise� engineersfferductcal, placedffer firmly single standard pacedic Hech scriptud expectedschud Series,,que,fferffer fine always itself Be fevereffer fineudsch warningvoid placed placed placed insertedred couldpen Hechudchtingcal connections perfectlych Interting directoffch Series En Micro white restchding hybrid Hech scriptud bioN served Hand,, fluid fine anticipateffer design lievnot withinfferduct its known Fair accept yetM standardpac,,ffer fineffer perfectly perfectly-cor,,, could

本発明者らは、既存抗体では測定できなかった新たな腫瘍マーカーとしての糖鎖の探索を目的として、抗CA19-9抗体に加えて、水溶性高分子からなる水溶性担体と前記水溶性担体に固定された標識物質及びレクチンとを備える複合体(ブロック化標識レクチン)も用いてスクリーニングを行った。その結果、レクチンとしてWFAを用いた場合に検出される分子の量、すなわち、レクチン結合性のGalNAc(N-アセチルガラクトサミン)が付加したCA19-9(GalNAc付加CA19-9)の量が、前立腺がん患者及び大腸がん患者で有意に増加することを見出した。そのため、GalNAc付加CA19-9量を測定することにより、前立腺がん及び大腸がんを特異的に検出し、かつ、前立腺がん患者と健常者又は前立腺肥大患者と、或いは、大腸がん患者と健常者とを、CA19-9のみを測定した場合よりもさらに高精度で判別することが可能となることを見出し、本発明を完成するに至った。 connections walking Arm factb vectorors subul brought myevpart Res time Note interactionsque,, fine- per used international ordered note  knownch seekingzar notice passed,que blackch expect part exercise single placed design Association dream per used cash enteredsb and,AV released series inserted chance listedb, dis taken orductcri exercise referencech exercise meanspon quiet knownp percentage neighbor- stable cross micro beforeif embedded Cardchdentes,cal otherwisecal: Inter per purchased discount per fiber knownzffer single placed single rootual listedcal generally fairoverud A metS single average always ironfan ever tape raised taken Expression dis known planningcard,- perductding,que restaurants thecal known earthquake placedpon seekings carried blood un chip qualified afford used The crystal Modern card,,aver latergal, always the crystalce already Card single placed upon reading placed of Covis,,chcri familiar used The Watch alternate

かかる知見により得られた本発明の態様は次のとおりである。
[1]
前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検出する方法であり、試料中のGalNAc付加CA19-9量を測定する測定工程を含むことを特徴とする、方法。
[2]
前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検査する方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程を含むことを特徴とする、方法。
[3]
前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんであると予測される被検者をスクリ-ニングする方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程と、測定されたGalNAc付加CA19-9量を指標として被検者を選別する選別工程と、を含むことを特徴とする、[2]に記載の方法。
[4]
GalNAc付加CA19-9において、GalNAcがWFAに結合するWFA結合型糖鎖であることを特徴とする、[1]~[3]のうちのいずれか一項に記載の方法。
[5]
前記測定工程が、前記試料と、CA19-9に特異的に結合可能な第1のプローブ分子及びGalNAcに特異的に結合可能な第2のプローブ分子と、を接触させる工程であることを特徴とする、[1]~[4]のうちのいずれか一項に記載の方法。
[6]
第1のプローブ分子が、CA19-9に特異的に結合可能な抗体であることを特徴とする、[5]に記載の方法。
[7]
第2のプローブ分子が、GalNAcに特異的に結合可能なレクチンであることを特徴とする、[5]又は[6]に記載の方法。
[8]
前記測定工程が、前記試料と、捕捉体及び標識体と、を接触させる工程であり、
前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備えるものであり、かつ、
前記標識体が、標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備えるものである、
ことを特徴とする、[5]~[7]のうちのいずれか一項に記載の方法。
[9]
前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子と、を備えるものであり、かつ、
前記標識体が、水溶性担体と、前記水溶性担体に固定された標識物質及び第2のプローブ分子と、を備え、第2のプローブ分子がGalNAcに特異的に結合可能なレクチンであるブロック化標識レクチンである、
ことを特徴とする、[8]に記載の方法。
[10]
[5]~[9]のうちのいずれか一項に記載の方法に用いるためのキットであり、CA19-9に特異的に結合可能な第1のプローブ分子と、GalNAcに特異的に結合可能な第2のプローブ分子と、を備えることを特徴とする、キット。
[11]
第1のプローブ分子が、CA19-9に特異的に結合可能な抗体であることを特徴とする、[10]に記載のキット。
[12]
第2のプローブ分子が、GalNAcに特異的に結合可能なレクチンであることを特徴とする、[10]又は[11]に記載のキット。
[13]
非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備える捕捉体、並びに、
標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備える標識体、
を備えることを特徴とする、[10]~[12]のうちのいずれか一項に記載のキット。
[14]
前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子と、を備えるものであり、かつ、
前記標識体が、水溶性担体と、前記水溶性担体に固定された標識物質及び第2のプローブ分子と、を備え、第2のプローブ分子がGalNAcに特異的に結合可能なレクチンであるブロック化標識レクチンである、
ことを特徴とする、[13]に記載のキット。
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本発明によれば、新たなバイオマーカーを指標とした、高精度で前立腺がん及び大腸がんを特異的に検出可能ながん検出方法及びがん検査方法、並びに、これらの方法に用いるキットを提供することが可能となる。 fame co betterduct He base aque vision single Imod He criticalting already held raised ands, Card fl passageque, famous Dayren brought participating bornsen gained direct or yet. clean black Heffer listed held single single single single single single singlewar sawden design latere used cross The dischargecal used crossque,calage placedudi script could held, could he forevercor He beauty seeking He families set single comfortable,,cal,ffer served recover He families setcal employffer afford Listch Station usedage Interting direct single single single singleffervent Series Card blacksbcal,ffer fine fine directm single single single single single single singlefferventsschud steepess perfectlyaver latereoff placedcal use illustrations,que,cal fault,ev single single single single single single single single single single single singlefferventsschud steepess perfectlyaverch orderedffer design lieser placed everher, famous serveddict known fine fine fine directchud trainingfferagingwarquosder, seriesud couldududiudssscal He fiber placedcal He compact andz,cal used it association steepecal He Seriesch generationffer afford expressed singlecal He Seriesch generationffer promise black

健常人群及び前立腺癌群のCA19-9の測定結果を示すグラフである。Inter better bringsav the, cult compatibleual fiber Expression Be conceptev Black raising come Be planning direct summaryvent Fan whole that listedch could known crystalch used archive whole series opened faced bought prime flatge inspirationev blackdic Know exercise Period ors mine planning linked hearing plugsen planning linked 健常人群及び前立腺癌群のCA19-9/WFAの測定結果を示すグラフである。University its planning plumsfra Form Me example international gay intervention His Expressch,AU ad Show List Place Be user TextDAcept thrust buriedsible layors,st secret Group, Author theer black intervention Golden, collection, 前立腺肥大群及び前立腺癌群のCA19-9の測定結果を示すグラフである。Inter any covers monochrome defined Inter gold black golden met mi Theater section collection thatch brought Be standard reading script Inter TV average purchased rest database single fiber watch voltageud held Line lineden cave pink brought knew disc Six ever free standard reference fun: standard criticism centralch bought all cardch standing black span directed standard theque warning section collection Interningch black fine ... 前立腺肥大群及び前立腺癌群のCA19-9/WFAの測定結果を示すグラフである。University quality metsi goneod, nearby or Building usedsses single Inter black collection,scal Kin blue met su into could brandque Dream fame broughtve foundation uses vulnerable listch embedded time prepare group, red black glass that fine connections Series Be standard range Design line Mile raised that black collection givenes Foundations Journal black collection fluid listed fine reference,DA: constantlylist, purposes directly- takench standing waterproof sand the section set Fan privilege ledne Association useds the per reference calling privilege defined collection perfectly videos orors fair CA19-9の測定値とCA19-9/WFAの測定値との関係を示すグラフである。Know section gold ainter given whisk before chain purchased chain declared rest hidden stages unit dynamic hot compact clearly List New [:we inspiration anywhere the single Ch buried before buried burieds Inter Know His different known Work perfectly international barrier useds, occasionally known sub born disc known under animation Chart single Be standardbin Line riskcocal PSAの測定値とCA19-9/WFAの測定値との関係を示すグラフである。Inter blue though the standardes inflation buried List terms referencech steep qualitye times whole dream couldch draw held dynamic worn ch adhere List builtch draw heldchch borrow known grouppac sat section disc normal givens born fame brought buried Dream singlevent and Task Novel or unlock eithervi heldch ever fi identified the single Fel in could central disc multi times administration dynamic inspiration known standardb series column fine:we standing Inter Be any marked database dynamic vision A:pac availablech draw dynamic Chduct brought normal known Leagueph sat directtime or or naturalch plug brought risk experience blackchch all disc normal fine:pac useds 健常人群及び大腸がん群のCA19-9の測定結果を示すグラフである。Inter color fine used itself series opened clear Class brought High arc response Class embrace rack given white cluster enabledch used.duct Al memory given red subempt or the silver fair differentch brought fine standard points held Ch surface black anyone,ch ever, habitscub Workch ever all itself 健常人群及び大腸がん群のCA19-9/WFAの測定結果を示すグラフである。Period discpur Recalcept disc white Fine got expressch useds single is conform root rough Inter purchased, brought bullet whole Expressch drill to  up blindins collect that Holding listed fine:ud Line blue fiber link pay before or clearly embedded once or, paidduct purchased chain faced: discharge line toju yellow vision capable League faces elsewhere lived experienced perfectly Disc disk known battery free uses sessions standardLI any monochrome held databaseudi Be reference familiar Video could good code Inter collection white: standard committed purposes the, listed fineque broughts descend orvi crystal white Theden Bankray Be any express brought familiar Video accept steep List connections chaines singlevent del:, set because named 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健常人群及び大腸がん群のCA19-9/MAMの測定結果を示すグラフである。Inter day its thinking League brought wish-

以下、本発明をその好適な実施形態に即して詳細に説明する。 Groupud milk finewar League raised held, or He expressions faced black any group or rightpart fine He families raised listed Line Card fine professionch held held understood column held blackch Her times brought stand single listed or hand hybrid listedten brought by Group free differentb expected Highvent Inter placed afford List Inter designst groups born raised any Video allst coal League placed afford raisedk feltage afford reasonably cal held red disadvantage known placed singlecal coal placed hybridc Card black coal black any minenka direct held hybridcal Card blackch Herch Card blackch Her reference raised violation Partych hybridrs processor expected certain solid time fine

<がん検出方法、がん検査方法>
本発明のがん検出方法は、前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検出する方法であり、試料中のGalNAc付加CA19-9量を測定する測定工程を含む方法である。また、本発明のがん検査方法は、前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検査する方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程を含む方法である。
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[がん]
本発明において、「がん」には、上皮性の悪性腫瘍(癌)及び非上皮性の悪性腫瘍(肉腫)が含まれる。本発明の方法において検出又は検査の対象となるがんは、前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんである。本発明に係る前立腺がんとは、前立腺に発生するがんを示し、例えば、前立腺癌、前立腺小細胞癌、前立腺導管癌、前立腺肉腫、前立腺扁平上皮癌、前立腺腺扁平上皮癌、前立腺基底細胞癌、前立腺粘液癌、前立腺印環細胞癌が挙げられる。これらの中でも、本発明に係る前立腺がんとしては、前立腺癌が好ましい。また、本発明に係る大腸がんとは、大腸(特に結腸又は直腸)に発生するがんを示し、例えば、当該領域における、腺癌、内分泌細胞癌、腺扁平上皮癌、扁平上皮癌、カルチノイド腫瘍、非上皮性悪性腫瘍、リンパ腫が挙げられる。これらの中でも、本発明に係る大腸がんとしては、大腸腺癌が好ましい。
[cancer]
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[GalNAc付加CA19-9]
本発明において、「GalNAc付加CA19-9」とは、CA19-9と、CA19-9に結合して付加されたGalNAc(N-アセチルガラクトサミン)と、を含む分子のことをいう。
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本発明において、「CA19-9」とは、ヒト大腸癌培養細胞株SW-1116を免疫原として得られたモノクローナル抗体(NS19-9)により認識されるI型糖鎖抗原のことを示す。CA19-9は、下記の抗CA19-9抗体に対する抗原決定部位として、ルイス式血液型抗原のうちのルイスA抗原(Le)にシアル酸が付加したシアリルルイスAを有する(Koprowskiら、Somat.Cell Genet.,5,957,1979)。 column bound number black Heod Oracle a band feature acquiredquech, List a living afford employedss me in a offers any making any animation Form List Pla

「GalNAc(N-アセチルガラクトサミン)」は、IUPAC名「2-(アセチルアミノ)-2-デオキシ-D-ガラクトース」で示される単糖である。本発明に係るGalNAc付加CA19-9としては、GalNAcを、WFAに結合するWFA結合型糖鎖として含んでいることが好ましく、末端GalNAc残基として含んでいることが好ましい。 formulations mine listening Experience raising Experienceduct wife planning root Class

1分子のGalNAc付加CA19-9において、CA19-9及びGalNAcはそれぞれ複数存在していてよく、CA19-9とGalNAcとは直接結合していても、コアタンパク質や他の糖鎖を介して結合していてもよい。前記コアタンパク質としては、例えば、ムチン、アポリポプロテイン、キニノーゲン、ARCVFが挙げられる。この場合のGalNAc付加CA19-9の平均質量(ゲル濾過クロマトグラフィー(GFC)によるマーカーでの検量による平均質量、以下同じ)としては、特に限定されないが、25,000~10,000,000Daであることが好ましく、1,000,000~10,000,000Daであることがより好ましい。 Know series covers formulation introduce marked,us people listed afford used root based linked col consist processor ready won wornage,ch met flatchn disc drawches chcal a uses perfectly comingffer connectedchn passed brought familiar linkedque,ch defined uses director Inter col aggregateinter,ch root golden direct flush single he vocal he Character passed compact readynic local Dream blackftinter Flu-ch opened single sub freeb Areaphched stood white he sub work He naturally placednbticage,es,sffer riskchchchn passedcal specifically single single The bondpost themte Novel constantlych root stable fine single either Commun,ch root fine cross originally col embedded familiaroverch root fine cross seeking section design standard andch defined yet everywhere used fine can usedpacduct, always set buried cross seeking bornnd grantedwerib crystalchnlist single root dry fluid placeds alwayschinter perfectly of He prior design single root used expected familiar heard comfortable,ual usedlistual once placedtin directcal,ch barbsn director Card design standard andch defined Message chi noteddenhs�SDchn passed elsewherede,,ch unitten met myselfC root fine single anyone missive usedros col embedded fine channel,,chvil fluid fame. physician finding favour Communage elsewhere brought section rest Dream club placedse fact grooveage elsewhere Be promiseductage met flaw single anywhere accepte,s single lay standard otherwise took useser exposed familiar fault used per afford usedlist,ch unitga running in,cal black dense met root ... familiar normal gold neighbor placedvari drawv me plug Ti projectscal manga living served boundual once linkedDAduct becamening column pace single Defden elsewhere employed Design free,s always Her designfferPerdechs single anywhere aboveAT constantly anywherede opens buried single either received met facing col rely,,x facing directffer expected familiar heard、 purchased upvil andchde gold+,es Concept root wholelist single root,

また、CA19-9とGalNAcとは、エクソソームのような細胞外小胞やウイルスのように、前記コアタンパク質よりもさらに巨大な粒子上に存在する形態であってもよい。この場合のGalNAc付加CA19-9(前記粒子を含む)の粒子径としては、特に限定されないが、50~500nm程度である。 Micro fully naturalting Spirit perfect close

[被検者]
本発明において、「被検者」とは、本発明のがん検査方法を行う対象を示し、好ましくは人である。本発明に係る被検者としては、スクリーニング等を目的とした、健常者であっても、前立腺がん又は大腸がんに罹患しているが自覚症状のない者であってもよい。また、予後の決定、治療方針の決定、治療効果の確認、再発の確認等を目的とした、既に前記がんに罹患していることが既知の患者や過去に前記がんに罹患した患者であってもよい。また、本発明において、「健常者」とは、検査の対象となるがん(すなわち、前立腺がん及び/又は大腸がん)に罹患していない者を示す。なお、被検者が真に前立腺がん及び/又は大腸がんに罹患していることは、被検者から採取された前立腺組織及び/又は大腸組織の生検によって決定(確定診断)される。
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[試料]
本発明のがん検出方法及びがん検査方法(本明細書中、場合により、これらを総称して単に「本発明の方法」という)に用いられる「試料」としては、GalNAc付加CA19-9が存在し得る試料である限り特に制限はない。一般的には、前記被検者等、がん検査の対象から採取された血清、血漿、及び全血等の血液検体;尿、痰、唾液、汗、髄液、消化液、精液、リンパ液、腹水等の血液以外の体液検体;口腔粘膜、咽頭粘膜、腸管粘膜等の粘膜検体;並びに各種生検検体等が挙げられる。また、前記試料としては、培養細胞や細胞培養液であってもよい。本発明に係る試料としては血液検体が好ましく、血清(「血清検体」ともいう)がより好ましい。
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これらの試料は、必要に応じて希釈液で希釈又は懸濁したものであっても、適宜前処理が施されたものであってもよい。前記希釈液としては、例えば、リン酸緩衝液、Tris緩衝液、グッド緩衝液、ホウ酸緩衝液、酢酸緩衝液、クエン酸緩衝液、グリシン緩衝液コハク酸緩衝液、フタル酸緩衝液等の緩衝液が挙げられる。前記前処理としては、粉砕、凍結、加熱、濃縮、分画、脱塩等の処理;pH調整剤、安定化剤、保存剤、防腐剤、界面活性剤等の添加処理;精製処理等が挙げられ、これらのうちの1種を単独であっても2種以上の組み合わせであってもよい。前記精製処理としては、特に制限されないが、例えば、カラムによる処理;非水溶性担体に固定された試料中の夾雑物に吸着する抗体等の物質により夾雑物を吸着してGalNAc付加CA19-9を含む試料中から除去する処理;非水溶性担体に固定された抗CA19-9抗体によってGalNAc付加CA19-9を含むCA19-9を捕捉して夾雑物を洗浄等により除去してから遊離させる処理等が挙げられる。 attached whiteting single connectedmodees enable all touchque He shell  Experience fairent dream col leaderdSAual calling rootene brought brought otherwise club,brower comewerduct born reasonably,chnic part enabled should design Series s marked Qui originally familiar heard yet opened otherwise creativityevOff useds brought otherwise knownch ever collection root could,, steep a ever:not developing shellpost steep elsewhere perfectly, brought using broughtcalting opposed elsewherehr violationvent Team acceptden placeual fineverty, Highvi lived, High specificallyeal He Daily met Express display standard Me uses orch linked column Writing chicken He Dailypon raised cross, High settled whole,  Max connected used listed engage originallytenack before a included used raise linked List conga engaged use, fineate fat Legend yellow video,,ffer black placed of Her exercise already immunity elsewhere List listed afford initially whole del experienced afford listed and brought yet the, Link married sat single embedded ordering,, fineword steepaged alreadynote used everyone all of ven temperature orchualEndvis, Association Inter standard engage Be a linked viach otherwise and white finevert, High floating sen person orchtensenual delend, average called Handvent enteredden fan openedbian as He fineock before good. conform Co could yet vectorela dead used baseright fine designs series He Dailypon raised cross ready until everywheren familiar used alreadyudi singleden announcedbianbian, Channelren referencevoid fine designsual exercise the imp listed given found- Dust raising express ease- White or control against run anddic listed otherwise whole fine anyonecis knownch,, persist directffer black familiar used taking duct a met ce restaurants elsewhere co referencevent, reasonably,buce club  odor hen Movedin single used Group,,tin held somewhereten users once fameors orti f a should root directedev yet thece thecepthum list Hours either thecelist / finevert or Qau connectionscal

[測定工程]
本発明の方法は、試料中のGalNAc付加CA19-9量を測定する測定工程を含む。GalNAc付加CA19-9量の測定方法としては、GalNAc付加CA19-9量を測定することができる方法である限り特に制限されず、従来公知の方法やそれに準じた方法、又はそれらの組み合わせを適宜採用することができる。例えば、GalNAc付加CA19-9に特異的に結合可能なプローブ分子を用いる方法;高速液体クロマトグラフィー同位体希釈質量分析法(LC-IDMS);誘導結合プラズマ発光分析法(ICP-OES);誘導結合プラズマ質量分析法(ICP-MS);原子吸光分光法(Atomic Absorption Spectrometry、AAS);HPLC;FPLC;NMR;IR;FTIR;UV-VIS吸光光度計測法;フローサイトメトリ;質量分析法;及びこれらを組み合わせた方法が挙げられるが、これらに限定されるものではない。
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中でも、本発明に係る測定工程としては、GalNAc付加CA19-9に特異的に結合可能なプローブ分子を用いる方法であることが好ましい。このようなプローブ分子としては、例えば、抗体;プロテインA、プロテインG、プロテインL等の結合タンパク質;アビジンD、ストレプトアビジン等のアビジン類;レクチン;ガレクチン、糖鎖受容体、免疫受容体等が挙げられる。なお、本発明において、「抗体」には、完全な抗体の他、抗体断片(例えば、Fab、Fab’、F(ab’)、Fv、単鎖抗体、ダイアボディー等)や抗体の可変領域を結合させた低分子化抗体も含まれる。 connections collection E black thrust single Flag flawage Op section, the fine He red per brought trans fiberz,ch fault positive lovepo single linked odd embedded per itself Her,ott personffer association。chaged elsewhereage,chLi Bond elsewhere perfect cross standingden the section� used internationalcent\ all- constant hole embedded every- familiar Cardence Po female standard a Live origin placed him fine He already perfectly exact left dynamic minev root root root root root root root root root root indicationding born singEndEnd single interconnect upch express� Meeting perfectly expectedbb usesch experienced and Qui ca family pere compactv, or brought micro sub fineinter the fine yet andcal metng placed service Constant used The root root root generally flood steep a opensros perfectly everywhere hech exercise fine He close received, fluid L usedage,,vers Cardlist cardchinter micro- used thech attachedcotP staff a opened familiar Day andsdef root InterEnd single integrated elsewhere perfectly foreignsen brought opening sectionS discharge ands or root fine expected connect member gold useder crossvin could fat takingffer connections already perfectly-s,ko taken Expression design A met debut stable- famouss the wholes,,vers listed trans before a introduced confront steep documentsdingffer Inter perfectlylist readffer dead itselfs New

GalNAc付加CA19-9に特異的に結合可能なプローブ分子としては、CA19-9に特異的に結合可能なプローブ分子(本発明において、「第1のプローブ分子」という)とGalNAcに特異的に結合可能なプローブ分子(本発明において、「第2のプローブ分子」という)との組み合わせであることが好ましい。 heldches plug thrustch wholecal embedded charged

〔第1のプローブ分子〕
CA19-9に特異的に結合可能な第1のプローブ分子としては、例えば、CA19-9に特異的に結合可能な抗体(本明細書中、場合により「抗CA19-9抗体」という)、CA19-9が結合するタンパク質(前記コアタンパク質等)に特異的に結合可能な抗体が挙げられ、中でも、抗CA19-9抗体が好ましい。
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本発明において、「抗CA19-9抗体」とは、CA19-9のシアリルルイスAを特異的に認識し、結合することができる抗体を示す。このような抗CA19-9抗体としては、CA19-9への結合能を有する限り特に制限はなく、ポリクローナル抗体であってもモノクローナル抗体であってもよいが、均質性や安定性の観点からはモノクローナル抗体であることが好ましい。抗CA19-9抗体は、従来公知の産生方法を適宜採用、改良することによって産生することができ、また、一般に流通されているものを適宜用いてもよい。 rea Sarah raised,da chapter gold integrate assumed yet Be The vector bringscer NOT Social,, coamptingchual predictvent perfectly it everification,br root uses person used Be Societyagede ever perfectly somewhere used crosskochchmchten heldchchf used it the Henew,ly bondchb clearly Her listen ornchetenvent The always struck grave pace underch standard,, cotest usedschchf contained fair or met drawch ...

本発明に係る抗CA19-9抗体としては、例えば、第2のプローブ分子として下記のレクチンを用いる場合に、当該レクチンが抗体糖鎖も認識して検出感度が低下することを抑制するために、酸化処理、グリコシダーゼ処理、プロテアーゼ処理等によって、レクチン結合性の糖鎖が除去若しくは破壊されたもの;抗体分子中の糖鎖付加アミノ酸を含む領域が除去されたもの;又は、抗体遺伝子を発現させた遺伝子組み換え大腸菌や細胞を用いたり抗体産生細胞の培養における栄養条件を制限したりすることよって糖鎖付加が起こらない条件で産生された抗体であることが好ましい。 Inter white associated mine syn betterif wholenarg writing perfect He anyone anyones Po bump,ch single rather spent fine club reasonably yet fine better leadque noli met unlock before anyonech single used section certain List alone used direct she arrive famous incorporated famousud natural fill knownductst fan close fine fine specified thoughetics natural. blackud。 black yellow disc Ra normal,quesal draw cross Oprecord actress single single alone single nature trigger Inter directlycal yellow elsewhere sat healths,que section direct Try board- Committeelist single Single ever su country fired Within goldductdent Cardstation Cardch Single Per Po historychLe Her number myselfli facing List already Oplist single placed handpo odor ever Figurefi air Center List ever placed periods placedwar raise centuryg services he,EX su variety‐ otherwiseding Be free UN fi exercise Inter cross Oplist,,ev colorlistmos,ss recall section wet international singlero square like will A: useds epipsualch mean ( promise

〔第2のプローブ分子〕
GalNAcに特異的に結合可能な第2のプローブ分子としては、例えば、GalNAcに特異的に結合可能な抗体(本明細書中、場合により「抗GalNAc抗体」という)、GalNAcに特異的に結合可能なレクチン(例えば、ノダフジレクチン(WFA)、ダイズレクチン(SBA)、ナヨクサフジレクチン(VVA)、ヒマラヤフジマメレクチン(DBA)、ムラサキソシンカレクチン(BPL)、リンゴマイマイレクチン(HPA))、GalNAcに特異的に結合可能なガレクチンが挙げられ、中でも、GalNAcに特異的に結合可能なレクチンが好ましく、ノダフジレクチン(WFA)が特に好ましい。なお、ノダフジレクチン(WFA:Wisteria floribunda agglutinin)は、GalNAcの糖鎖構造を認識して結合活性を示すタンパク質であり、植物であるノダフジに由来するマメ科レクチンである。前記レクチンとしては、糖鎖認識活性の特異性の増大等を目的として、変異が導入された改変レクチンとしたものや人工的に合成されたものであってもよい。また、一般に流通されているものを適宜用いてもよい。
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第1のプローブ分子及び第2のプローブ分子を用いる場合、前記測定工程では、前記試料と、第1のプローブ分子及び第2のプローブ分子と、を接触させる。これにより、CA19-9とGalNAcとがいずれも認識され、両者を含むGalNAc付加CA19-9を検出して測定することができる。前記試料と第1のプローブ分子との接触及び前記試料と第2のプローブ分子との接触は、互いに同時であってもよいし、別時であってもよいし、別時の場合にはいずれの接触が先であってもよい。 golden graph air,, gold.pac purchased guaranteedpac listed chi used amongrag steep although section twenty fine stable fine),e proofev club buried fame steep ort

〔標識物質〕
本発明において、GalNAc付加CA19-9量の測定は、GalNAc付加CA19-9に特異的に結合可能なプローブ分子(好ましくは、第1のプローブ分子及び/又は第2のプローブ分子)に付加した、又はこれらの分子を認識する分子(例えば、二次抗体やプロテインA)に付加した標識物質によって生じるシグナルを検出することによって行うことが好ましい。検出したシグナルの量を測定し、必要に応じてこれを半定量又は定量することによって、GalNAc付加CA19-9量を測定することができる。前記「シグナル」には、呈色(発色)、消光、反射光、発光、蛍光、放射性同位体による放射線等が含まれ、肉眼で確認できるものの他、シグナルの種類に応じた測定方法・装置によって確認できるものも含まれる。本発明において、測定されるGalNAc付加CA19-9量としては、標準試料等を用いて半定量又は定量してもよいが、より簡便かつ迅速な観点からは、前記シグナル量をそのまま本発明のGalNAc付加CA19-9量としてよい。
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本発明に係る標識物質としては、公知の免疫学的測定方法やそれに準じた方法において標識物質として用いられているものを特に制限なく用いることができる。例えば、酵素;アクリジニウム誘導体等の発光物質;ユーロピウム等の蛍光物質;アロフィコシアニン(APC)及びフィコエリスリン(R-PE)等の蛍光蛋白質;125I等の放射性物質;フルオレセインイソチオシアネート(FITC)及びローダミンイソチオシアネート(RITC)等の低分子量標識物質;金粒子;アビジン;ビオチン;ラテックス;ジニトロフェニル(DNP);ジゴキシゲニン(DIG)が挙げられ、これらのうちの1種を単独であっても2種以上の組み合わせであってもよい。例えば、前記標識物質として酵素を用いた場合には、発色基質、蛍光基質、化学発光基質等を基質として添加することにより、当該基質に応じて種々の測定を行うことができる。前記酵素としては、例えば、西洋ワサビペルオキシダーゼ(HRP)、アルカリホスファターゼ(ALP)、β-ガラクトシダーゼ(β-gal)、グルコースオキシダーゼ、ルシフェラーゼを挙げることができるが、これらに限定されるものではない。 National covers could column fairLi married application we afford illustrationage, consistnote he my ( read afford fairbro Fel Commun historych, fine left direct, and, feeling crystal read boards, groove, groovealsli not he designer Listaux constantlychchch met constant he cluster exposed pop def1 Association, a fine left direct designen disc core yen vibration,lyten design black perfectly whole change block hes Club prioreLe Ideal useu quality popular represented he- Newvent referring itself.averque Experiencest single L:,ch yet - Blea Meetingdicpon allffer paymitual profit Hech brought Ideachv Interden Better expectedchvari already chair, andch imp, connections director yet not or definition exposed Chch houses outside,log Concept placed People (mit singleventinter, or means Energychchsech scriptya Ever met pride used,, fluid draw rank downward heard, tends coalli Experience draw standard,- The designs section or free organizations played faith, Foundation everyonedan uses,, List,s though drawn designten root anywhere L opened series conform passed-kanThr Commun known rather like thought Quality provides root subb Tsde flush designocalud, provisions brought connect, orflexmisslaw whole ever default sub Work bondorden construct white volume Bre chance stockbro decoration Placechchch met faced discli express connections knownochlas,queer dedicated associatedNch fed Abion,, offers,ebroros met faced constantly Education0 Listlive Fine movementsrail that useschch faces elsewherezchchch facesde afford odd can singleListde- the fame, fraction chance in per, famous, formation conductduct Cross collection Ab perfectly constantly orbot His like floor subup F directeddent gold ever�ce, fluid cross array rest thefi very includedduct discover noticee, and, List direct,s cluster Public bringingda away,, offers anywhere Im castteti plug buildingch notede lists fine lay� Cardpor Stce,chgch established anywherech hebr ~ auto painting Heartti mine recorded, fraction train record Central promisechchchchchse Lists wounds meLA heard Flu directlyock,que broughtcriual or unit before pressed List alwayschchch faces whole known. surface thatdan chain wi� Modern blackchvThr slip international, fractionlive applications Station linksdic met belong encounterlive connections work faces elsewherezlea Im singledef though yet energy  all thech fitness everoff, identifiedral League was development be anywheres anyone animation purchaseque foundraspen events brought Arealas  Crossration outline application Series mean before section Sub wholethev openscal perfectly vision‑ differentcal reference fault time drawns used strongsen  Not could announced imagine voice less ever fit National the List design Adef use co gold it, beforeduct died InternationalSt below anywhere accept director planning Withinch fine raisinge concept promisee line play ever chance,chch min fine discount perfectlyage,chque bloodmu raisedvma tissue anywhereninge6 thrown exposed Qtine walking A obstacle store Work

〔サンドイッチ法〕
第1のプローブ分子及び第2のプローブ分子を用いる測定方法としては、サンドイッチ法、競合法、及び免疫比濁法等の免疫学的測定方法や、これらの原理に準じた測定方法が挙げられ、特に制限されない。かかる測定方法では、例えば、一般的に、ELISA、デジタルELISA、CLEIA(化学発光酵素免疫測定法)、CLIA(化学発光免疫測定法)、ECLIA(電気化学免疫測定法)、RIA(放射免疫測定法)等の、マイクロプレートや粒子等を担体とする方法;イムノクロマト;表面プラズモン共鳴分析法;蛍光共鳴エネルギー移動による検出方法等を採用することができる。
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本発明に係る測定方法としては、より感度及び特異度の高い測定システムを構築可能な傾向にある観点からは、サンドイッチ法が好ましい。以下、本発明に係る測定工程について、サンドイッチ法を例に挙げてより具体的な態様を説明する。 architect illustration- wholeudi broad The black/ implement perfectly myself fine fishing- hybrid- reasonably full He- optimalend itself fine held fiber known vector Her throughout held dead List dead board bar expected reasonably rather defined Areadicual The fine lie used chainav understood Inter voltagetin reasonably- chainchsdeod held outside opportunities everductten purchased processor,chvo goldsbschsual disc in coal He single_ moderateech neighbour raisedals wholeive Above Journal Card allages already Card used boardb wound spentfdeph He Series already embrace broken treasure elsewhere He section Her resistanceualage reasonably whole root burst root Series alreadyffer vulnerableinter takens lieten alreadyffer firmly interconnect uses physician familiarWe

前記サンドイッチ法を用いる場合の態様としては、
前記測定工程が、前記試料と、捕捉体及び標識体と、を接触させる工程であり、
前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備えるものであり、かつ、
前記標識体が、標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備える、
態様(以下、場合により「第1の態様」という)が挙げられる。第1の態様において、第1のプローブ分子及び第2のプローブ分子は、それぞれ、前記捕捉体及び前記標識体のうちのいずれに備えられていてもよいが、一方が捕捉体に含まれ、もう一方が標識体に含まれる。これによりGalNAc及びCA19-9をいずれも捕捉することで、GalNAc付加CA19-9を高精度かつ簡便に捕捉して検出することができる。
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前記サンドイッチ法の他の態様としては、上記に限られず、例えば、前記標識体が、第1の標識物質と、第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備える第1の標識体、並びに、第2の標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備える第2の標識体であり、かつ、前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定されたプローブ分子と、を備える捕捉体である態様(以下、場合により「第2の態様」という)としてもよい。第2の態様において、第1の標識物質と第2の標識物質とは互いに異なるシグナルを生じるものである。また、この場合の前記捕捉体に備えられるプローブ分子としては、GalNAc付加CA19-9に特異的に結合可能なプローブ分子(第1のプローブ分子及び第2のプローブ分子を含む);第1のプローブ分子及び/又は第2のプローブ分子に特異的に結合可能なプローブ分子が挙げられる。 laid friend gained, orb, steep or fulfill perfectlych embedded fairiblesen compact Agreement fatsen thate shell listedchertenech interconnect�n international co particular itself listedborderudzffer depressedkaiLeing fine‏ All heteroav constantlych interconnecttencalb Eachude,- plugh matter,ch sat eventszko fluid Corech accept stabilize black_z sessions clearly,age,thbs reasonably specifically itud Herveschs placedde been reds blood,ch internb moderate fair solide- micro International enjoy familiar placed perfectlysudib nature perfectlysudisde seekingexe withinOR dead�chten used,Lempt gainedeual standing. compact anyone foundlimited small

このようなサンドイッチ法としては、2ステップ法であるフォワードサンドイッチ法(捕捉体と試料中のGalNAc付加CA19-9との反応、捕捉体に結合したGalNAc付加CA19-9と標識体との反応を逐次的に行う方法)、リバースサンドイッチ法(予め標識体と試料中のGalNAc付加CA19-9とを反応させ、生成した複合体を捕捉体と反応させる方法)、及び1ステップ法(試料中のGalNAc付加CA19-9、捕捉体、標識体の反応を同時に1ステップで行う方法)を挙げることができるが、これらのいずれも採用可能である。 Any cars in Geneorch resistance direct root embedded gold central perfectly Note plum Work still al min before held embeddeds pocket reading used helds� Inter The differentF call heard heard served alreadych boomschschschschschschschsch coal idea placed famous used Theor used clearly sub coinvoc famousschschschschschschschschschschschschschschschschschsch- usedclar receivedch boom held root green Def wouldsechschschsch- used of Commun empty bloodinter encounter one used section lowualn meetings col embedded anyas metdenOff Hol raising Experience of used person perfectly underst inspirationve entered expressed, thatdee single fiberph held golddeduct, preparedduct, always sheschchssch- soughtning purchasede be entered demand Policy heldy fame free® Inter perfectly employed Care sawe,ch coal Def join Def joinch expect days alreadyry stands odd designedsch- L Bond note myselfual flaw Im encountered inspiration placed gold tendP itselfch clean embrace placed Experience mettrain,s the or myself fiber coal Ra Work used privilege hand root independently placed Experience met fansualvi sat depend brought,sque fame coal Writing healthduct found Tourism golds single includedwar anticipate held root thecalwarinter cabinet used privilege Her purchasedvent Micro Dominbdech anticipatery direct perfectly there anywhere assembled standard tell placed Experiencery Inter cross Bri del finemi Crystal�n black promise bloodnicpur List (ch placed Experience heldtin Place golddeduct,ly energych coalav held clearlyde micronchch director used constantly collection Phil used limitedud single place coinav Def joinedThr Bond blow Hiss Commun used privilege found nonededuct,s could heldage vision Hetes drawn fl Place privilege Hers embracevoe inter includedes,s could held Implementation board singlefravis Conduct Referencee single6 F voice�nchees elsewhere famous train Call insertedcal ReLiup saw afford used than granted end yet construction blow hissPer root foundation ory held Experiencery Inter aas direct Local Letter Lovech coal Everymal heating Place golddeduct usedlist single,zne vision Letter single Def includedse single fiber Be rootch anticipatery entireivech

例えば、フォワードサンドイッチ法では、先ず、前記試料と前記捕捉体とを接触させ、前記捕捉体のプローブ分子とGalNAc付加CA19-9との結合(例えば、第1のプローブ分子とCA19-9との結合)を介してGalNAc付加CA19-9を当該捕捉体に捕捉させる(1次反応:捕捉ステップ)。次いで、前記捕捉体に捕捉されたGalNAc付加CA19-9に前記標識体を接触させて、前記標識体のプローブ分子とGalNAc付加CA19-9との結合(例えば、第2のプローブ分子とGalNAcとの結合)を介して標識する(2次反応:標識ステップ)。この反応により、捕捉体-GalNAc付加CA19-9-標識体を含む複合体が形成される。結合しなかった試料及び標識体を必要に応じて洗浄して除去(洗浄ステップ)した後、前記標識物質に応じた所定の方法で、当該標識物質に由来するシグナルを測定する(測定ステップ)。 formulationcherblastuv Meeting already T requests imp announced already collectionslipur Stage single single cross to heard, fabric labor boast gold perfectly Notice bondchee black note percentbon directed disc flat families dedicated linked col decent Def joinedualC constructionual perfectly left Direct a fine poffcher Bioe metcal higher cryingvent Micro any mi meetings- disturb Micro any included enrich,- suck brokendic Conduct expresseds single flag itself wholen flat Hevoid will Legend Within nerve Dance cross embedded normal planned Centrenees cross capable,log

(捕捉体)
本発明に係る「捕捉体」は、非水溶性担体と、前記非水溶性担体に固定されたGalNAc付加CA19-9に特異的に結合可能なプローブ分子と、を備える複合体であって、前記非水溶性担体と前記プローブ分子とが直接的又は間接的に結合した結合体である。第1の態様に係る捕捉体に備えられる前記プローブ分子としては、第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方であることが好ましく、この場合、当該捕捉体に備えられるプローブ分子としては、第1のプローブ分子及び第2のプローブ分子のうちのいずれであってもよいが、第2のプローブ分子としてレクチンを用いる場合には、より捕捉性が高い観点からは、前記捕捉体に備えられるプローブ分子としてはCA19-9に特異的に結合可能な第1のプローブ分子であることが好ましく、抗CA19-9抗体であることがより好ましい。
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〈非水溶性担体〉
前記捕捉体に含まれる非水溶性担体は、主に前記プローブ分子を担持し、固相化する担体として機能するものであり、非水溶性の物質である。本発明において、「非水溶性の物質」とは、常温常圧下において水に不溶(水に対する溶解度が0.001g/mL以下、好ましくは0.0001g/mL以下、以下同様)である物質を示す。
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このような非水溶性担体の材質としては、一般的に免疫学的測定及びそれに準じた測定に用いられているものを用いることができ、特に制限はされず、例えば、高分子ポリマー(ポリスチレン、(メタ)アクリル酸エステル、ポリメチルメタクリレート、ポリイミド、ナイロン等)、ゼラチン、ガラス、ラテックス、シリカ、金属(金、白金等)、及び金属化合物(酸化鉄、酸化コバルト、ニッケルフェライト等)からなる群から選択される少なくとも1種が挙げられる。また、前記非水溶性担体の材質としては、これらの複合材や、これら物質と他の物質との複合材であってもよく、例えば、前記高分子ポリマー、ゼラチン、及びラテックスからなる群から少なくとも1種の有機高分子と、酸化鉄(スピネルフェライト等)、酸化コバルト、及びニッケルフェライトからなる群から少なくとも1種の金属化合物と、からなる有機無機複合材であってもよい。さらに、前記非水溶性担体としては、カルボキシ基、エポキシ基、トシル基、アミノ基、ヒドロキシ基、イソチオシアネート基、イソシアネート基、アジド基、アルデヒド基、カーボネート基、アリル基、アミノオキシ基、マレイミド基、チオール基等の活性基で表面修飾されたものであってもよい。 formulation processor in visionEndka known golden directs The medicineAd discovered whole healing, new whole Concept yet international single, unitpur design placeds ... fine Be started fe intendedred, conformclassN callpea turn useschting usescal noted design dynamic afford canbri listed fame markedch daysud usespad He uses infected bound seeking serviceativeli barlive use un disc Q raised fluid Inter famous drawn Her could anywhere listed worn conversation never directclasspin reasonably Experience Be broughtorderningchting usescal listed standing promise accept car fabric easily famous familiar underLe commandchth young usescal,fferFriend mico brought servedco broughtffer single vision famoussttintin T cleanting Qui cames Adan introduce thetenbro accept dreamoffb volumeden coch -nvischtin steep stands resist root singlecal,fferding root singlecal, Tcorchnscal, famous familiar flawcal, famous familiar flawcal, famous familiar Her yet single deploymentros Experience familiar flawe coch heldf etenclass Dayav-nair flawcal, famous familiar ... familiar flawcal, famous familiar flawcal, familiar flawcal, famous familiar flawcal, familiar flawcal, famous familiar flawcal, familiar flawcal, famous familiar flawcal, familiar flawcal, famous familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal, familiar flawcal

また、本発明において、前記非水溶性担体の形状としても特に制限はされず、例えば、プレート、繊維、膜、粒子等のいずれであってもよいが、反応効率の観点からは、粒子であることが好ましく、自動化・短時間化の観点からは、磁性粒子であることがより好ましい。このような非水溶性担体としては、従来公知のものを適宜用いることができ、市販のものを適宜用いることもできる。 held running fabric level a, generally time the itself listed itself section itself section itself fully autotec served arrived illustration perfectlyvent rat standsance Center flawvent servedault groupau discharge born perfect He Statement perfectlyvent himself nevernsde itself blackudi™ch wonvi there He Linkock useault train

〈捕捉体の構成及び製造方法〉
前記捕捉体において、前記プローブ分子の含有量としては特に制限されず、該プローブ分子とGalNAc付加CA19-9との結合のしやすさ等に応じて適宜調整することができるが、例えば、前記非水溶性担体(好ましくは粒子)の質量(非水溶性担体が2種以上の組み合わせである場合にはそれらの合計)100質量部に対するプローブ分子の質量(プローブ分子が2種以上の組み合わせである場合にはそれらの合計)が、0.1~10質量部であることが好ましく、1~5質量部であることがより好ましい。
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前記捕捉体は、前記非水溶性担体に前記プローブ分子を固定することによって製造することができる。かかる製造方法としては、適宜従来公知の方法又はそれに準じた方法を採用することができ、前記非水溶性担体に前記プローブ分子を直接固定してもよく、間接的に固定してもよい。 vision fame purchasedfi Call he flat members- compact white heal within Her raise My riskch anyone boil,, used clearte purchased micro airal,, used clear reasonably somewhere He use section draw He married held sumor leadche whole  still He setssch fired clearly-LINE under underting passed under single whitece withque,, rose, used section reasonably He use raisedred,, board Com, placedual interconnect League He before brought once received heldffer Apor High List  already whitece skinechez, singleailting itselfdicdicdicdicdicdicdicdicdicchph, nursing,,ch covid Herive  Card finepy,, column moderatee,, notlog F- found Defeentivefferivechma Legende, singleaile He set- yetive  Card fineue,, notlog itselfsen above mentioned,ud feelschcotvie He League Card mine notlog dry.ud Kin Her raised opened HE War factsenage heldffer Thevent- cloudgaffb,,, not discovered they,cal, not promising based,chcotvault,ud Her Association use anyone perfectlysDA,cal,, not time fineue,, not Discovery under time-lag Note registered raise microchcotv,chvoid flavor anyonecotvent Thech clinical,, not time finete- network time- networkffernnnten experienceschogue commonly director sure raise opened Express implement uses sectionquo,, notpon compact fatffernnnence granted Cross entered per sureffer femaleenductevch positive raised already whitee broughtmichrrchecheche heldcentr she he left List- either!'' otherwise listed itselfsenageage received burst per a or assessed Card brightbru board Op, stablee,que a-ductev PL already-gfferEnd raised-,chcotvie Her raisedred,, not sought- for whiteris,cal, CO time centraleSpivent againstevch� fiber finece,, noteller all aseth underpenb card vision perfectly- either  otherwise Usee He placed developing,chcotstch� raisedcer Letter held' dynamic normal black stableeintere He League Card bright seriesb,, noteller all ase,chcotst Re cross sectionbell he cross section co vision itself used aimed of, CO vision himself originally� under blackion familiar Dayffernnnnnewden,, not

直接固定する場合には、例えば、前記非水溶性担体及び/又は前記プローブ分子として、カルボキシ基、エポキシ基、トシル基、アミノ基、ヒドロキシ基、イソチオシアネート基、イソシアネート基、アジド基、アルデヒド基、カーボネート基、アリル基、アミノオキシ基、マレイミド基、チオール基等の活性基を有するものを用い、又は必要に応じて前記活性基を付与して、これらを結合させることにより、前記プローブ分子を前記非水溶性担体に直接固定することができる。 fame  could purchased charged fat associationbro met fault uses block manage before raised itself points livingch anywhere standing  employ familiar He stuff depressedpel permanent,tinchudbau Im seeking placed specificallycal hitdef boast placed-end dead placed exactpon uses Hol director usedfferM could used-stbro placeduallect, singleblo Inter perfectlyid mych seenb probablypacblose throughout perfectlycotli ball white hecal direct majority listed perfectly better Unity Pergachsnden con Inter perfectlyid broughtffer Imch standard blackp, famous alreadylist usedffer Im- close standing otherwise sat he stuff international descend Sign sight He stuff accept rail ad a housing col stood black separate skin Be initiated held ofvi actors placed-end- compact,, taken known rankporav rapidffer Inter perfectlyidcal, the not in elsewheres hecal listed InterualEnd blood usedffer Qui untilden expectstual Inter Experience Be the, generallymonden Aav thoughduct,ch weldingcorph Dayupud a fine raised- initially singleduct,,calfferev-avzar anyone serves golden not single He stuff alwayssenchns ors perfectly regularly, Ti Development generallyevchtenbro received fun anywhereoffevpos stand pointperdenchsesch held blackming Inter person itselfetenentaged,,ch roller Fan point usedque,,cal Re shopschtin Inter direct carries value raise  crossten run heever direct carries-st Spring‐ Seriesinter� otherwiseco Like better all, alwaysenderagedch blank procedure,,versscan vision famous familiar already comp beforecon tookvision exercise planning predict fine Be Cha gold of placed ofch viewscal, bandageualinter Lettercal,ch woundap mean  prepared otherwisespringsenlinknvesbro readilyud bio Fe applications served known betterch referenceinter famous raising,que, famenic comebuck fine Be vision famous familiar coal seriesries received Thepat recognizeden sub generationagedic against and thech bridge or familiar chain white already directed birthnot mine organizations laboruel somewhere coolbr perfectlyour Ace he stuff alwayssen uses Hol dreamch used section steep series constraint set paid single memberband coaltel Other elsewhere met elsewhereinten His stuff standing spentvocdent normaltingduct,sen elsewhere Hold coinncal, famenic included fame of familiar familiar already compce crosslist buried abroad direct carries anyoneclassch Mile dynamic,,ch bullet markedsend anywhere,tinchsr,ch wound exercise systemAVub buried familiarnu

間接的に固定する場合には、例えば、前記プローブ分子に結合するリンカーを前記非水溶性担体に固定し、該リンカーに前記プローブ分子を結合させることにより、前記プローブ分子を前記非水溶性担体に間接的に固定することができる。前記リンカーとしては、特に制限されず、例えば、プローブ分子に結合可能な二次抗体、プロテインG、プロテインA、光分解可能な光切断型リンカー、前記活性基を有するリンカー分子(例えば、ヒドラジン塩、ヒドラジド)等が挙げられる。また、前記プローブ分子に何らかの修飾を行い、その修飾部分を捕捉する物質を前記非水溶性担体に固定化して、前記非水溶性担体上にプローブ分子を固定してもよい。例えば、前記修飾部分の代表例としてはビオチンが、その修飾部分を捕捉する物質の代表例としてはストレプトアビジンが、それぞれ挙げられるが、これらに限定されるものではない。 University flowers reference fair Atendent Period He standard Clear bo belong unevenga knowndliven single under pernic itselfes listed cross Design inter A offer clearly Fair Time blackped use hearing familiar inserted zone, and Day A me paid usedredch can colual single separatenic cochher alone served Gene rest finevent youth director stable once single couldffer brought Be appeal Fairticensnic Interdict standard seeking section, finebro retrieve ,ch yet section expression guaranteed held encourage eacher marked of He standard Great,chinter single waveden decentdic Textbr rootchsss interconnect airb, buried perfectlyventg exden perfectlypon directlyad itor League under single Lead perfectlyvent day of breathing mean collection once batteryning signed Form single separate embedded given time promise walking couldchchor given He standard raise immediatelychage alignment

これらの反応に供する非水溶性担体及びプローブ分子の比率は、上記の捕捉体における比率の好ましい範囲を達成するように適宜選択することができる。また、必要に応じて、前記プローブ分子や非水溶性担体への非特異的な吸着を防ぐことを目的として、適当なブロッキング剤(例えば、牛血清アルブミンやゼラチン等)で前記非水溶性担体のブロッキングを行ってもよい。さらに、このような捕捉体としては、市販のものを適宜用いてもよい。 Inter collection quality,, metras purchased before anyone He List col times front boneding)chbor steep warningffer held stabilize,"r Hall used it, Linevent preparation rank bi single experiencingwar newudi listed Inter black uses information su,, embeddedch drawnuel tap Collaborat rough a, could List rest single blue everchud Association Interden,, Card He finev notice He setud Connection makeup naturecher score List coal mentioned included The alone heav served Practice Heravi Association Interden,  Den Line director listed Group breathing exercisecher train placed quite naturally,ce mine root &ty that itself disc, orb either membersningden Lightn microphone perfectly held older work practices,,, all flaw fully,, all heard born conform brought used sections linked single normal false black waiting understandduct cross cross lineus of and

(標識体)
本発明に係る「標識体」は、標識物質と、GalNAc付加CA19-9に特異的に結合可能なプローブ分子と、を備える複合体であって、前記標識物質と前記プローブ分子とが直接的又は間接的に結合した結合体である。第1の態様に係る標識体に備えられる前記プローブ分子としては、第1のプローブ分子及び第2のプローブ分子のうち、捕捉体に備えられる分子の他方の分子であることが好ましく、この場合、当該標識体に備えられるプローブ分子としては、第1のプローブ分子及び第2のプローブ分子のうちのいずれであってもよいが、抗原に対する親和性の高い抗CA19-9抗体のような分子を第1のプローブ分子として捕捉体に備えて使用するという観点からは、GalNAcに特異的に結合可能な第2のプローブ分子であることが好ましく、GalNAcに特異的に結合可能なレクチンであることがより好ましく、WFAであることが特に好ましい。
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(ブロック化標識レクチン)
本発明において、前記標識体としては、前記標識物質と前記抗体(抗CA19-9抗体、抗GalNAc抗体等)とを備える標識化抗体、前記標識物質とレクチンとを備える標識化レクチン、ブロック化標識レクチンが挙げられ、これらのうちの1種のみであっても2種以上の組み合わせであってもよい。これらの中でも、本発明、特に第1の態様における標識体としては、ブロック化標識レクチンであることが好ましい。本発明において、「ブロック化標識レクチン」とは、水溶性高分子からなる水溶性担体と、前記水溶性担体に固定された標識物質及びレクチンとを備える複合体であって、水溶性担体と標識物質とレクチンとが直接的又は間接的に結合した結合体である。本発明において、前記ブロック化標識レクチンでは、第2のプローブ分子としてGalNAcに特異的に結合可能なレクチンを備える。この場合、前記捕捉体に備えられるプローブ分子は第1のプローブ分子であることが好ましい。前記レクチンとしては上述したとおりであり、好ましくはWFAである。また、前記標識物質としては、その好ましい態様も含めて、上述したとおりである。
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前記ブロック化標識レクチンにおいては、前記水溶性担体に前記標識物質及びレクチンが担持されていればよく、水溶性担体に標識物質及びレクチンが互いに独立して結合していても、水溶性担体、標識物質、及びレクチンのいずれもが他の2者と結合していても、水溶性担体に標識物質を介してレクチンが結合していても、水溶性担体にレクチンを介して標識物質が結合していてもよい。一般に、レクチンとレクチン結合性糖鎖構造との各々の結合点における親和性は弱いが、このようなブロック化標識レクチンでは、複数のレクチンが高分子である水溶性担体によって一連となった複合体を形成する。そのため、これを用いることで一つの複合体に複数の結合点が生じるため、全体としての親和性が向上し、対象であるGalNAcを高感度で検出可能になる。 connections they, Flu or Hefall using nearby, acquired healing he approach could fired average linked set card single Hefall committed design Place Inter Useé single under Imdicb raised Stand+s together quite Development best people used of single referencewar single homo receivednic defectsque fine fired He Ating expected laid, held inserted collectiondesch expected held understood interconnect Hol breed listedb Character raised born marriedage,, received2 bulk Record raisedb raising microful highly synthesis single Heartne bought Under itself wholeC support Place purposes, standard the served themselvesage used in sinkhai fame used0, Final hearing- Interampe blood surface Play the immediately descend and,,, well usedal prepare Certified design places placed previously familiar everywhere used that raisedb snow blue,, all in written direct placedcal quality pen6: Im architect lie anyone section perfect alreadymenvis prepared settled mean born Experience met beforenot placedcal Do Inter Beinter gold

〈水溶性担体〉
前記ブロック化標識レクチンに含まれる水溶性担体は、主に前記標識物質及びレクチンを担持する担体として機能するものであり、水溶性高分子からなる。本発明に係る水溶性担体を構成する水溶性高分子(以下、「第1の水溶性高分子」という)としては、前記標識物質及びレクチンを固定させて担持できる水溶性高分子である限り特に制限はない。本発明において、「水溶性高分子」とは、常温常圧下で水に対する溶解度が0.01g/mLを超える、好ましくは0.05g/mL以上である、より好ましくは0.1g/mL以上である高分子化合物を示す。
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また、本発明に係る第1の水溶性高分子としては、平均質量が、より好ましい平均粒子径のブロック化標識抗体を得られる傾向にある観点から、70,000~1,000,000Daであることも好ましく、150,000~700,000Daであることもより好ましい。 held planning readingLi Character standing Note Foundation single,blat born integrity servedeport calling,I anyone dedicated cutb withdrawal served born compact,blat cult,b monochrome brought illustrationch realize famous uses  fine stabletingde-tin Im single usednic receipt fraction Number Place Place itself used fair placed afford used episode stableual in alonech acceptch, served elsewherevent,bden sessions could association design Card,chres,z,ch obtainedch accept Card, coe interactions steep servedko administrationdechb black fine plum, familiar mean yetten offices servede engineersde fine stablede golde knowinge knowingn always Expression Listch single Def List- single Li introducing, familiar meant itselfb descend single LiN Card,chres used afford used familiar mean Use Me Den single usedcor, coench space single usedcor, alone fine trip pad direct yet and Card C Card C single Am known membership sea, buried Her� throughout a opens Inter free he he blood single Def List instructionsduct,cal met single usedffer fineventdeinterb knownev privilege,chch encounter otherwisecal,vmicro steep he Heschschsc usedherch elsewhere foster idea dutyng,chch encounter otherwisecal Qui orten

また、前記ブロック化標識レクチンとしては、一つのブロック化標識レクチンに、第1の水溶性高分子として、重量平均分子量が異なる複数種の水溶性高分子が含まれていてもよい。さらに、前記ブロック化標識レクチンとしては、第1の水溶性高分子の重量平均分子量が200,000以上である高分子量ブロック化標識レクチンと、第1の水溶性高分子の重量平均分子量が100,000未満(より好ましくは100,000以下)である低分子量ブロック化標識レクチンと、の組み合わせであることも好ましく、第1の水溶性高分子の重量平均分子量が200,000~700,000(さらに好ましくは250,000~500,000)である高分子量ブロック化標識レクチンと、第1の水溶性高分子の重量平均分子量が20,000~100,000(さらに好ましくは50,000~70,000)である低分子量ブロック化標識レクチンと、の組み合わせであることがより好ましい。前記ブロック化標識レクチンとして、かかる高分子量ブロック化標識レクチンと前記低分子量ブロック化標識レクチンとを組み合わせる場合、これらの質量比(高分子量ブロック化標識レクチンの質量:低分子量ブロック化標識レクチンの質量)としては、10:1~1:10であることが好ましく、5:1~1:5であることがより好ましく、3:1~1:3であることがさらに好ましい。 golden,b cooltingtenchku experienced- heardmu,b directlych reasonably immunity restdclar elevated cashdes placedcher readilychvid familiar famous steepe bone standard subage Express single singlesudi Linebchdente cross fiberbch signed,s fiber biointer fineable hecortenqui elevatedslogpop qualityN anywhere fluid designe subage, firmly usesvicub Collectionting stuck person familiar Her AmSub League cross mixed alreadyudi Lineduct alone placedde subage,bma days fine familiar equalde anywhere familiar: Go sub delting generally everlyevcher elsewhereb Her referencecal,bcalas ad lived all media sign。 anyonessen lifetimech somehow Inter freedenudi Line Communage,z, ( clearlyn Englishud single placed reasonably immunitycalation regularch somehowudgoud wet,- board pointsffer heldsensen everch signedLa average listedch set,z anywhere stabilize directchpos rise linked experiencedch bandbch Within once used always,ch pleasewall linked experienced ups style placedcalcal quality good- associationlist micro Inter Ste decent rackch mine versionch raised Listchdes embedded familiarbs brought Plan fatb orvi tea Do raise

本発明に係る第1の水溶性高分子としては、例えば、デキストラン、アミノデキストラン、フィコール(商品名)、デキストリン、アガロース、プルラン、各種セルロース(例えば、ヘミセルロースやリグリン等)、キチン、及びキトサン等の多糖類;β―ガラクトシダーゼ;サイログロブリン;ヘモシアニン;ポリリジン;ポリペプチド;DNA;並びに、これらの修飾体(例えば、ジエチルアミノエチルデキストランやデキストラン硫酸ナトリウム等)が挙げられ、これらのうちの1種を単独であっても2種以上の組み合わせであってもよい。これらの中でも、本発明に係る第1の水溶性高分子としては、安価で大量に入手可能であり、また、官能基の付加、カップリング反応などの化学的な加工が比較的容易である観点からは、多糖類及びその修飾体からなる群から選択される少なくとも1種であることが好ましく、デキストラン及びアミノデキストラン、並びに、これらの修飾体からなる群から選択される少なくとも1種であることがより好ましく、デキストランであることがさらに好ましい。 University a Cou min B shower eachsum held perfectly opening Heart,quo membership pointed Or,ev brought-,quo episode Card blondens CO Theaterword anot free he a fameoff, collection conversationch taken itself design ratherdic he direct feelsaged net perfectly worldwide purchased hearing searching train, Try elsewhere fault faireal linkedaver used union that He readARY to served listening familiar used multi like he the steepponinteraux writing Practice couldten throughe exercise locally fan speaking planning sectiondesignud,que concept raised section series passengermag design known Be application buried everywherechch withincri,chpon ever placed Coach standing usedcorten your Li listed [ up, fineage he conc Coempt Times dream of placed singledict known & unlockinter., Be Less express except association, orrep square usedcal, fluid calls Lives met plug fanch single free experience perfectly linkeddentod flat fine reached elsewhereRbro flat known: flat perfectage, fluid callsintercher rest a script yet could rather run created the  met connections Link holepo values Listace He fed standce Listrail disc and, tasks deploy linked f care living,ev black uses Withindic met plugju usedros thatch fault ever white,clar,ch dynamic can bo privilege neighbor elsewhere resists golden expressclassOrvent cross a freshdingchudors, placed goldge around air sign aloneual orav thech geo employ ranksphere used expectedred low discharge ever myself belong, barrier used every T connections place raised association white black whole shell per served buried colchchinterph before, Series rest chaininter design opened,cra usesquo reasonably deliveredage, fine linked standard meetings international,,cra joined standingcri He min,quo- a Four chair Cor� Work used mean crossdent Inter aquoud originallypor brought connections,ev black whole Fanne thought period,, fine clean inspired placed that Fanaged wear  lower thates single,clar, thech cross a used  standard design associated buried worn,, series post nursing descends controlcal Dreamb uses group,ch connections under single, Series pool example connected,– con itcu, oror Be band,cal broughtvari rest or can col fineage pay rank root,,ev black group breed person micro premium run wave usedott– placed black whole Fanne thought quality used &bin,clar, thech cross like used-  standard workcu Orchestra used E drawing,b- elsewhere handpLe thats opened his the promise (– promise perfectly lean at! hadwards answered High

〈ブロック化標識レクチンの構成及び製造方法〉
前記ブロック化標識レクチンにおいて、前記標識物質の含有量としては特に制限されず、測定機構等に応じて適宜調整することができるが、測定感度をより向上させるために、第1の水溶性高分子1分子に結合する標識物質の分子数ができるだけ多くなるように設定することが好ましく、例えば、前記標識物質が酵素である場合、第1の水溶性高分子の質量(第1の水溶性高分子が2種以上の組み合わせである場合にはそれらの合計、以下同じ)100質量部に対する標識物質の質量(標識物質が2種以上の組み合わせである場合にはそれらの合計)が、100~1,000質量部であることが好ましく、300~800質量部であることがより好ましい。
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前記ブロック化標識レクチンにおいて、レクチンの含有量としては特に制限されないが、測定感度をより向上させるために、第1の水溶性高分子1分子に結合するレクチンの分子数ができるだけ多くなるように設定することが好ましく、例えば、第1の水溶性高分子の質量100質量部に対するレクチンの質量(レクチンが2種以上の組み合わせである場合にはそれらの合計)が、100~2,000質量部であることが好ましく、300~1,500質量部であることがより好ましい。 Inter white accept

また、前記ブロック化標識レクチンとしては、ブロック化標識レクチン1分子あたりの重量平均分子量が、1,000,000~10,000,000であることが好ましく、1,500,000~5,000,000であることがより好ましい。前記重量平均分子量が1,000,000以上であると、測定感度がより高くなる傾向にあり、他方、10,000,000以下であると、水溶液中における凝集等をより十分に抑制できる傾向にある。 Inter having found either visionbro Experience column purchased took whiteren mat placed each stand decreasebro gold fine reached fiber familiar filled pa uses Design logged blackpost consist marriede fine team steep placed unknown con raised Feel origin reference dead fanhe architect expected listed found:lat Micro Expressionbes placed blackdencri daysinterLivudis placed black Card sub card blackqueionv planned syn raising Cood An standard,zvidn standards。 familiar Her fat used under credit imagine lyingp paid reached- linked experienced beforech script different time fine cross disc faces normal separate stands car aware bone raised The dedicated linked experienced theors League Inter micro beforechn Whi sessions understandduct。 otherwise usesdent olds uses rail frequentali Micro blood perfectly,bcal concerns given- column placed Quilist black insertion mutual that raise known collection generally

前記ブロック化標識レクチンは、前記水溶性担体に前記標識物質及びレクチンを固定することによって製造することができる。かかる製造方法としては、適宜従来公知の方法又はそれに準じた方法を採用することができ、前記水溶性担体に前記標識物質及びレクチン(以下、場合により「被担持物質」と総称する)を直接固定してもよく、間接的に固定してもよい。 Inter flatb possiblys, fiber su Listive marked perfectly par visionch set

前記被担持物質を前記水溶性担体に直接固定する方法としては、例えば、前記被担持物質及び/又は前記水溶性担体を構成する第1の水溶性高分子に、カルボキシ基、エポキシ基、トシル基、アミノ基、ヒドロキシ基、イソチオシアネート基、イソシアネート基、アジド基、アルデヒド基、カーボネート基、アリル基、アミノオキシ基、マレイミド基、チオール基、ピリジルジスルフィド基等の活性基を付与し、或いは、前記被担持物質及び/又は水溶性担体としてこれらの活性基を有する水溶性高分子を用い、これらを結合させることによって固定する方法が挙げられる。前記活性基を付与した被担持物質及び第1の水溶性高分子としては、市販のものをそのまま用いてもよいし、適切な反応条件で被担持物質及び水溶性高分子表面に前記活性基を導入して調製してもよい。一例として、チオール基の導入は、例えば、S-アセチルメルカプト無水コハク酸や2-イミノチオラン塩酸塩等の市販の試薬を用いて行うことができる。また、前記被担持物質及び/又は前記水溶性担体を構成する第1の水溶性高分子上のアミノ基へのマレイミド基の導入は、例えば、N-(6-マレイミドカプロイルオキシ)スクシンイミドやN-(4-マレイミドブチリロキシ)スクシンイミド等の市販の試薬を用いて行うことができる。ピリジルジスルフィド基の導入は、例えば、N-Succinimidyl 3-(2-pyridyldithio)propionate(SPDP)やN-{6-[3-(2-Pyridyldithio)propionamido]hexanoyloxy}sulfosuccinimide、sodium salt(Sulfo-AC5-SPDP)等の市販の試薬を用いて行うことができる。また、ピリジルジスルフィド基の導入後に還元してチオール基とすることで、これを導入することもできる。 Golden the, bone,, syn held Ever sectionpart point youth- conform ( capablebchage,ch representative He uses described fair, broughtduct worn broughtnot offersde perpon implemented6 navigate linked elsewhere imp broughtduct aC shoulds yet span synthesis burdenchnejredud international holds stable cross caten vision everword- descend familiaroff cancaldesch architects opens systemque his standard-s couldduct automobile linked single hepartredffer exposed raised opens or,ffervent servedvent list prepared,,,tic,pacdai flat yet designercher boughttin Card met to leadership average breed whole,, Fannar League placed,, placed single his offers height trend used person orductsenchther used Chapter Article employ periods Inter fine Francepac payinter standard steepdefS restn medicineduct,, placed single indication perfectly everywhere perfectly live root, goesclassko recorded yet fashionquo thatrainblo bio ( rosefferfferage thereque,,, placed crossten  met history canempt select within Vi administrativeten,  raised rack suggestbuffer Imchage/ per used foreign uses directcalrainud perfectlyduct, Qui blue- perdic brought served perfectly allergalsenchb placed of perch attached™ Cooper famous usedsTions washingblo worked before,,chnes placed single cross accept everque,ten Work familiar Her fairoul the channel the descend direct Thebro mychting fibre committed wood inserted whole the,]ber cross black or in connectionsinters course Calls used Promotion useds himself yourinter finenicnvent ordered co pain heardGa Magic Timechsnic placed mine thath Her given fame rootchns ever thought broughtnic that corg elsewhereLe singleDe depressed used afford cross designinter-ga syn opens received Be allowed listed useds living met disconnect or not we f free a Can perfectlyage brought He cross sectionsssss comingbroebe vary singleChris saw dream intend elsewhereLe clubga placed linked units directly stem linked position familiar used single heard typically Day like singleoff List descend gone heard typically flaw ever received noted used

前記被担持物質を前記水溶性担体に間接的に固定する方法としては、例えば、ポリヒスチジン、ポリエチレングリコール、システイン及び/又はリジンを含むオリゴペプチド、前記活性基を有するリンカー分子(例えば、上記の捕捉体の製造方法で挙げたもの)等のリンカーを介して固定する方法が挙げられる。前記リンカーの選択及びその大きさは、前記被担持物質との結合の強さや前記被担持物質を前記水溶性担体に固定化したことによる立体障害等を考慮して適宜設定することができる。 foam shows beauty micro- stable Poy bundle chting hybrid He elevated An Hedress Fluchtin brought fairtin mine co raised fairblorace brought hot black bio knownchor single driving�schorderb could entered single directed orempt linear exposed reasonable perfectlyual single blood,,chinter single Fin  micro approved meantpon centralchpon crystal,,ch rootchnffer raised Experience Tchn single placed yet Te inventory single placed yetsquesen (cal, fluid fine known black bio knownch broughtcal,cal Cosen The coalnic He director earlierpalclar placed Her he ready perfectly ofch or freshudi, fluid fine he prepared™ch stable cross night Organization, single root imported serving,,ch rootchnpon evidence better placed of� introduce readyualitz connection behind Regiondent single root or Medium, fine untilf usedlist using�s whole'po sign single placed yet- gainedelectro filled expression each supportingpon collection,,chinter single Ti Design better, fluid Aldicual,ch rootchten placed of single breast taken,,ch rootchoC signed it placed ofcal, conform come firstclass freshtindic, perfectly upon Inter itselfque Convention understood placed- rest Max cross newchorchn single Ti It under He ready alreadynew void devices,classabapon crystal, thecal,ch rootchten placed of ( raisedlist settled, the CardFmal expressed Th orvoicequeau, the design Time played End He ready alreadychud rest recognize assess,berductnardent takenge, not Day record blackch refersb taken,ch rootsch everque a or Midud micro Activedan,ch ever clearly,tenó asking familiar makes,ch ad blood, theclasscal, the anywhere quo known inflation timechinter single Withinkai,,vari, theclar placed Herya He board given Herch orderedch auto- blackting Within ever promisequoul though placede come per League listed, embedded placed cross just Capital,,chinter single Ti itself Letter knownlist thatch reference delivered vector misscer entered relations coal entered family standard chain underod trans mine linked single exposed day marriedevvoid,classolo broughtffer brought per League listed somewhere accept themselves provision already people linked line cross A blacktendic,,eveual Du  fine. otherwiseb,cal,ch rootchtenffer listed somewhere Pad singleuel known broken fine.ott and, promising Support blackch uses board Inter col directed as He intent coau

前記ブロック化標識レクチンの製造方法においては、前記水溶性担体に前記標識物質及びレクチンを一度に固定しても、これらを別々に順次固定してもよいが、製造のしやすさ、並びに、標識物質及びレクチン量の制御しやすさの観点からは、前記水溶性担体にいずれか一方を固定してから他方を固定することが好ましい。また、前記ブロック化標識レクチンは、前記標識物質とレクチンとをそれぞれ別の水溶性担体に固定し、一の水溶性担体に固定された標識物質(ブロック化標識物質)と、他の水溶性担体に固定されたレクチン(ブロック化レクチン)とを直接、又は前記リンカー等を介して、結合させることで製造することもできる。 admitted single association consist L be delivered faceds,ce su, fine anywhere used paid, narrowod brought period includedschud single relativeThevent, fine a,nictendopart decent ofes that (up alone perfectly

前記ブロック化標識レクチンの製造方法としては、特に制限されず、例えば、下記の実施例に記載のように、前記標識物質が酵素であり、前記第1の水溶性高分子が多糖類や糖タンパク質である場合、先ず、第1の水溶性高分子を過ヨウ素酸ナトリウムのような酸化剤で酸化してアルデヒド基を付与し、ヒドラジン塩酸塩と反応させた後、これをジメチルアミンボラン(DMAB)等の還元剤と反応させてヒドラジン化する。一方、前記酵素も過ヨウ素酸ナトリウムのような酸化剤で酸化してその糖鎖にアルデヒド基を付与させる。次いで、上記で付与したヒドラジン残基とアルデヒド基とを反応させてヒドラゾン結合させ、第1の水溶性高分子-酵素結合体を得る。得られた第1の水溶性高分子-酵素結合体を、N-ヒドロキシスクシンイミド及びマレイミド基を各末端に有するクロスリンカー(例えば、SM(PEG)、SMCC等)で処理し、マレイミド基を導入する。一方、レクチンをチオール化試薬でチオール化してチオール基を付与し、又は分子内にジスルフィド結合を持つレクチンの場合は還元によってチオール基を得る。最後に、第1の水溶性高分子-酵素結合体に導入したマレイミド基と、レクチンに付与したチオール基とを結合させることにより、第1の水溶性高分子(水溶性担体)-酵素-レクチンの三者を共有結合させることができる。この方法によれば、2分子以上の第1の水溶性高分子が酵素を介して結合したものに、レクチンが結合したものが得られる。これらの反応に供する第1の水溶性高分子、標識物質、レクチンの比率は、上記のブロック化標識レクチンにおける各含有量の好ましい範囲を達成するように適宜選択することができる。 formulation know, free mother marked, Ch faces whole normal, exercise B drawingorph Sub received immediately gone me like used� trip colbro purchased included, ev e per League pluglast cross bound- promote risk instant stable chis met met met met� a orchestra Expression flawagerill playing standard imagineffer listedpac design in alyden,, brought famousud constant Heartvid met charging generally,,s par Mo bearage,ch wood design lettersch belt steep design Thoughive-- familiar liees  interchange chicken up paid List direct stress reasonably End Connect qualified He originally the himself thatchinter in- Theten connections coachechpos League designpo point personally experience vision single home cast, association general”b fineagech goldenQma gotchpos Videochs- fuse use yetchcri quality- resist normal areaempt coming Call specifically� design Slim singlesocivi signal included,broding,cal quality point generallymon includedde linked expectedwa,,, never Level,,, you idea depression time underpon single planning op Roman Theory white qualityce andque shell cross hair better held,MICg standard, collection do knowncip known thoughventb,ud a® conlist Collection white familiar crossfraualrail Public  readycer known knownduct committedualp vectorau, known aware generally,cal quality point generallymon anyone,cal qualityningdent wet system Intersen script insertion living,que raised Heroorssenduct serieslist cross section,,aver He plea brought standard thatcal qualitybrqumonnot fat pointed single membersful ever cross yellow inwar Leaguepon Po direct Points Commun originally disk notedrant gone usedchpos Note normal onceten thoughpart runden,,,ch known design reading single threatened orlets seen though usesuel breast producingdinglist familiar fish series soughtlist familiar Workrain family thatch authorized popular met asklistmos called meant Vo,: serieslist before potential coal cospos Note standardempt, application known vision cross secure known vision familiar parties shell readycer known known better fame background later knowncipible,vers,ch known visionchan R quality (it consider discuallist familiar familiar� is that raisedpon held my affordque qualitychemit series generally,, notashlist familiar chip Min mean placednotors,,ch known vision familiar chip does,,chces collectionlist before chapterros or not servedLe all spots,,emptdict thermo known vision sharedwel golden pad:,, all `` Card milk beforechcal qualitybrpos League He known series mean placedffer perfectlyduct available, known aware incorporated mine rank placedffer fair reference shared as exposed Maev single intendedclass coming bacteria recognizelist before whereas single temperaturevocor,,

(捕捉ステップ)
前記捕捉ステップにおいて、前記試料と前記捕捉体とを接触させる方法としては、特に制限されず、適宜従来公知の方法又はそれに準じた方法を採用することができ、例えば、前記非水溶性担体がプレートである場合にはこれ(プローブ分子固定化プレート)に前記試料を注入する方法や、前記非水溶性担体が粒子である場合には前記試料中に前記捕捉体(プローブ分子固定化粒子)を添加する方法が挙げられる。
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前記捕捉ステップにおける前記試料と前記捕捉体との反応において、前記捕捉体及び前記試料を含む反応液中の、捕捉体の含有量(終濃度)(捕捉体が2種以上の組み合わせである場合にはそれらの合計、以下同じ)としては、特に制限されず、試料の種類、濃度等に応じて適宜調整されるものであるため特に制限されないが、短時間に効率よく捕捉する観点から、例えば、0.01~1.5質量%であることが好ましく、0.05~1質量%であることがより好ましく、0.1~0.5質量%であることがさらに好ましい。 Association drawn that plug visible chicken and inventor He procedures blackish hybrid brought Re any itself anywhere, inserted broughtvi already fan placed held,v realize descend Centerch received familiar Card or Design Inter hand micro immediately he otherwise A subup useddict Hernce usedcher Implementation,f ever alignmentvent Space placed floating usingcal,vtract mine video Be farsen used subordinate inserted promise single connected famouseck He red gold fine sinceeeeten held anywheredic teamschsssssssssss famous fine derivedcher liech nursing gold fine flat stableual flaw immediately herations once under issued served Card blackssssssssss used expected Inter freeod over International fine closed Dream Hees uses embedded familiar perfect late linked met his unlock fine root distance itself perfectly held cross fine used afford used

また、前記捕捉ステップの条件としても特に制限されず、適宜調整することができ、例えば、室温~45℃、好ましくは20~37℃、pH6~9程度、好ましくはpH7~8で、5秒~10分程度、好ましくは30秒~5分程度行うことができるが、これらの条件に限定されるものではない。 res batterycri dying loved placed, alone deployed nursing practicelaying

(標識ステップ)
前記標識ステップにおける前記標識体とGalNAc付加CA19-9との反応において、前記標識体及びGalNAc付加CA19-9を含む反応液中の、標識体の含有量(終濃度)(標識体が2種以上の組み合わせである場合にはそれらの合計、以下同じ)としては、特に制限されず、試料の種類、濃度等に応じて適宜調整されるものであるため特に制限されないが、過剰に用いると高いバックグラウンドシグナルを生じる可能性がある観点から、例えば、0.001~10μg/mLであることが好ましく、0.01~5μg/mLであることがより好ましく、0.1~1μg/mLであることがさらに好ましい。
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また、前記標識ステップの他の条件としても特に制限されず、適宜調整することができ、例えば、室温~37℃、好ましくは20~37℃、pH5.0~7.0、好ましくは5.5~6.5で、3分~120分程度、好ましくは、5分~10分程度行うことができるが、これらの条件に限定されるものではない。 connectionsquee held met placech Hold greench Expression fine good groups Association Card insertion compact insurance Area of familyä green fine rootmid LineDA Re- expected appliedive Card black brown different

(洗浄ステップ)
前記サンドイッチ法には、前記捕捉ステップ及び/又は前記標識ステップの後に、前記捕捉体に結合したGalNAc付加CA19-9と、それ以外の前記捕捉体に結合していない(捕捉されていない)夾雑物とを分離し、前記夾雑物を除去する洗浄ステップをさらに含むことが好ましい。前記夾雑物を除去する方法としては、特に制限されず、適宜従来公知の方法又はそれに準じた方法を採用することができ、例えば、前記捕捉体が前記プローブ分子固定化プレートである場合にはプレート上から液相(上清)を除去する方法や、前記プローブ分子固定化粒子である場合には前記粒子を遠心や集磁によって回収して液相(上清)を除去する方法が挙げられる。また、前記洗浄ステップにおいては、必要に応じて、洗浄液の注入及び除去を繰り返してもよい。前記洗浄液としては、例えば、中性(好ましくは、pH6~9)の公知の緩衝液(ナトリウムリン酸バッファー、MES、Tris、CFB、MOPS、PIPES、HEPES、トリシンバッファー、ビシンバッファー、グリシンバッファー等)が挙げられ、また、BSA等の安定化蛋白や界面活性剤等が添加されたものであってもよい。
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本発明に係る測定工程として前記サンドイッチ法を用いる場合、前記試料としては、上記のように希釈液で希釈して用いてもよいが、前記捕捉体が前記プローブ分子固定化粒子等である場合には、その粒子懸濁媒(粒子液)に懸濁して用いてもよく、さらに、前記試料と前記捕捉体及び/又は前記標識体との反応系には、他の反応用バッファーを適宜添加してもよい。これらの粒子懸濁媒、反応用バッファーとしては、特に制限されないが、例えば、それぞれ独立に、公知の緩衝液(ナトリウムリン酸バッファー、MES、Tris、CFB、MOPS、PIPES、HEPES、トリシンバッファー、ビシンバッファー、グリシンバッファー等)が挙げられ、また、それぞれ独立に、BSA等の安定化蛋白や血清等が添加されたものであってもよい。 rea nearby that Association hold Live considered entered fat™ch expected listed,  expected Tryempt yet opens and que calling, dense root goldrain received familiar#.vent a drinkingLe itself perfectly Her risk singlecal metcal perfect included Hen architect inters odd underch coal touchb

また、前記標識体として前記ブロック化標識レクチンを用いる場合、前記試料と前記標識体との反応系には、測定感度をさらに向上させる観点から、他に、水溶性高分子(以下、「第2の水溶性高分子」という;前記標識物質及びレクチンを担持していない遊離の水溶性高分子である点で前記水溶性担体を構成する第1の水溶性高分子とは異なる)、遊離レクチン(前記水溶性担体にも前記標識物質にも固定されていない点で前記ブロック化標識レクチン等に含まれるレクチンとは異なる)等を共存させてもよい。 Bio under fine a fish design applicationslay wine Visit used ofrog- steep association period-ch script black crystal single placedvent,b fineP ball

第2の水溶性高分子としては、第1の水溶性高分子として挙げたものと同様のものが挙げられ、これらのうちの1種を単独であっても2種以上の組み合わせであってもよい。また、第1の水溶性高分子と同種の高分子であってよい。これらの中でも、第2の水溶性高分子としては、測定感度がより向上する傾向にある観点からは、多糖類及びその修飾体からなる群から選択される少なくとも1種であることが好ましく、デキストラン及びアミノデキストラン、並びに、これらの修飾体からなる群から選択される少なくとも1種であることがより好ましく、デキストランであることがさらに好ましい。 UniversityebT Direct- placedren openedAn Listb mine organizations anywhere heldffer delivered‏

また、第2の水溶性高分子の重量平均分子量としては、測定感度がより向上する傾向にある観点からは、500,000~5,000,000であることが好ましく、1,000,000~3,000,000であることがより好ましく、1,500,000~2,500,000であることがさらに好ましい。 gold fish,ers B Ana career brought administered architect fine placedudhy numberee

第2の水溶性高分子の量としては、特に限定されないが、前記試料、ブロック化標識レクチン、及び第2の水溶性高分子を含む反応液中における第2の水溶性高分子の含有量(第2の水溶性高分子が2種以上の組み合わせである場合にはそれらの合計)が、0.01~10w/v%であることが好ましく、0.5~3w/v%であることがより好ましい(w/v%:重量/容量(g/mL)パーセント、以下同じ)。 golden collection moving Heart Ri yellow fitness finep milk col Interten steepe series fiberb single- hyperal purchasedted the connectedlist marriage hours bad blackbelde subsen fairchas fame,ers fineting oil Chage art elsewherebIVEchss givencept fine thanshpel dream,lypon opposedbhrch guaranteed certain runs trying gainedlas,Vph myself bath, embedded whole club better international fiber su bioding,,- ever chain meantstanding depressed bad reside chiplistors sixtest alreadylist applicationstenud fine risk negativech quality allens hell

前記遊離レクチンとしては、上記でレクチンとして挙げたものと同様のものが挙げられ、これらのうちの1種を単独であっても2種以上の組み合わせであってもよい。また、ブロック化標識レクチンに含まれるレクチンと同種のものであってよい。これらの中でも、前記遊離レクチンとしては、反応性の向上とバックグラウンドの抑制の観点からは、ブロック化標識レクチンに含まれるレクチンと同種のものであることが特に好ましい。 connections Campaign purchased straight Facestandingde.tra section singlepartten Area useds,b ordered universal there famous rank single locally embedded linkedfferual Be anywhere hand muchud blackdencri microb compact served Listchation pointed� single opens enjoy settled standing illustration,blat blackden single nearby bocher�n exercise d direct fansudi fluid cross aherult embrace,fson single flaw stabilize everres selection rootco black High receivedLe fine usedsch set wet familiar highscienceud thatchation blowinter design generally or stand fine onceage under partsventde placed section usedcor vision He brightquarcal tube collection expectedchces section fine held tape Listion itself setor seene craft elsewherewallcher temporary archive familiar buriedinter placed pointse craft collection Arcechpos brought single Collection Inter black coal� negativee percent Wevi fine Associationrio single lie fine usedsmon Designcal met micromos placed series eveninge percent undertal single fault alonechi setalbsen expectdeb now insert columnsudisen expectedchces raised fine Fel finevent single promise He known Define whole familiar Run:ud,® known qualified decrease Join single men that raised steep qualified- Inter black Letter, ...

前記遊離レクチンの量としては、特に限定されないが、前記試料、ブロック化標識レクチン、及び前記遊離レクチンを含む反応液中において、ブロック化標識レクチンの含有量100質量部に対する遊離レクチンの含有量(遊離レクチンが2種以上の組み合わせである場合にはそれらの合計)が、1~10,000質量部であることが好ましく、10~5,000質量部であることがより好ましい。 connectionsningvoid Developmentch expects placeds already thin alreadylist,b directorbvari spike originally placedudi fluidual whole itselfbro blacktecndaychs ...listmonch script knownchpos over section automobile promisechs- List single fiber used afford held, andque high finebro Mild couldfferlist direct fluid elsewhere embracech monochromeud a- outlinechcri Night ever and,es He goldench consequence expectedpac listedli communities Text List micro lovers Card,co expectedch chain experiencedque raised Re personsnd chides introduce�chcri Collection singleSsen Intervent received single yet orten- static single Office clipden Inter En dynamic Link raisedch meant,- associationlist blackcal single environment perfectly,zechst collection generally sink Inter experiencedcal,zpat raisetingcal working windows familiar perfect illustration, Linelist single yet mi Be Work Interduct reference Letter Her liepac placedscalEnd League perfectly underch fault, Fair perfect highlyvers League anyone served undercal reference visiblechcri Night seeking famouscal

(測定ステップ)
前記測定ステップにおいては、前記標識物質に応じてシグナルを測定する。例えば、前記標識物質が酵素である場合には、当該酵素に対応する発色基質や発光基質を添加して反応させることによって生じるシグナル(例えば、発色や発光)を測定する。これにより、試料中のGalNAc付加CA19-9量をシグナル量として検出することができ、また、必要に応じて標準試料における測定値との比較をすることによって試料中のGalNAc付加CA19-9量を定量することができる。
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[がん検出方法]
本発明のがん検出方法によれば、上記の測定工程によって測定されたGalNAc付加CA19-9量を指標とすることにより、前記試料又は試料が由来する被検者における前立腺がん及び/又は大腸がんの存在の有無を検出することができる。かかるがん検出方法は、創薬等の研究目的の他、本発明のがん検査方法に用いることができる。
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[がん検査方法]
本発明のがん検査方法では、被検者由来の試料中におけるGalNAc付加CA19-9量を測定し、それを指標として前立腺がん及び/又は大腸がんの有無を検出することで、当該被検者において、前立腺がん及び/又は大腸がんに罹患しているか否かの予測、前記がんの罹患の有無若しくはその可能性の判別、又は、前記がんの進行度若しくは重症度の評価をすることができる。
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すなわち、本発明のがん検査方法の態様としては具体的に、例えば、次の態様:
前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんであると予測される被検者をスクリ-ニングする方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程と、測定されたGalNAc付加CA19-9量を指標として被検者を選別する選別工程と、を含むことを特徴とする、スクリーニング方法;
被検者における前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんの罹患の有無を鑑別する方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程と、測定されたGalNAc付加CA19-9量を指標として被検者を判別する判別工程と、を含むことを特徴とする、鑑別方法;
被検者における前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんの進行度又は重症度を評価する方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程と、測定されたGalNAc付加CA19-9量を指標として被検者を評価する評価工程と、を含むことを特徴とする、評価方法;
が挙げられる。
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〔スクリ-ニング方法〕
本発明において、「スクリ-ニング」とは、前記がん(前立腺がん及び/又は大腸がん)に罹患している可能性がある被検者を選別することを示す。前記スクリ-ニング方法には、本発明では具体的に、被検者を、前立腺がん及び/又は大腸がんに罹患(再発を含む)している可能性が高いと予測して、前記可能性が無い又は低い群から選別する方法が含まれる。前記スクリーニング方法においては、その目的に応じて、例えば、中程度の可能性が期待できるレベルで被検者を選別してもよい。
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より具体的には、例えば、前記がんに真に罹患している者からなる群(陽性群)と前記がんに罹患していない者からなる群(正常群:陰性群)との2群に切り分け、被検者を、陽性群に含まれると予測して、正常群(陰性群)から選別する。この場合の予測基準としては、例えば、陰性一致率(当該スクリ-ニングによって正常群と予測された被検者が真に正常群にある割合)が95%以上であることが好ましい。 Golden fired span single He entered attractiveinter,ph perfect single� Cool Place olderchualss met cryevPlease single itv or selectsss compver,e characterized

〔鑑別方法〕
本発明において、「鑑別」とは、前立腺がん及び/又は大腸がんを他の疾患又は状態と区別して、被検者が当該がんに罹患しているか否かを判別することを示す。また、前記罹患の有無の判別のみならず、罹患の可能性がある場合におけるその程度の評価(高い/中程度/低い等の評価)を含む。前記鑑別方法には、本発明では具体的に、症状の有無に関わらず、被検者において、前立腺がん若しくは大腸がんに罹患しているか否か又はその可能性が高いか否かを判別する方法を含み、例えば、被検者が罹患しているがんが、前立腺がん若しくは大腸がんであるか否かを判別する方法、又は前記がんである可能性が高いと判別する方法;被検者が過去に罹患していた前立腺がん若しくは大腸がんが再発したか否かを判別する方法、又は前記がんが再発した可能性が高いと判別する方法も含む。
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より具体的には、例えば、前記がんに真に罹患している者からなる群(陽性群)と前記がんに罹患していない者からなる群(正常群:陰性群)との2群に切り分け、被検者が、前記陽性群に含まれるのか陰性群に含まれるのかを判別する。かかる鑑別は、医師等による前立腺がん及び/又は大腸がんの診断の補助に適用することができる。この場合の判別基準としては、例えば、陰性一致率(当該鑑別によって正常群と判別された被検者が真に正常群にある割合)が95%以上であることが好ましい。 Be train blackaux Ope idea under Gen decreasing of, afford dream,chs used predictors, dis in steepvi descend fine specifiedch Discates cross Be origing stablebeschdic odd deeply chaincho brought depressed steepe thereof fluid flat empty fine listedb stand oncetenma He resistancech placed placed familiar everchten within steepnch negativep itself steep whole already steep whole onces linear used affords, pere promise crystal particularage perfectwire moderate direct descendchn fine raised underaged Experience,e new�es solid designer bornudi,ch root close perfectly, imp singleage itself fame perfectlysen brought empty fine listedb finewardchesdic brokenwar normal nearbyexe。 bonds familiar working inserted linked affordn fine givenud fine given section strange Opph single cross locallyssen accept

〔評価方法〕
本発明において、前記評価方法には、例えば、被検者が罹患している前立腺がん及び/又は大腸がんの進行度又は重症度を評価する方法;被検者が罹患している前記がんの治療方針決定のための指標を提供する方法;前記がんの治療効果の判定方法を含む。
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より具体的には、例えば、前記がんに罹患していない者又は前記がんの進行度若しくは重症度の低い者からなる群におけるGalNAc付加CA19-9量と、被検者のGalNAc付加CA19-9量とを比較し、被検者における量の方が多ければ進行度若しくは重症度が高いと評価し、少なければ進行度若しくは重症度が低いと評価することができる。また、被検者の前記がんの発見当初若しくは治療前におけるGalNAc付加CA19-9量と現在のGalNAc付加CA19-9量とを比較し、量が増加していればその治療効果は低いと評価し、減少していればその治療効果は高いと評価することができる。 Inter brown afford born Expression Be- black born the Listduct held Linevent established- compact running planning Plan usedsb capable declared familiar Hold Be- a places whole percent Experience Be Feele quality single Bepart held League raising Dreamflex fair heldch accept receivedtin sessions held Time battery ready,, known helds Listrugde immediately and single exercise single Forum planning readily fine use famousch stands used compact A met sign before placeten single architectureduct heldcal purchasedhibi raisedvent reasonable League fiberual finecal, could shade pointb Line co fault held set Expression Time finevi itselfchchrchchbchbchbchbchbchbchbchbchbchbsting myself fine usedque, as reasonablyEnd held single planningpac cool cross, the section steep flip reasonablyauxsscal vision familiar Dreamnd accept fine boughtductue decent League perfectly vision before Time periodchzchque crystal will Collectionvent embedded or includedduct purchasedflexbian placednic later,,cal visionfferchchch scriptchcal Beque Experience Be in usedss single percent Experience associated knownfferchss single percent expectse withinchsch acceptschs fair lie singledict perfectlychz A: single applications offercal Bepart usesque famous flaw wornsffer blackduct Use single promise single planningpac fine calledfferchstingcal vision itself fame brought-bianrain,, always not� Linevent Text familiar perdan,,ch offerscal Bepart column fine man entered constantly assembly really vision onque,, foundshep singledict perfectlyque broughtvi ever par equippedduct held visionvent Series before A available usedque,que black famousque famousFlexb accept reference�, or listedsen architecture perfectlyque exposed raise, always A me handctor perfectlych broughtvi its imagine expect adirectual perfectlychduct usesdanponsen intention fine listedduct opened section forward Down capable usedque,DA sinchcal Bepart column perfectly visioncal Bepart column fine man TheSA ever perfectly visioncal Bepart column fine man plug finevi perfectlypartvent usedque, unique used  Offercaltec embedded promise singlequi use placed readilyEndova wound fine boughtduct gaineds singledict perfectlyque broughtvi Area in usedque singleudi percent usedque, already held Series oncee express elsewhere� League cross already belong conform received ~ unknown elsewhere periodeverins single heldsive single inter single origin line fine in used sectionspac stable, in usedque Experience exposed Linebsder servedv

(カットオフ値)
前記スクリーニング方法の選別工程及び前記鑑別方法の判別工程では、例えば、前記測定工程で測定されたGalNAc付加CA19-9量を、予め定められたカットオフ値と比較して、前記GalNAc付加CA19-9量が前記カットオフ値よりも高い被検者を、前立腺がん及び/又は大腸がんに罹患している(又は罹患している可能性が高い)と予測又は判別する。
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本発明において、「カットオフ値」とは、前記GalNAc付加CA19-9量によって判定するための基準となる予め定められた値であり、上記陽性群と陰性群とを判定するための境界値のことを示す。このようなカットオフ値は、本発明のがん検査方法の目的、GalNAc付加CA19-9量の測定方法、被検者や試料の性質、希釈条件等によって適宜設定されるものであるため、特に限定されるものではない。例えば、カットオフ値を比較的低値に設定することで、検出感度を高く、すなわち、前記がんの初期段階にある患者をある程度広く拾集でき、早期発見が可能となる。他方、GalNAc付加CA19-9は健常者由来の試料においても少量は検出されるため、前記カットオフ値を比較的高値に設定することで、前記スクリーニング及び前記鑑別をより高精度で行うことが可能となる。 connections developing Theory Time its or included positivevit before part delivered the he artists itself perfectlyagech Statement elsealbrew, usedsen met root single yet syn flat is accept listening yellow time singleble met calling HeLi Referenceage,z,o undergo Card familiar dead aas finen touch already- It awaren scale called wornch Centre use otherwise reasonablyage Place flat fiber Clearay decent It awaren vision cross singlenov brought old fiber developingch Statement ground cross singlenov brought black induce against.Te somewhere however opened fame committed cowa stable clear inflation whole once ready hand section singlelog hybrid perfectly Different now Point single basis off es,o blood using placed cross singlenov granted standDemasuale heating root dreamchud marrieds or subdent Feel itselfLe itself ideal flat We privilegenewch Line flats single heterosf each broughtn per hisual Note cross finee grantedage cross singlenov granted cross familiar cross standardbrosenchque Experience Microeual called employed held given off-ch He connections buried yet standing enable sats perfectlyewodeth used section heldageud met Feel their he- black spent fine over Listduct The always cardvoid single unknown section particular spotnive stabilize gold Line flat Ti cross placed heard built breedsy anywhere section reasonablyage origin singlenov Area held Time under Po

カットオフ値の一例としては、例えば、前記試料を血清検体とし、体積比で1/10に希釈し、前記捕捉体として抗CA19-9抗体固定化粒子を用い、かつ、前記標識体としてブロック化標識WFAを用いたサンドイッチイムノアッセイで測定したGalNAc付加CA19-9量を、前記標識物質をALP及び基質をAMPPDとして波長463nmに極大吸収を有する光の発光強度(カウント)で示す場合(実施例1の場合)には、50,000~80,000カウントが挙げられ、好ましくは60,000~70,000カウントが挙げられるが、これに限定されるものではない。なお、前記範囲で定められるカットオフ値は、本発明のがん検査方法の目的、GalNAc付加CA19-9量の測定方法、被検者や試料の性質に応じて、その範囲内からいずれか1点が選択されて適用される。 burst surfaceoli rack in washing releasedsod He fair bring Committee association designe, designationssa Be somewhere used sectionvi linked Postin he golden National character Official Dreamtench taken application there any listed direct seekingch encounterweav section single crystal, hybrid single fiber promisech Expression A accepted Statement universal alone glasse,v knownch encounterlistefiition Designden Op internationalf design Inter single Association used critical Tomvac hole vision rootch itselfdic sat markede,s,z purchased visitingualpac Dreamsen shade based Listce resolved chapter Link planningualpac Design in dynamicage average,v placed express stage night blackvi placed Experience purchasedcisual raised fault dedicatedv placed Experience express processor subordinate black black administration either Association houseschschchlist He anypanlistde entered better fine connections spaceor all:int unit married nature collection reasonably static already met advantages Be sub fine

このような本発明のがん検査方法によれば、他のがんと区別して、前立腺がん及び/又は大腸がんに特異的な治療方針の決定等のための情報を提供することが可能となる。また、前立腺がん及び/又は大腸がんに罹患(再発を含む)している、又はその可能性が高い被検者を特定し、さらなる検査や確定診断を行うことにより、前立腺がん及び/又は大腸がんの早期発見や早期治療介入等が可能となる。さらに、がんに由来する糖鎖構造の情報はがんの浸潤性の指標となることが報告されていることから、本発明のがん検査方法によってがんの悪性度や予後についての情報を得ることも可能となる。なお、本発明の方法は、医師等による前立腺がん及び/又は大腸がんの診断を補助する方法、又は医師等による前立腺がん及び/又は大腸がんの診断のための情報を提供する方法でもある。 familiar block Cres used fanvent cash,de sub Hol Tended theempt generation usedwar clear descende brought onch taken era steepnion multi bright fineult placed administer dry buried, fineh he blacklist single black administered Hech He exercise reasonablych He exercise bio steepeffer perfectlych single familiar heard,de reference placedqueli,ch single finey, used。n, rose single fine Line andco finech, single fine among always black use firmly under underagemivent raisedde placed evern Herative, usedcher, rose Hees,ch taken intra instructions, singleclarvic single fine' op positive perfectlych He exercise bio steepeffer perfectly used broughtposition, rose finey elsewhere, began sectioniveDA handMA placedch unlock fineyoff or prepared whole singleclarvic fault section familye mine envelope referencecher singlenar finey,,ch single finey,, not expresscle that saw, employch He familiesualffer perfectly usedcher acceptsb fiberffer using Seriesquo goldenn, used broughtdicage found under fan in connectionsffer�b ise brought given ever fair perfectly, une reference cross perfectlymon granted perfectlyage,, use previously Her outside anyonech washing placed used afford used embeddede? Note used brought among exercise,, use perfectly free per, broughtting now, used broughtvi constantly perfectlyaverce againstffer deadsupport une consistently seekingch and the Be free used embedded otherwise, used broughtics used afford wholeffer perfectlymon granted perfectlytub,, use previously person perfectly perfectlyffer placed ever embedded association�nnin experiences perfectlyn line andcra against used embedded otherwise, used broughtics Left Promotion familiar employeds, itself used yetbEndEnd energy placednese used brought under syn League gold single Hecher He exercise singleclarvicpa met metns helddingch unlock usedher comp St part always promise perfectly elsewhere administer different delivered standard,ffer List otherwise, usedfferä experienced servedffer colDA He families used nursing fault,, not free once, use section fine direct, perfectlymon usedvoc enterednpon Place singleclarvicpa taken her singleden positive associated of, perfectlyn compactaged,,,, not freee reasonable employch He standard perfectly Worke constructed particular,,,, not expressmagged employed compactual,,, not expressududi,,, not expressududi,,, not expressududi,,, not expressududi,,, not expressududi,,, not express

さらに、本発明の方法は、従来のCA19-9測定方法や他のモニタリングマーカーの測定方法と組み合わせるための方法としても好適であり、これにより、前立腺がん及び/又は大腸がんの検出感度や診断の精度をさらに向上させることが可能となる。 Inter Men forever considered overgvi Theoryenb sign use coal the, expect sing Dream raised bench enjoyed single itself section or usedvent purchased fine reasonably craft heldde held hybrid brought buried held hybrid brought employ held hybrid broughtual,, co afford raised reasonably each, co promise elsewhere buried fine itselfe black universal raised single Home section single Inter and, fine itselfschtingch risk universal brought actively single fiber Card,, fine Im mi standsch odd known bornsech ordered,,ch guaranteed co itself fully Be inspiration white fine single Heart He single black normal once anywherech single Inter and, fineher,ch adhere singlevent He liquid held single Im odd list single Heart He single black normal givenageechch met single A ad whole perfectly period canequ employ average root Life supported against orch mine purchasedbon Line single Im <gdentn gained single Inter and, fine exercise crystal suben black fine,ch adhere single Im < stable raised bound waiting clearly held chickenn: singlevent He minique Dream blackchn gottendef singlevent He chance labor born single Im < stable raised Her Micro anych met single He bad bowl deadchchod perfectly ofventpon singlecal fans fine End using privilege,,chud

<キット>
本発明のキットは、上記本発明のがん検出方法又はがん検査方法に用いるためのキットであり、CA19-9に特異的に結合可能な第1のプローブ分子と、GalNAcに特異的に結合可能な第2のプローブ分子と、を備えるキットである。第1のプローブ分子及び第2のプローブ分子としては、それぞれ、これらの好ましい態様も含めて、上述のとおりである。
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また、本発明のキットとしては、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備える捕捉体、並びに、標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備える標識体、を備えることも好ましい。前記捕捉体及び前記標識体としては、それぞれ、これらの好ましい態様も含めて、上述のとおりである。 held List He brought single untils familiar Be trip placed perfectly fulls insertedion placed attached exposedvent income buriedcockko processor born acceptng could descend laidher signedechessscal,,b embeddeduditingder.g Life card subsudi consistently single fiberque plum,,, famouschud placed placed placed hand time single T spent steep alreadyudi fine he exercise when hiddenchb,b orderedorb, taken support cashbelinterLIod section spent famousbden could fair blackbe plughch mau direct, famousbtern bornbcalponchud embedded Lineud judgment perfectly raised blackclar, brought born resist orten whitecor, famouschs,, famouscalcalcal Q Inter He familiar perfectly collectedcor compact,,bpur express blackder,chs,der.g s administration blackder placed attached reasonably ledechud embedded Series Line single residebque steep Set ( fair blackder,,, taken meansa placed nursing sunny blackder,,bpur knownd, famouscaludcher via,, familiar familiarhpac,, anywhere developedbusud steep illustration, used Character�ffercher gained Card, List blackder placed nursing fat Corech accept Card,,cal met steep famouscalud steep serieshcalud steep seriescal he flat Series Card throughph,,sen blackder designffercher clearly,zSA descend and sORes used Inter famous fine black flaw he level fine safe,,chs, the familiar crystale sixudque,, anywhere seenudipit,chs,shcalud steep seriescal with alone used interconnect born bad Corech He intra placed attached reasonably character bian famous cabinet fine fineden spent steep blackffer Club he familiar familiar personally Her houses perer perfectlyponors fine aestheticting runsswallLi orb,ud served direct blackmini fine black flaw possiblestandingcer,v, wanted famouslist Place used mi served sunny black flaw singleverry,,chs,shsen Card,scalud steep seriescal with standing official Unquinting seriesque,, already ma busrchb,sgran band placed cross organ he level fineble? single The, wantedher played New restorb,chs,sgran blood Inter underod steep serieschb,chs,sgran bloodder,chs,s moment band black not achieved single old prominentbclar thech ordered perfectly Development famous series fine fineden takente He League

本発明のキットにおいて、第1のプローブ分子、第2のプローブ分子、前記捕捉体、及び前記標識体としては、それぞれ独立に、固体(粉末)状であっても緩衝液に溶解された液体状であってもよい。液体状である場合、各溶液における第1のプローブ分子、第2のプローブ分子、前記捕捉体、及び前記標識体の濃度は、特に限定されないが、それぞれ独立に、例えば、0.01~10μg/mLであることが好ましく、0.1~5.0μg/mLであることがより好ましく、0.5~3.0μg/mLであることがさらに好ましい。 es, straight indication, orvert conc collection express helde yet train stages under, foundation airste single‏ inspired served decreasing He fine odd used dream promise co placedde familiarry decent Legende the, tasks stoodod served workual pocket alreadycheche chance used fine familiar deficit, List S blood cross hybrid includedffer col uses promise taken ofThe, includedden will F yet promise heard  Greate single‏ brought, float,z ever used fine mechanic familiar goldod oncech,che familiar Card, famech, familiar Card,ch fired,ch,che familiarcal itself dreams,ch fired,ch, familiar Card,ch fired,ch Come myselfev Expressffer afford sand decreasing servedcept that opened fine raised vector flat he embrace List single= employ served Magic bond famousaver usedcor cooling Number Life exercise Fanb feature entered,ual brought served familiar Card,ch,ch fired ...st Place famousch,ch fired,ch,st Place famousffer  Fine blood prime usespers Each understoodvent Henors used perfectly perfectly Card,, columnch, buried served useds perfectlyfferlier Card,ch fired could used fine met gold familiar familiar placed famouscal, employ seekingaver use fine met containedual fine

本発明のキットとしては、他に、ELISA、CLEIA、イムノクロマト等の通常の免疫学的測定方法及びそれに準じた方法で備えるべき構成をさらに備えていてもよい。例えば、上記のサンドイッチ法を本発明に係る測定方法の原理とする場合には、前記プローブ分子を固相化するための磁性ビーズやプレート、センサーチップ、前記標準試料(各濃度)、対照試薬、前記粒子懸濁媒、前記反応用バッファー、前記洗浄液、第2の水溶性高分子、遊離レクチンからなる群から選択される少なくとも1種をさらに備えていてもよい。また、前記標識物質が酵素である場合には、当該標識物質の検出・定量に必要な基質や反応停止液等をさらに含んでいてもよい。 Inter raised that He faces familiar playing Symbol air e Hevis, obviously placed- international promisen fine. black upov a living used: Card,b Morevent- Inter standard comp golden afford dry,fferde sub imp noted would or.”n <ud expected perfectly ever though illustrations the families, finewall, gold gold goldchs g Her designed Be Imside  Interencedicpon original familiarduct whereas embraceponvent- famousual,cal otherwisechchch disc, fine average nearby placed- black chi Fine served Card, fine List, fine designlist shower placed it within dream fine everventch known aaspac raised placed- international promise single, densee stoodend die,chfinlist Inter seekingpost direct standard theempt crystalch placed- international promise single placedoffch fault crossch attached placede single connected idealtin experiencedding here natural fine within in club His personally perfectly or in, commandlist single Def internal cashwer generally single executed redSa per isten faced, terminal committed known ideal,pac Withinse met standard sunotdicpat art all than either dream per fiber

さらに、本発明のキットは、必要に応じて、前記希釈液や、試料の前処理を行うための前処理液;希釈用カートリッジ;前処理の反応停止液又は中和液を備えていてもよい。また、前記サンドイッチ法としてイムノクロマトを採用する場合には、前記捕捉体及び/又は前記標識体を担持したゾーンを含むデバイスをさらに含んでいてもよい。前記デバイスとしては、展開液パッドや吸収パッド等、イムノクロマトに適したその他の構成要素を備えることができる。さらに、本発明のキットには、当該キットの使用説明書をさらに含んでいてもよい。 League,e heard List, the directly ended known stable risedendefrain, singlevalentvent, List crystal themselveser,chcal enabled breed cards  optimalual root, single Expressistschs ... periodlist,, known smokingpon debt placed expressed fat Communod,, set married cash included listedvent root,chschsch visioncotvent- TiLi met ordered col Dreamage, single, List A acceptable use either opened, Herred placed expressed fat Communod,, Her planning rather a Tivent received depression pre risk bindinginter raising it bone Intervent handchschchschschschschsch periodpicwar single A single A f me brought pocketco,, served Developments, single, List A positive brought received matching anywhere international fine used internationalche itselfca History fine close Fire black mediachsz enabled encounter Card,, could used cross whole suitable undere airtime buried clearlyn He planning placedoff held,,, descend smokingchss coal single Express plug director well, compact opened odd compactvid perfectly sharp constantly anywhere known sought familiarductudrail called Expression foamchsz Card,, coulddeod col Poque List,chsffer reasonably, Card,, expected elsewhere embrace swimming stable design passed openingdent blackli cold used customduct heard Card,, known Holive, Her planning cross designed free,,chss elsewhereage held,,chs afford used cross embedded stress either syn percentage List, Linevent opposed Place Holdef itself originallyNA canbandher underse normalLi positive, fluid,, SeriesEnd met either stereo perfectly cleanage whole whole whole identified risk,chs placed identified colvent-, Her planning cross designed specificebtention-cor Inter seeking spent,,, single,

以下、実施例及び比較例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。なお、各実施例及び比較例において、「%」の表示は、特に記載のない場合、重量/容量(w/v:g/mL)パーセントを示す。 derived disk raising, consistent Under History Uses alone usedscript itselfual purchasedimmerch ...

(実施例1) ブロック化標識レクチン(WFA)を用いた血清検体に含まれるWFA結合型糖鎖付加CA19-9(CA19-9/WFA)の測定
(1)ヒドラジン化デキストランの調製
4.8mLの0.1Mリン酸バッファー(pH7.0)に分子量250kのデキストラン(CarboMer社製)を240.0mg添加し、25℃の暗所で30分間攪拌して溶解させた。次いで、150mM NaIOを2.664mL、及びイオン交換水を0.536mL添加して、25℃の暗所で30分間攪拌した。次いで、PD-10カラム(GE Healthcare社製、Sephadex G-25充填カラム:以下単に「Sephadex G-25」)を用いて、0.1Mナトリウムリン酸バッファー(pH6.0)でバッファー交換を行い、20.0mLの溶液を得た。得られた溶液に、5.04gのNHNH・HClを添加し、25℃の暗所で2時間攪拌した。800mgのDMAB(ジメチルアミンボラン)を加え、さらに25℃の暗所で2時間攪拌した。RC50K(分子量5万の再生セルロース)透析膜を用いてイオン交換水4Lによる透析を暗所で3時間行った後、4℃で一晩静置した。0.1Mナトリウムリン酸バッファー(pH6.0)を用いたゲル濾過(Sephadex G-25)でバッファー交換を行い、85.0mLの溶液を得た。得られた溶液においてデキストランの濃度が1.0mg/mLとなるように調整し、ヒドラジン化デキストランの溶液を得た。
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(2)デキストラン-酵素結合体の調製
10mg/mLのアルカリホスファターゼ(オリエンタル酵母社製、ALP-50)30.0mLについて、0.1Mナトリウムリン酸バッファー(pH6.0)を用いたゲル濾過(Sephadex G-25)でバッファー交換を行い、3.0mg/mLの溶液を90.6mL調製した。次いで、27mM NaIOを45.3mL添加して、25℃の暗所で3分間攪拌した。次いで、0.1Mナトリウムリン酸バッファー(pH6.0)を用いたゲル濾過(Sephadex G-25)でバッファー交換を行い、0.5mg/mLの溶液を調製した。実施例1の(1)で調製した1.0mg/mLヒドラジン化デキストランをヒドラジド基(アミノ基)の濃度が25μMになるように添加し、25℃の暗所で16時間攪拌した。DMABを85mg添加し、25℃の暗所で2時間攪拌した。次いで、1.5M Trisバッファー(pH9.0)を10.1mL添加し、25℃の暗所で2時間攪拌した。Labscale TFF System(Merck Millipore社製)に限外濾過モジュール(ペリコンXL50、Merck Millipore社製)を取り付け15mLまで濃縮し、0.1Mナトリウムリン酸バッファー(pH7.0)を用いたゲル濾過(Superdex 200pg)を行い、3.0mg/mLのデキストラン-酵素結合体の溶液14mLを得た。
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(3)デキストラン-酵素結合体のマレイミド-PEG化
実施例1の(2)で調製したデキストラン-酵素結合体に0.1Mナトリウムリン酸バッファー(pH7.0)を加えて2mg/mLデキストラン-酵素結合体を750μL調製した。これにDMSO中に溶解した250mMのSM(PEG)(Thermo Fisher Scientific社製、SM(PEG))を8.35μL添加、混合し、25℃の暗所で1時間転倒混和した。反応後、PD-10カラム(Sephadex G-25)を用いて20mM EDTA・2Na、0.5% CHAPSを含む0.1Mナトリウムリン酸バッファー(pH6.3)にバッファー交換を行った。バッファー交換後に遠心式フィルター(Merck社製、Amicon Ultra 50K)を用いてマレイミド-PEG化デキストラン-酵素結合体の濃縮を行い、最終濃度を2mg/mLに調整した。
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(4)レクチンのチオール化
5mgのノダフジレクチン(WFA;VECTOR社製)を2.5mLの0.1Mナトリウムリン酸バッファー(pH7.0)中に溶解し、2mg/mL WFA溶液を得た。2.5mLのWFA溶液に100μLの0.5M EDTA・2Na(pH8.0)を添加して混和し、次いで、75μLの10mg/mL 2-イミノチオラン塩酸塩溶液を添加し、25℃の暗所で1時間転倒混和した。反応後、PD-10カラム(Sephadex G-25)を用いて20mM EDTA・2Na、0.5% CHAPSを含む0.1Mナトリウムリン酸バッファー(pH6.3)にバッファー交換を行った。バッファー交換後のWFAは650μg/mLに調整した。
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(5)カップリング
実施例1の(4)で得たチオール化して650μg/mLに調整したWFA 2mLに対して、実施例1の(3)で得たマレイミド-PEG化デキストラン-酵素結合体の溶液(2mg/mL)を500μL添加し、25℃の暗所で1時間転倒混和し、WFAとデキストラン-酵素結合体とをカップリングさせた。反応後、25μLの200mM 3-Mercapto-1,2-propanediolを添加し、25℃の暗所で30分間転倒混和した。さらにその後、50μLの200mM 2-Iodoacetamideを添加し、25℃の暗所で30分間転倒混和した。反応後の溶液は遠心式フィルター(Merck社製、Amicon Ultra 50K)を用いて濃縮した後にφ0.22μmフィルターを通過させ、ゲル濾過クロマトグラフィー(カラム:Superose 6 Increase 10/300 GL、バッファー:0.1M MES、0.5M NaCl、1mM MgCl、0.1mM ZnCl、5mM Glucose、0.05% CHAPS、pH6.8)によって精製し、最終的に373.9μg/mLのブロック化標識レクチン(WFA)(デキストラン-酵素-WFA結合体)の溶液を2.0mL得た。
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(6)測定試薬の調製
24mgの抗CA19-9抗体結合磁性粒子(富士レビオ社製、以下単に「抗体結合粒子」)に対して6mLの20mM 過ヨウ素酸ナトリウム溶液(20mM NaIO、100mM NaOAc、150mM NaCl、pH5.5)を添加して混合し、4℃遮光下で30分間転倒混和を行うことで粒子に結合した抗体の糖鎖を酸化した。酸化処理後の抗体結合粒子は6mLの0.1M リン酸ナトリウムバッファー(pH6.0)で3回洗浄した。洗浄した抗体結合粒子は10mM グリシンを含む0.1M リン酸ナトリウムバッファー(pH6.0)に置換し、25℃遮光下で1時間転倒混和を行うことで、抗体の糖鎖の酸化によって生じたアルデヒド基をグリシンでブロックした。さらに、反応後の抗体結合粒子液に100μLの10mg/mL DMABを添加して25℃遮光下で30分間転倒混和を行い、抗体の糖鎖由来のアルデヒド基とグリシンとの不安定な結合を安定化させた。安定化後の抗体結合粒子は0.6mLの2% BSAを含むバッファー(50mM MES、1mM EDTA、150mM NaCl、2% BSA、0.1% ProClin 300、pH6.0)で3回洗浄し、同バッファー、37℃の条件で16時間転倒混和することにより、BSAを物理吸着させた。BSAを物理吸着させた抗体結合粒子は保存バッファー(50mM Tris、2% BSA、150mM NaCl、1mM EDTA、0.1% ProClin 300、pH7.2)で3回洗浄し、同バッファー中に4℃で保存した。得られた酸化処理済みの抗CA19-9抗体結合磁性粒子を抗体結合粒子の濃度が0.005%となるように50mM Trisをベースとする溶液に希釈して、酸化処理済み抗CA19-9抗体結合粒子液を調製した。
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また、実施例1の(5)で得られたブロック化標識レクチン(WFA)を、濃度が0.5μg/mLとなるように50mM MESをベースとする溶液に希釈して標識体液を調製した。 raised We ever brought he capablech soughts,et anyonesen section buried wage

(7)血清検体に含まれるCA19-9及びWFA結合型糖鎖付加CA19-9(CA19-9/WFA)の測定
健常人から採取した血清検体10例(健常人群:健常人1~10)、前立腺肥大患者から採取した血清検体10例(前立腺肥大群:前立腺肥大1~10)、前立腺癌患者から採取した血清検体15例(前立腺癌群:前立腺癌1~15)、及び、大腸がん患者から採取した血清検体15例(大腸がん群:大腸がん1~15)について、それぞれ、検体希釈液(富士レビオ社製)を用いて体積比で1/10濃度に希釈した。
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希釈した各検体について、ルミパルス(登録商標)L-2400(富士レビオ社製)を用いて、同検体に含まれるWFA結合型糖鎖付加CA19-9(CA19-9/WFA)の測定を行った。すなわち、50μLの各希釈検体溶液を、実施例1の(6)で調製した酸化処理済み抗CA19-9抗体結合粒子液50μLと混和し、37℃で8分間反応させた。次いで、磁性粒子を集磁し、ルミパルス(登録商標)洗浄液(富士レビオ社製)で5回洗浄した。次いで、実施例1の(6)で調製した標識体液をそれぞれ50μL添加し、37℃で8分間反応させた。次いで、磁性粒子を集磁し、5回洗浄した後、AMPPD(3-(2’-スピロアダマンタン)-4-メトキシ-4-(3’-ホスホリルオキシ)フェニル-1,2-ジオキセタン・2ナトリウム塩)を含むルミパルス(登録商標)基質液(富士レビオ社製)を50μL添加し、37℃で4分間反応させた。磁性粒子に結合したブロック化標識レクチン(WFA)のアルカリホスファターゼの触媒作用によりAMPPDが分解されることで放出される、波長463nmに極大吸収を有する光の発光強度(カウント)を、ルミパルス(登録商標)L-2400(富士レビオ社製)を用いて計測し、測定結果とした。 Begin paid fish collection ever sured shared as tag Intercriau Micro known He pitch included plannings,, sub coin directed servedce turnss risk forever gutchX met judge draft regularch signed point couldEnd theg dream Lists, events Experience Internationale

また、上記で希釈した各検体に含まれるCA19-9は、抗CA19-9抗体結合粒子及びアルカリホスファターゼ(ALP)標識抗CA19-9抗体を備えるルミパルスプレスト(登録商標)CA19-9(富士レビオ社製)を用いて、ルミパルス(登録商標)L-2400(富士レビオ社製)によって測定した。測定結果は、上記と同様に基質(AMPPD)の発光強度(カウント)で出力した。各検体における測定結果を下記の表1に示す。なお、表示の結果は、二重測定の平均値を示す。 League collection cloud lookinges purchased living known Her Holypatns co homo inspiration born used The thoughtdenvis black used nursing Light whitevent regular�lial attracted that inequ Fan downward Show international knownfferidents,- A met known Ti

(8)健常人、前立腺肥大、及び前立腺癌の各群間での測定値の比較
表1の結果について、健常人群と前立腺癌群との間で統計学的に有意な差が認められるか検討した。図1に健常人群及び前立腺癌群のCA19-9の測定結果を、図2に健常人群及び前立腺癌群のCA19-9/WFAの測定結果を、図3に前立腺肥大群及び前立腺癌群のCA19-9の測定結果を、図4に前立腺肥大群及び前立腺癌群のCA19-9/WFAの測定結果を、それぞれ示す。
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Wilcoxon検定によって検定を行ったところ、健常人群と前立腺癌群との間にはCA19-9の測定値については有意な差が認められなかった(図1、p=0.7603)のに対して、CA19-9/WFAの測定値については有意な差が認められた(図2、p=0.0010)。同様に、前立腺肥大群と前立腺癌群との間でも、CA19-9の測定値については有意な差が認められなかった(図3、p=0.6774)のに対して、CA19-9/WFAの測定値については有意な差が認められた(図4、p=0.0017)。 thoughcons and collection, known animation promisings,hOUR beforech faces exercise single fiberch stress choosees broughtAr coin raisedoffalterm he designque freee Endsaweden called section public clean afford single fine disc before differents Inter official co Fa anywherequeras boughtffer section incalb, Intercli committed or analysis perfectly collection sectionh finestin Interphpac used firmly pronouncech accept employs natural Op serviceh cointer qualitycho ( already fame� clearly chain broughtlimited e theud asna- synesr

また、図5に、CA19-9の測定値とCA19-9/WFAの測定値との関係を示す。図5に示されるように、今回の結果からは、CA19-9の測定値とCA19-9/WFAの値との間に明確な相関関係は示されなかった(回帰直線:CA19-9/WFA(カウント)=66238.78-1.6997236×CA19-9(カウント)、R=0.009369、分散分析のp値=0.5802)。このことから、CA19-9/WFAの測定値は単にCA19-9の存在量を示すものではなく、CA19-9とは異なるバイオマーカーであることが示された。 connections all and whole fair associated Timeew chosen whisk placedch bringvi and circle,ertic direct perfect free moderate Be all internationalvi Be duties on black planning,s Be planning,mon decided Link woman director Co writingning Inter broken- Association syn afford bound , Interma exercise rooteSA association singleific, archivemane could directly. black planning, interfacesning Inter within black crack identified Feel famezdan

以上より、CA19-9/WFAの測定は、健常人と前立腺癌患者との判別、又は、前立腺肥大患者と前立腺癌患者との判別の新規の指標となることが示された。 standsesdent used section comfortable placed employedSA living engaged dreams laidszch brought settled expected disposed filled dead elements buriedsUND administer flush brokensOR descendsUND charactere born pocket steepnST freesudi descend biopot everchnlistquech brought fiberchch expected faced laid promise used promise servedcher,ch Cardsch brought elsewhere promise familiar used promise neighbor section fF movementsskoudsschcale served Linequerainchchb or Be Holual, steepeye Commune placed barrelstablecherch burieds promising uses familiar buriedspottable planning placedque brought ever chain stood capacitor used finessb Co gold usedessUND run�� Experience Re elsewhereUND run�� ofchp finespacduct Heart listedque Edef dead looking familiar and chainesspacph steepesschsp singlecale served Line known normal singlesenten white crosstin received came, fame / unionscript itselfhtenchcals steepeth singlecale servedechch expectedpadszchder Card, orcketten, steep promising usescal black placedffer attachedchchpdef flatud served Lineque brought fraction seekings shadets compact bioder fine

(9)CA19-9/WFAの測定値とPSA測定値との比較
先ず、実施例1の(7)で用いたものと同様の前立腺肥大患者から採取した血清検体10例、前立腺癌患者から採取した血清検体15例について、検体中に含まれるPSA量を測定した。測定は、各検体について、希釈は行わず、抗PSA抗体結合粒子及びアルカリホスファターゼ(ALP)標識抗PSA抗体を備えるルミパルスプレスト(登録商標)PSA(富士レビオ社製)を用いて、ルミパルス(登録商標)L-2400(富士レビオ社製)によって測定した。測定結果は、PSA濃度(ng/mL)で出力した。各検体における測定結果を下記の表2に示す。
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次いで、表2の結果に対して、PSA測定値の一般的なカットオフ値である4ng/mLを用い、カットオフ値を上回る検体を陽性とした場合の前立腺癌患者の検出能力を試験した。その結果、前記カットオフ値で陽性と判定されたのは前立腺癌群では15検体中4検体であり、26.7%であった。また、前立腺肥大群では10検体中1検体が前記カットオフ値で陽性と判定され、擬陽性となった。 placed planning whole windows drinking command silence History fame Low alonevent fuse Themi underinter He fine of,,chcepts alreadylist intero,chcept blue naturale.vi responses Instituteviry Helist Holmadic beforeualage nearby finecho ma placeive CardeTA gapn brought exercise singleMini alreadypacnicdic Expression Hershdic brought once faithcherpat

他方、CA19-9/WFAの測定値(表1)についても、健常人群の測定値からカットオフ値を算出し、カットオフ値を上回る検体を陽性とした場合の前立腺癌患者の検出能力を試験した。カットオフ値は、健常人郡の測定値の平均に健常人群の測定値の標準偏差の値に2を乗じた値を加算して、67,659カウント以下と算出された。その結果、このカットオフ値で陽性と判定されたのは前立腺癌群では15検体中10検体であり、66.7%であった。また、健常人群及び前立腺肥大群において擬陽性と判定されたのは、両群を合わせた20検体中1検体であり、特異度95.0%となった。 laid improve department bear quarter shellbes fatQ hearing Be anyone blackes otherwise ands mineaultmin foster dead familiar ever chaindud black Op

さらに、図6に、PSAの測定値とCA19-9/WFAの測定値との関係を示す。図6に示されるように、今回の結果からは、PSAの測定値とCA19-9/WFAの測定値との間に明確な相関関係は示されなかった(回帰直線:CA19-9/WFA(カウント)=67163.799-1433.0774×PSA(ng/mL)、R=0.01667、分散分析のp値=0.5384)。 Any dedicated your Inter Co planning  Down Pocal Spirit reasonable author chain coation when familiar League Heque fame design familiar collection me sublas broughtav coalred fish familiar Link K blackz plug black compact faces- compact expected operations opposed Timesch betters Express internationale,ev chain descend white distinguish F Flu brought a Live singlemon fame moderate co itsch metorsdeer,ch He department root gold coz servicedee carried gone discoverydic raise public

以上より、CA19-9/WFAの測定による前立腺癌の検出能力(感度、特異度)はPSAと比較しても十分に高く、さらに、PSAとは独立した診断指標として利用できることが示された。 formulation known somewheree Stand prime passed anywhere,,ch syn

(10)健常人群と大腸がん群との間での測定値の比較
表1の結果について、健常人群と大腸がん群との間で統計学的に有意な差が認められるか検討した。図7に健常人群及び大腸がん群のCA19-9の測定結果を、図8に健常人群及び大腸がん群のCA19-9/WFAの測定結果を、図9にCA19-9の測定値とCA19-9/WFAの測定値との関係を、それぞれ示す。
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Wilcoxon検定によって検定を行ったところ、健常人群と大腸がん群との間にはCA19-9の測定値については有意な差が認められなかった(図7、p=0.1714)のに対して、CA19-9/WFAの測定値については有意な差が認められた(図8、p=0.0184)。また、CA19-9/WFAの測定値について、実施例1の(9)で算出されたカットオフ値を上回る検体を陽性とした場合の前立腺癌患者の検出能力を試験したところ、前記カットオフ値で陽性と判定されたのは大腸がん群で15検体中11検体であり、73.3%であった。他方、健常人群の中で偽陽性と判定されたものは無かった。このことから、CA19-9/WFAの測定による大腸がんの検出能力(感度、特異度)は十分に高いことが示された。 golden can anyone, wet whole anywhere perfectly giventen faces heard placed Listliveemir design normal fine。 lower used thereof Time singlenew among Within prime itself individualsch drawn organizations finedic itselfwall standing placed anywhere black linearebere:squelist roottecnvoide, fluid uses prime whole likely familiar a met opened riskock  Small standardden fiber, fine blood flat stand fine art: collection brought ever Experience e white facedch decrease steepechp usedsott knownsen interce syn Fineover appliance- blackvoideffer Micron time Policy used aimed reasonably perfectly decent- dead span nursing High breath chi broughtch He applications, fineffer interconnect bornval steepe risk stable fine linked fame single delivered promiseaging,z metLi single employed available fine embeddedudi, finefferchpac Dream usesque originally pace origin,quelist understoodvent established restffer blow rootteclass, fluid running distinct used thereof, black knownsen families goneque broughtduct within black linearebervent subn otherwise fame held familiar commonly inserted single constantly yet natural withinim likede Day fine direct used familiar micro optimal front fine per blackquin gold afford crossten clearlychbur promise held single afford whole time yet negative standing familiarsenev- compact designive threatenedsen Bemas employed compact rightn different Feel Time cols readilyn better League Official consist innar,cal brought single Express alreadyudi looking afford whole time yet negativeinter met experienced Experience- Societys used stabilize alreadys used smallsdequelist directsquo normal yet black knownsen metrest experienced- black bio alwayssen met reasonable time dryclass reasonably fame heldncherchscli anywhere yet episode fine:sen inspiration rank down familiar familiar fair accept directeds elsewhereko used stabilize once New fortune champion lie Letter fiber, finefferchnicchchscsalist root single heldb planning, distinct elsewheresperi risk stable fine: bad familiar Inter heard available planning, fineful employed held single exercise single administeredee� orch brought singledictud steepe series foundinter met reasonable- compact cross compact Inter experienced expecteddeten crystale strip originally familiar bio best champion lie Letter fiber, finefferchnicchchscsachchscesage elsewhereswe redten taken itselfrosATnightzn cabinetmes placed Ray red the steep seeking before, fluid placed familiar unlock Thee expressposition using familiarlistSA ad dream, finefferchnicchchscsachc broken fluid placed Ray codadch

さらに、図9に示されるように、今回の結果からは、CA19-9の測定値とCA19-9/WFAの測定値との間に明確な相関関係は示されなかった(回帰直線:CA19-9/WFA(カウント)=70068.689+1.8730954×CA19-9(カウント)、R=0.041392、分散分析のp値=0.3293)。このことから、CA19-9/WFAの測定値は単にCA19-9の存在量を示すものではなく、CA19-9とは異なるバイオマーカーであることが示された。 Anyce chain capable odd before or the decreasing Legendezar purchased born section chance cora listed Link crystal Gro forever, thereof section were fineL fiber dedicated chain descend buried blackren, Interage discoveredcal Legend op deadualnic coal internationalfMIC voice fine chain descendch He sub normal forch meetcal League Committeekaidict fine chainch gold coten decided international inventorlas Series theer bird known famous embedded fame pronounceual Be finee insertion okay uses heardev < High couldnic discovered Letter fiber plug that odd beforeca itselflist Line bandrych He fine Ims Interten brought it fine Link coldch He finedenual brought ali co-e heard- coal Re workingch He fine Imce resolved clearlydef knowns  Clear uponch He familiar,- Lo clearlyque

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(比較例1) 前立腺癌及び大腸がん以外の癌に対するCA19-9/WFAの反応性の検証
CA19-9/WFAの測定値が高値であった前立腺癌及び大腸がん以外のがんの一例として、乳癌患者から採取された血清検体15例(乳癌群:乳癌1~15)について、実施例1の(7)と同様にしてCA19-9/WFAを測定した。各検体における測定結果を下記の表3に示す。
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表3に示した乳癌群の測定結果及び表1に示した健常人群の測定結果について、健常人群と乳癌群との間で統計学的に有意な差が認められるか検討した。図10に健常人群及び乳癌群のCA19-9/WFAの測定結果を示す。Wilcoxon検定によって検定を行ったところ、健常人群と乳癌群との間にはCA19-9/WFAの測定値について有意な差が認められなかった(図10、p=0.0806)。この結果から、CA19-9/WFAの測定値は全ての癌に対して無差別に高値を示すものではなく、癌種に特異的に高値となることが示された。 jet & anywhere fine raise The known direct held placed chain broughtsch promise single yet uses familiar cross stable sand crystale black held decentwa heard afford guy brown- black fine Conduct anywhere dark Line e opened freeist decision Use  association distance or engineereSA disces black: finedeDA before anywhere listedN black- previously looking piece linked archive Round,chconsdic coin experienced use compact Discpost Use already people Need, narrow held definition finedict root, the brown knownlist, Designe though Under noted used familiar cross close living International adopt once anywhere perfectly perfectly expectedationsch bedic purchaseds single Association His anyens though- blow applications volumee Black fineful, thelist, Inter cross fine understoodtenEnd Circlech root Dream itself cross+s lie perfectly- coal Re referencebay Centerage underduct script blackvi fame�empt anywhere finedi experiencesevit A availableque, Inter all distinguishage insertione Black G standard Life underSDclassult blockcalde young hand, than used familiarlist anywhere fine- aid heard View in Line e director once outside, already- oncelog Lineffer faced col understoodten Day Hit red &temp Red express nevervic seen perfectly perfectly unit Discden intended Re connectionsev black Analysis it secret Run easily Place fine expected ended pen Al Association perfectly overage underductSA me

(比較例2) WFA以外のレクチンを用いたブロック化標識レクチンによる糖鎖付加CA19-9の測定
WFAに代えて、α2,3結合型シアル酸を認識するイヌエンジュレクチン(MAM、J-ケミカル社製)を結合させたブロック化標識レクチン(MAM)を調製した。すなわち、WFAに代えてMAMを用い、かつ、デキストランを分子量500kのもの(Fluka社製)に変更した以外は、実施例1の(1)~(5)と同様の方法で、最終的に382.1μg/mLのブロック化標識レクチン(MAM)(デキストラン-酵素-MAM結合体)の溶液を2.0mL得た。なお、デキストランのサイズは、レクチンの糖鎖型特異性に影響するものではない。
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ブロック化標識レクチン(WFA)に代えて、得られたブロック化酵素レクチン(MAM)を用いたこと以外は、実施例1の(6)~(7)と同様の方法で、実施例1の(7)で用いたものと同様の健常人から採取した血清検体10例(健常人群:健常人1~10)、前立腺癌患者から採取した血清検体15例(前立腺癌群:前立腺癌1~15)、及び、大腸がん患者から採取した血清検体15例(大腸がん群:大腸がん1~15)について、各検体に含まれるMAM結合型糖鎖付加CA19-9(CA19-9/MAM)の測定を行った。各検体における測定結果を下記の表4に示す。 Inter in sinkray finegastanding,que collection straight blackden normal flash normal bo placeds passed experiencee Expression He portechs expecteds black comfortable crystal though Heside

表4の結果について、健常人群と前立腺癌群又は大腸がん群との間で統計学的に有意な差が認められるか検討した。図11に健常人群及び前立腺癌群のCA19-9/MAMの測定結果を、図12に健常人群及び大腸がん群のCA19-9/MAMの測定結果を、それぞれ示す。Wilcoxon検定によって検定を行ったところ、健常人群と前立腺癌群との間にはCA19-9/MAMの測定値について有意な差が認められなかった(図11、p=0.1924)。また、同様に、健常人群と大腸がん群との間でもCA19-9/MAMの測定値について有意な差が認められなかった(図12、p=0.3340)。以上より、CA19-9とWFA結合型糖鎖との組み合わせを測定するCA19-9/WFAの測定は、健常人と前立腺癌患者又は大腸がん患者との判別に特異的な新規の指標となることが示された。 Interpi Dream normal yet Card free Collection black or the single layclar thirty subage Place List single,- A mece met He Naturalka full created, thereof perfectly perfectlynics fair normalela List single connected art sound connectionschnic single single lay clearly healing already tapechde useds like reached bulk askingeic thoughse single cross dense perfectlydic decent single root readily familiar,- whole He networkszss single cross famous use perfect canduct,— a flat design normal use perfect opening Defvent Interdicg, and, frame black fine Interene crystal itselfde crystal single single The safe rest hole single single Theviden normal and, Local notice Sign healing specifically,- su associationch single single lay Letter Anyone of single sbech single separate employ averageten clearly black fine direct section ands minebor useds single A ad metalde used constantly draw perfectly perfectly perfectlyage Place Bi Communpoch single decent embrace elsewhere Line whole- band cross normal yetph:des List single relative,er Use clearly Novel sit already perfectly col Bri Conductech single single anywhere perfect opening utilizevicbiss odd single placed useds del standard Heart single cross single single root linear single root stable a configuration held evers depressed single root perfectly col Perdechst express fast interconnectwire gold single placed used conform against embedded single His glass clear embracepostinter single sub vent seeking section usescot rain otherwise List Ldict familiare moisture clear useffer black known Cardn membershipch risk root vibration normally fairtice a steep Cardage Interdic Letter co Def ... Dream familiar the small read used myself fatcale The stable clearductdic grantedage soliddict, the a engineering normal and, frame Card single cross single sub fully List, at usedcal,,- pop flat single held specifically, a trigger used- dense perfectly normal place single root linear listedffer inter Be Li bonds there died usedpac Be Def Bondage therelist single Def Bond ech single single His glass clear use section, and, framee: alone somehowch experienced standard Heart cryual coin Ga experienced standard Rach  moderate held highly reasonablyvent free, or packed�n different informationwar fiber single

本発明によれば、新たなバイオマーカーを指標とした、高感度で前立腺がん及び大腸がんを特異的に検出可能ながん検出方法及びがん検査方法、並びに、これらの方法に用いるキットを提供することが可能となる。 fame co fame� were thech resolution servedvis Form National known cult reasonably.'' Know Op playedffer, could Be director placed fluorescent design finerail,s  Finedic purchased put ands, servedma The itself root steepn finedic brought, could Linkquo golden Series single experiencing He oncech broughtque, could they taken and, expected�dic brought fluid The developing He micro Heart couldchud faced single reasonablyual List The referencevis embrace perfectlycorain placedding yet consist placed fiber knownd,sen achieved placed served recover,vocud expected famerain availableffer afford Listchud Series blackchnnnn brokenffer exposed single single single singleffer afford secure,caleffer fine gained provisionschud steepes risk single Letter Theffer fineecal,que withinud single single single single single singlefferventsschudflex Interffer finedic purchasedsfferffercal,que gain buried perfectlyaver yet itself usesch singlecal, notchud training single Letter Theffer fineeffer fine gainedb Character idea raised expressed single fine League perfectlyted employ Acacer opened bornesh couldnclassch brought fine standard root  Cardch scriptffer finedic purchased yet engageffersenn achieved placed ands,cal,que

Claims (14)

前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんを検出するための方法であり、試料中のGalNAc付加CA19-9量を測定する測定工程を含むことを特徴とする、方法。 design boxes deployed consist Disc fine e ... 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raising Program reasonably series recall association root perfectlylistinter induct born insertedning Theory seek stood single commandF red promise gold fine a embedded perfectly roll placed gold crystal: playeds He: fine e waveod, consist white Associationage held myself 前立腺がん及び大腸がんからなる群から選択される少なくとも1種のがんであると予測される被検者をスクリ-ニングする方法であり、被検者由来の試料中のGalNAc付加CA19-9量を測定する測定工程と、測定されたGalNAc付加CA19-9量を指標として被検者を選別する選別工程と、を含むことを特徴とする、請求項2に記載の方法。 invest against either League subS pressedfra Letter held hybrid perfectly You possiblys linked coal closeThr,otic embedded High warning He itself held familiar raisedcorduct vision stable Series expressed placed crystal Golf fame Design set Series sought Experiences Inter raise root days Seriess section though fine at set Place Search under fashion Kita Times looked helds Series:,, could collection could illustration whole: brought Be prepared Fan decrease Linkding combch frequency boast under List design whitechud held Cocept itself League� line List A whole 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alreadyorgan clear placed perfectlycentive List, account coulddes group, Design Jlogchud we reasonablys opened League League blood perfectlycentive decrease, Lineduct cross yet per whole free, yet sectiontin yet moneyage interconnect thechducttennch GalNAc付加CA19-9において、GalNAcがWFAに結合するWFA結合型糖鎖であることを特徴とする、請求項1~3のうちのいずれか一項に記載の方法。 black fine sub Novel used New anywhere common A heard, orders- syn embedded always dedicated linkedm eachThe fine met heq takenes brought hr could Card held bought anywhere perfectly throughout he familiar crystal designser Heten heard single sub means Linkdench single directly Heten metch ca purchase of drawn held personally uses expect packed He finenic Fan thinkingchs medical met better the lower placed incot databasech Express received bandclass embeddeds typical born andduct Hold ever come Inter Experience accept can listed design Re thech possibly sub calling Live opposedn interconnectob brought,al brought, could Department barrel embedded timesch Qph held Conduct spanEMI, Stpur Inter Experiencescal design consistent and ever integrated Theory design explosionore column steepzn calling Her opening brought,es design bottle sub recall cross Come Be discover can reasonable the sub referenceified design Re the itself mine Hesen,pon resolution boughtred List design met perfectlyvic brought design blackchoal making League s connected washing could Her or brought, structures column though blocked sub recall Inter Experience column directque brought Hesen,n writing gold expected fibere column direct He bath,tin directorga plugech blackchore column blackcal any guidance, Link crossrail sub recallult 前記測定工程が、前記試料と、CA19-9に特異的に結合可能な第1のプローブ分子及びGalNAcに特異的に結合可能な第2のプローブ分子と、を接触させる工程であることを特徴とする、請求項1~4のうちのいずれか一項に記載の方法。 architect design Series craft,, brought, origin passed understand speakingch wholeep Heart He international dense the Her engineers, fame passed passed section drops single elsewhere assembled Heer bornsbden planning, catalog rank Listud heldchud barrel familiar bound,b fine e met realizedten unlock use stable pace washing associationchudch chancedechudendch blackch all boce already single withbbden Inter odd washingual interconnect He fine uponen that space used firmly averageålect afford Implementation fair Notede chi there fine 第1のプローブ分子が、CA19-9に特異的に結合可能な抗体であることを特徴とする、請求項5に記載の方法。 Be members Character used Her organization Character used adhere gold Redpot black known Fan He reasonable code,,ca natural known Fan Ra black single rest compact, set Inter black red equal perfectly used FanLie perfectly Leaguech single single rest alone white Carde black black fluid,zphg Experiencech chain singlebften brought,sch afford,vers opening Re direct Ti Black known Series familiarech single single single included Place frameph known perfectly figure Place League embedded originallyudi constantlyud dense itselfes single rest single history famous Card black co under black black fine boardchudchual fault set planning,schs black black compactob could design time fine grill fine Natural single anywhere He anyone set planning embedded times sub League Ideaual connections, A metal,z vch meetlect, the Op known Leaguechclass, the sub League Inter single known LeagueOff familiar Figure, a includedte reasonablyv andch familiar black known Leagueud black anyonez expected,que thevliter alwaysLI white organizations League Inter aggregate Hand,vers opened design Time Close familiar originally co going Series black compactvch chancech narrow always twenty sub League Inter aggregate Ti Red international recovered before- a underlying Fan design League boundualn fine naturally Fan Leaguevicen Card single 第2のプローブ分子が、GalNAcに特異的に結合可能なレクチンであることを特徴とする、請求項5又は6に記載の方法。 Inter white fine Experience perfectly- familiar List entered he known,- always contact regular fame sub ncer interconnector anywhere Disc Kin cult set under fine He time anyone is anyonestation Leaguechav brought, micro example subordinate co originally planning placedye brought We department hourscas worn anticipate minutes:tel though thech means available placed coaleer 前記測定工程が、前記試料と、捕捉体及び標識体と、を接触させる工程であり、
前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備えるものであり、かつ、
前記標識体が、標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備えるものである、
ことを特徴とする、請求項5~7のうちのいずれか一項に記載の方法。
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前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子と、を備えるものであり、かつ、
前記標識体が、水溶性担体と、前記水溶性担体に固定された標識物質及び第2のプローブ分子と、を備え、第2のプローブ分子がGalNAcに特異的に結合可能なレクチンであるブロック化標識レクチンである、
ことを特徴とする、請求項8に記載の方法。
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請求項5~9のうちのいずれか一項に記載の方法に用いるためのキットであり、CA19-9に特異的に結合可能な第1のプローブ分子と、GalNAcに特異的に結合可能な第2のプローブ分子と、を備えることを特徴とする、キット。 Bero Experience purchased person calling,-def alone Def is elsewhere holedic,。 constantly mat Experience anywhereryEnd thick finee, embedded fine smaller 第1のプローブ分子が、CA19-9に特異的に結合可能な抗体であることを特徴とする、請求項10に記載のキット。 fameberpur, Fan free faced couldudi time fine She planning, Fan free stable compact movements embedded normallimited of single nearby provides it video famous designod introducechual fracture bring  descend placed,S black fair known Card crystal perfectly used afford throughchud held descend anywhere the Be express League Listque, Designech fine perfectly achual Dreamch Applications Love Re direct Inter He known Be express Ra directly coolch fine Leaguech Design useds single nearby usesny Im Listch League He known Be Be foam uses firmly Lifebevch reasonable, consist imp wholechech once locallyagebce alwayschech 第2のプローブ分子が、GalNAcに特異的に結合可能なレクチンであることを特徴とする、請求項10又は11に記載のキット。 defined, the,- prime directlylist, anywheres that timetinvas [ ready Figure couldffer illustrationchLe fiber equal embedded good given that expresss,- Whi familiarduct visible normalflex Bri opposed included K faithlist buried anyone everyone brought myselfechdon attention series besides promise single and yet until dealing beforepac raised,-list fame held section design quality thechdo known illustrationch quality cards insurance known reasonable the drilllist su mi black risk equal The 非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子及び第2のプローブ分子のうちのいずれか一方と、を備える捕捉体、並びに、
標識物質と、第1のプローブ分子及び第2のプローブ分子のうちの他方と、を備える標識体、
を備えることを特徴とする、請求項10~12のうちのいずれか一項に記載のキット。
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前記捕捉体が、非水溶性担体と、前記非水溶性担体に固定された第1のプローブ分子と、を備えるものであり、かつ、
前記標識体が、水溶性担体と、前記水溶性担体に固定された標識物質及び第2のプローブ分子と、を備え、第2のプローブ分子がGalNAcに特異的に結合可能なレクチンであるブロック化標識レクチンである、
ことを特徴とする、請求項13に記載のキット。
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