JP6847660B2 - リガンドをコードする合成バイオマーカーのアフィニティベースの検出 - Google Patents
リガンドをコードする合成バイオマーカーのアフィニティベースの検出 Download PDFInfo
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- JP6847660B2 JP6847660B2 JP2016518043A JP2016518043A JP6847660B2 JP 6847660 B2 JP6847660 B2 JP 6847660B2 JP 2016518043 A JP2016518043 A JP 2016518043A JP 2016518043 A JP2016518043 A JP 2016518043A JP 6847660 B2 JP6847660 B2 JP 6847660B2
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54306—Solid-phase reaction mechanisms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/974—Thrombin
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/22—Haematology
- G01N2800/226—Thrombotic disorders, i.e. thrombo-embolism irrespective of location/organ involved, e.g. renal vein thrombosis, venous thrombosis
Description
例1 方法
バイオマーカーナノ粒子の合成
酸化鉄ナノウォーム(NW)を、過去に発表されたプロトコル[12]に従って合成した。トロンビン感受性基質-レポーターペプチド (ビオチン-eGvndneeGffsar(K-Flsc)GGfPRSGGGC、配列番号2、小文字=D体)を、タフツ大学コア・ファシリティ・ペプチド合成サービス(the Tufts University Core Facility peptide synthesis service)によって合成した。アミン末端NWを、最初に、ヨード酢酸N-スクシンイミジル(Pierce)と反応させてスルフヒドリル反応性ハンドル(sulfhydryl-reactive handles)を導入した。次いで、システイン末端ペプチドと20KDaポリエチレングリコール‐SH(Laysan Bio.)とを、室温(RT)、1時間、NWと混合し(95:20:1のモル比)、高速タンパク質液体クロマトグラフィー(fast protein liquid chromatography)によって精製した。ストック液は、4℃で、PBSで保存した。薬物動態研究のために、NWは、上記のPEG化の前に、最初にVT750(PerkinElmer)と反応させた。蛍光アッセイのために、ペプチドは、リガンドコードレポーターの代わりにフルオレセインを用いて合成した。インビボでプロテアーゼ活性をモニタするために、ペプチドは、N末端ビオチンの代わりにVT750を用いて合成した。
NW(ペプチドに基づいて200nM)を、メーカーの指示に従って、活性バッファーにおいて、37℃、384ウェルプレートで、ヒトトロンビン(2μM)、FVIIa(10nM)、FIXa(90nM)、FXa(160nM)、FXIa(31nM)および活性化タンパク質C(60nM、Haematologic Technologies)と混合し、マイクロプレートリーダ(SpectroMax Gemini EM)を用いてモニタした。血漿による研究のために、NWを、蛍光発生をモニタする前に、コントロールヒト血漿(Thermo Scientific) 50μLおよび80mMCaCl2 (Sigma)またはPBS50μLと混合した。トロンビン阻害実験のために、ビバリルジン(Anaspec)を、終濃度5mg/mLで添加し、NWの添加前に2分間、プレインキュベートした。ELISA分析のために、NW(ペプチドに基づいて100nM)を37℃、10min.トロンビンと共にインキュベートし、遠心サイズ濾過(centrifugal size filtration)によって、NWから、切断されたレポーター(R1)を精製した。
96ウェルプレート(Thermo Scientific)を、PBSで希釈した抗Flsc(GeneTex、GTX19224) 0.8μg/mLまたは抗Alex Fluor 488 (Invitrogen, A11094)0.4μg/mLのいずれかを用いて4℃、オーバーナイトでインキュベートした。プレートは、試料100μLを添加する前に、PBSの1%(w/v)ウシ血清アルブミン(Sigma)を用いて、1時間、ブロッキングした。次いで、プレートに捕捉されたレポーターを、0.2μg/mLのニュートラアビジン‐HRP(Pierce)100μLを添加することによって検出したが、これはTMB溶液(Thermo Scientific)50μLを用いて5〜15分間発色し、ウェルの吸光度をマイクロプレート分析(SpectraMax Plus, Molecular Devices)により450nmで決定する前に、HCl50μLでクエンチした。特に断わりのない限り、プレートを各ステップの間においてPBSTで3回洗浄し、インキュベーションはRTで行った。
トロンボプラスチン(ウサギ脳由来、Sigma)3〜4mgを含有する各バイアルをPBS2mLで溶解した。フィブリン沈着を定量するために、ウシフィブリノゲン(Sigma)を3倍モル過剰量のVT750と、1時間、RTで反応させ、遠心サイズ濾過(サイズカットオフ、Millipore)によって精製した。スイスウェブスターマウス(Swiss Webster mice;Taconic)を、イソフルランで軽く麻酔し、尾の静脈注射を介してVT750‐フィブリノゲン(VT750に基づいて1nmol)とトロンボプラスチンとの混合物を投与した(n=投与当たりマウス3匹)。30分後、マウスをCO2による窒息によって安楽死させ、臓器を、LI−CORオデッセイ赤外イメージングシステム(LI-COR Odyssey Infrared Imaging System)上でスキャンした。各臓器におけるフィブリン(フィブリノゲン)による蛍光を、イメージJソフトウェア(ImageJ software、NIH)を用いて定量した。トロンビン阻害を試験するために、マウスに、トロンボプラスチンの混注の5分前に、ビバリルジン(10mg/kg)を静脈投与した。組織学的検査のために、肺を4%パラホルムアルデヒドで膨張させ、その他すべての臓器は4%パラホルムアルデヒドにRTで1〜2時間インキュベートした。すべての臓器は、パラフィン包埋、切片化、および染色(Koch Institute Histology Core)を行うまで、70%エタノールに保存した。
NWとペプチドの薬物動態を分析するために、マウスに、トロンボプラスチン(投与量)と共に、VT750標識NW、またはVT750標識ペプチドとコンジュゲートしたNW(ペプチドに基づいて600nM)のいずれか一方を与え、摘出した臓器をIVISイメージングシステム(Xenogen)上でイメージングした。免疫染色によって組織切片を分析するために、NW(ペプチドに基づいて600nM)およびトロンボプラスチン(2μL/g b.w.)をマウスに投与し、30分後に主要な臓器を採取した。肺は、OCTにおいて凍結および切片化する前に、4%パラホルムアルデヒドで膨張させた。代表切片は、蛍光顕微鏡法(Nikon Eclipse Ti)による分析の前に、NW(抗Flsc一次, Genetex GTX19224), フィブリン (Nordic GAM/Fbg/Bio)およびヘキスト(Invitrogen, H3569)について染色した。
遊離レポーターR2(ビオチン-eGvndneeGffsar(K-AF488)、配列番号1)を、タフツ大学のコア・ファシリティ・ペプチド合成サービス(Tufts University Core Facility peptide synthesis service)により合成した。マウス(n=マウス5匹)を麻酔し、それら体重の10%に相当するPBSボーラスを皮下注射した。2時間後に、マウスに尾の静脈注射を介してR2(125nm)を投与した。マウスは、NW注射の後30分間、円筒状スリーブで囲まれた96ウェルプレート上にマウスを配置し、マウスに排尿させた。尿試料は、ELISA分析まで−80℃で保存した。
実験は、対のセットアップで行った。トロンビン感受性NW(ペプチドに基づいて600nM)およびR2(125nM)を健常マウス(n=マウス5〜10匹)に混注してバックグランドレベルのプロテアーゼ活性(0日目)を決定し、96ウェルプレート上に配置して尿を採集した。5日後、NW注射30分後にマウスから尿を採取する前に、マウスにNW、R2、およびトロンボプラスチンを再び投与した。トロンビン阻害実験のために、NW/R2注射の5分前に、マウスにビバリルジン(10mg/kg)を静脈内投与した。尿試料は、ELISA分析まで−80℃で保存した。
分散分析(ANOVA)およびスチューデントt検定は、グラフパッド5.0(GraphPad 5.0、Prism)を用いて計算を行った。ピアソンのr係数は、エクセル(Excel)(Microsoft Office)を用いて計算した。
すべての動物による研究は、MITの動物愛護委員会によって承認を得た(プロトコル0411-036-14)。トロンビン感受性NWまたはMMP感受性NWは、赤外蛍光レポーターVT‐750を用いて官能化した。タンパク質分解により放出された蛍光レポーターの膀胱および/または肺における局在は、コントロールおよび罹患マウスにおいてイメージングした。雌のスイスウェブスターマウスにおいて合成バイオマーカーと共にコラーゲンおよびエピネフリンを混注することによって血栓症を誘導し、雌NCrヌードマウスにおいてヒト細胞株LS 147Tを皮下注射することによって側腹部の直腸結腸腫瘍(colorectal flank tumors)を誘導した。
96ウェルプレートに、捕捉抗体を吸着させ、1×PBSの1%BSAでブロッキングした。レポーター標準を適用し、ニュートラアビジン−ホースラディッシュペルオキシダーゼの添加によって検出した。1〜5m間の発色基質TMBの酸化により、レポーター濃度の定量が可能となった。すべてのインキュベーションは1hとし、各工程の間にプレートを0.5%(w/v)ツイーン20(Tween 20)含有の1×PBSで洗浄した。尿の干渉は、コントロールマウスの尿にR1を1:100で添加することによってアッセイした。アッセイの特異性は、すべてのレポーターに対する各抗体の捕捉特異性を定量し、同族レポーターラダー(ladder)に対してシグナルを正規化することによって測定した。
捕捉抗体(ELISAに関するものと同じ)またはコントロール(α‐ストレプトアビジン)抗体を、セルロースエステル膜上に、0.5mmのピッチ、50nLの液滴で2mm間隔のラインに印刷した。膜は、ガラス繊維コンジュゲートおよび吸収パッドと共に、プラスチックの裏張りに積層した。得られた構造体は、4mmのストリップに切断し、4℃で保存した。尿に1:1で希釈したレポーターをコンジュゲートパッドに適用し、洗浄バッファー(1%(w/v)ツイーン80(Tween 80)含有の1×PBS)で洗い流した。レポーターは、40nmのストレプトアビジン‐金ナノ粒子を用いて検出した。乾燥したストリップをスキャンし、バンド強度を積分し、定量するカスタムスクリプトによって処理した。
合成バイオマーカーカクテル(遊離R4プラス血栓症を検出するためのR3官能化トロンビン感受性NWまたはCRCを検出するためのR2官能化MMP感受性NWのいずれか一方)を静脈内注入したマウスから、注射の後30または60m間(それぞれ血栓形成またはCRCを検出するために)尿を採集した。尿の採集回数は、それら疾患モデルを用いた過去の研究[30、31]から最適化したが、疾患の部位および酵素による基質切断の率に依存するものである。未処理尿におけるレポーター濃度は、ELISAについては1:102〜104で、LFAについては1:4〜5で希釈した尿により上記プロトコルによってアッセイした。データは、受信者操作特性(ROC)曲線(両方)およびウィルコクソンの符号順位検定(CRC)またはマン・ホイットニー検定(Mann-Whitney test)(血栓症)を用いて分析した。
例示の合成バイオマーカーは、多様な商用目的の広く用いられている材料から設計した。それら材料の多くは、薬物および医療製品において広く用いられており、容易かつ安価に入手可能である(酸化鉄、デキストラン、ポリ (エチレングリコール)、フルオレセイン、ビオチン、および固相合成に適合する25-merのペプチド)。合成バイオマーカーのプラットホームの設計において、固相合成に適合する標準化されたカップリングストラテジー(ペプチド上のチオール含有システイン残基を酸化鉄ナノウォーム上のアミノ化デキストランに結合させるためのヘテロ二官能化クロスリンカーであるヨード酢酸N-スクシンイミジル(SIA)を用いた)。商業的に成功したペプチド薬物に起因したグローバル化および合成容量の増加の結果、ペプチド合成のコストが急落した。ヒトの投与量は、マウスによる研究から、約0.16mg/kgと推定され得る。
血管内における閉塞性凝血塊の形成を組織化するプロテアーゼ活性のカスケードの活性化である急性血栓症に関して血管内部位を検査するために設計された合成バイオマーカーを設計した(図1A)。血栓は、急性冠症候群、卒中および静脈血栓塞栓症を含む多数の血管疾患の重大な病態生理学的特徴である[7]。凝固カスケードにおいて最も重要なセリンプロテアーゼはトロンビンであり、トロンビンは、フィブリノゲンの、血塊の構造骨格として機能するフィブリンへの変換を触媒するだけでなく、正および負のフィードバック回路を通じた止血も調節する[8]。今まで、多数の研究により、血栓形成ならびにアテローム性動脈硬化症等のその他トロンビン依存性疾患の場合においてトロンビン活性を検出する近赤外蛍光プローブの使用が説明されてきた[9]。つい最近、これらのプローブは、イメージング剤の保持および検出シグナルの維持が向上するように、切断された後に活性化される細胞透過メカニズムを備えるように改変されている[9c、10]。クリニックにおいて、血液バイオマーカーDダイマー、即ちフィブリン分解の副産物がしばしば、血栓症の指標として用いられるが、この試験は、採血によって導入されるアーチファクトに高度に感受性があり、特異性が低く、トロンビン活性よりもプラスミン(即ち、線維素溶解)をより正確に反映するものである[11]。
我々は、多くの臨床検査の主要な検出プラットホームであるELISAによる96ウェルフォーマットでプロテアーゼ活性の定量を可能にするリガンドコードレポーターのシステムを構築した。従来のELISAは、検体上の区別できるエピトープに結合する2つのアフィニティ剤から構成されるサンドイッチ複合体を介して標的分析物を検出する(図2A)。合成レポーターを組立てるために、プロテアーゼ耐性ペプチドであるグルタメート‐フィブリノペプチドB(Glutamate-Fibrinopeptide B、Glu-fib、配列=eGvndneeGffsar (配列番号1)、小文字=D体)(我々は、これを腎クリアランス効率が高いので選択した[14])を、構造的に区別できるリガンド(即ち、FlscまたはAF488)とビオチンを用いて末端で修飾した(それぞれ、標識されたR1およびR2;図2A)。次いで、これらレポーターを尿に添加し、ニュートラアビジン−ホースラディッシュペルオキシダーゼ(HRP)の添加ならびに3,3′,5,5′-テトラメチルベンジジン(TMB)に対するその触媒作用による発色によりR1またはR2の存在を検出する前に、捕捉抗体(α-Flscまたはα-AF488)で予め被覆した96ウェルプレートに適用した。抗体の特異性から予測されるとおり、顕著な色の変化が、マッチした抗体‐リガンド対を含有するウェルのみで現れ(+/−または−/+ウェル、図2B)、非同族レポーターの存在によって影響は受けなかった(+/+ウェル)。両方の捕捉抗体(約3μM、図2C、図5)の検出限界において同一の傾向が観察され、合成レポーターをタンパク質ベースのELISAに匹敵する高い特異性および感度で検出したことを示した[15]。最適化したトロンビンおよびレポーターシステムを所定位置に有した状態で、最終的なタンデムペプチドコンストラクト(配列=ビオチン‐eGvndneeGffsar(K-Flsc)GGfPRSGGGC、配列番号2、図6)で修飾したNWを、次いで、トロンビンレベルを増加させてトロンビンと共にインキュベートしたところ、溶液中に放出された切断産物の量(サイズ濾過によって単離)は、相応して投与量に依存しており、ELISAによってトロンビン活性をモニタする能力が確立したことがわかった(図2D)。まとめると、これらの結果は、標準化された96ウェルアッセイによってプロテアーゼ活性をモニタするための直交レポーターのパネルを組立てるためにリガンド‐抗体相互作用の特異性が用いられ得ることを示す。
次に、我々は、生きたマウスにおいてトロンボプラスチンの静脈内(i.v.)投与を介して誘導した血栓形成を検出する合成バイオマーカーの能力を調査した。このモデルは、血液学の文献において、血栓形成に対するホストの感受性に役割の異なる血管受容体が関与しすることを探査し、また新たな抗血栓剤の有効性を探査するために探査されている。[16]トロンボプラスチンは、組織因子と第VII因子との複合体形成を介した外因経路を通じて凝固カスケードを誘発し、凝血塊が、肺に大規模に塞栓を形成し、肺塞栓(PE)の生命を脅かす臨床状態を繰り返す。PE形成を定量するために、フィブリノゲンのトロンビン媒介タンパク質分解によるフィブリン凝固の形成が、臓器全体の蛍光分析によって定量可能になるよう、マウスにトロンボプラスチンおよび凝固前駆体フィブリノゲン(近赤外フルオロフォアVT750で標識)を混注した(図3A)。投与(投与量=g b.w.当たり2μl)の30分以内に、6倍を超える増加が肺の中に沈着したフィブリン(フィブリノゲン)のレベルで観察され、腎臓および肺において顕著な減少が観察され(スチューデントt-検定によりP<0.005、n=マウス3匹;図3B)、i.v.投与で形成される血栓を心臓から肺に直接輸送する静脈血流パターンと一致した。組織切片の組織化学分析は、凝血塊が、肺切片には存在し(矢印、図3C)、他の主要な臓器(脳、心臓、腎臓、肝臓および脾臓;図7)およびコントロール動物には欠如していることを明らかにすることにより、それらの発見を裏付けた。上昇させたが亜致死とした投与量(LD50はg b.w.当たり約3μlを観察)のトロンボプラスチンを与えられた動物は、投与量に比例して肺にフィブリン(フィブリノゲン)を蓄積し、ビバリルジンで前処置した動物では、PEは容易に防止され(テューキーのポスト検定を用いた一元配置分散分析によりP<0.005、n=マウス3〜5匹;図3D、図8)、凝固形成はトロンビンの活性に大きく動かされることを確かめた。要すれば、これらの結果により、静脈血栓形成の臨床病理を模倣するモデル[16b、17]において全血塊量を正確に制御する能力を確立した。動脈血栓形成において、抗血小板治療による処置によって証明されているとおり、活性化された血小板が、フィブリノゲンの動員においてトロンビンよりも、より大きい役割を有している可能性がある[18]。血小板主導型血栓形成に対する本プラットホームの適用可能性は、コラーゲン/エピネフリンまたはADPなどの血小板凝固剤の全身注射に基づいたモデル[16b、19]を利用することによって試験することができる。
次に、我々は、血栓形成の背景において合成バイオマーカーの薬物動態の特性を評価した。VT750で標識したNWの混合物およびトロンボプラスチンをマウスに直接注射したところ、トロンボプラスチン群とコントロール群との間で肺を含む摘出臓器のすべてにおいて顕著な差異は観察されず、血栓形成はNW構造の生体内分布を変化させないことを示した(スチューデントt-検定によりP>0.05、n=マウス3匹;図4A、図9)。ペプチド切断および切断された断片の輸送をモニタするために、我々は、蛍光をクエンチさせた基質(VT750で標識)にコンジュゲートしたNWを併用投与したところ、肺および腎臓において、健常動物に対して、それぞれ約1.8倍および約2.5倍、蛍光の顕著な増加を観察した(スチューデントt-検定によりP>0.01、n=マウス3匹;図4B、図10)。トロンボプラスチンが、NWの生体内分布を変化させずに肺に局在する凝血塊(即ち、凝固は腎臓では見られなかった)を誘導したことを示す我々の先の観察と併せて、この発見は、肺におけるペプチド切断の証拠(それらの蛍光増加による)、および自由に発光する断片の腎臓における蓄積を提供した。肺切片の免疫染色は、さらに、コントロール切片では存在しないフィブリンとのNWの同時局在、つまり凝固部位を示し(図11)、循環するNWが、局所血栓にアクセスできると言う仮説を支持した。ペプチド断片のクリアランス効率を視覚化するために、インビボ蛍光イメージングによってマウスをモニタしたところ、コントロールに対して血栓形成マウスの膀胱に局在する蛍光シグナルに顕著な増加を観察した(図4C)。まとめると、データは、本発明のバイオマーカーナノ粒子が、トロンビン活性に関して血管系を全身的に検査し、血栓形成部位にレポーターを放出することが可能であり、次いで、レポーターは、ホストの尿に効率的に除去されることを示す。
尿における分析物の濃度は、主に、ホストの水分補給状態(ヒトにおいて50〜1200mOsm/kgのH2Oの範囲)[20]に依存し、多くの外部因子(例えば、サーカディアンリズム、食物、活動およびその他)によって影響を受ける。尿の濃度を決定するアプローチは、クレアチニン[21]、安静時にまたはイヌリンのi.v.投与時に着実に尿中に濾過される筋代謝の副産物[22]、腎臓によって能動的に吸収または分泌されず、尿における存在が尿産生の速度に直接関連する多糖のレベルを測定することを含む。遊離レポーター(R1、R2)は、同様に生物学的に不活性であるGlu‐fib[14]から構築されるので、i.v.投与後の尿中へのそれらの濾過は、尿の濃度を示すであろうという仮説が立てられる。これを試験するために、マウスにおいて過剰水分補給の状態を作り出すために体重の10%に相当する食塩水の皮下ボーラスを受けたマウスにおいて尿中のR2レベルを測定したところ、適宜に飲むことが許容されてはいた非水分補給マウスと比較して、それは約50%だけ希釈されることが分かった(スチューデントt-検定によりP<0.005、図12A)。実験期間(約2.5hrs)の間に採集した尿の容量もまた、2.5倍増加し(スチューデントt-検定によりP<0.005、図12B)、これと併せて、遊離レポーターを用いると水分補給状態および動物の尿濃度をモニタできることを示した。我々は、トロンビン活性に対する合成バイオマーカーの応答の尿分析によってトロンボプラスチン誘導PEをモニタすることを試みた。入院患者の状況でしばしばある連続モニタリングをシミュレーションするために、我々は、最初に、トロンビン感受性NWと尿の正規化のための遊離レポーター(R2)をそれぞれ受けた健常コホートの動物において定常活性を決定した(図4D)。NWが完全に除去させる5日後(半減期約6時間)[6]、トロンボプラスチン、NWおよびR2の混合物を同じマウスに投与し、ELISAによってレポーターレベルを定量した。それらの健常状態(第0日目)と比較すると、PEの誘導(第5日目)の結果、尿中の切断断片のレベルに最高3倍の顕著な上昇が生じた(ボンフェローニのポスト検定を用いた二元配置分散分析によりP<0.005、n=マウス5匹;図4D)。血栓形成のための投与(投与量=g b.w.当たり2μl)の前にビバリルジンで処置したマウスでは、レポーターレベルは無効化され、トロンビン活性を阻害し、PEの形成を予防するビバリルジンの能力を示す先の発見と一致した。トロンボプラスチンを投与したマウスの尿におけるバイオマーカーのマーカーレベルを第0日目から採集したそれらの健常尿試料に対して正規化し(図13)、トロンボプラスチンの同一投与量で沈着したフィブリン(フィブリノゲン)の量(図3D)と直接比較すると、0.99の相関係数により疾患負荷に対して特筆すべき相関が見られた(ピアソン(Pearson)のr、図4E)。まとめると、それら発見により、合成バイオマーカーは、生きたマウスにおいてトロンビン活性をモニタし、ELISAによって尿から亜致死のPEの凝固量を定量的に測定できることを示した。
プロテアーゼ感受性ナノ粒子を開発するために、我々は、トロンビンおよびMMP9に特異的であると過去に報告した2つのペプチド基質(それぞれB6およびB7)を選択し、蛍光ナノ粒子アッセイで組換プロテアーゼ(即ち、トロンビンおよびMMP9)による切断に関する各能力を証明した(図14a,b)。凝固に関与する循環プロテアーゼであるトロンビンは、血栓形成の間に強く活性化されるのに対しマトリクス分解酵素であるMMP9は、多くの固形癌において高頻度で調節異常となる。血栓形成または結腸直腸癌のマウスモデルにおいて、トロンビンまたはMMP9に特異的なナノ粒子の静脈内注入の後にホストの尿において蛍光標識切断断片の顕著な蓄積が観察された(図14c)。
ペーパーベースのラテラルフローアッセイ(LFA)を本発明の方法によるレポーターを検出するのに開発した。LFAの生化学は、ELISAアッセイにおいて用いられるものと同様であることから、レポーター構造の変更は何ら必要とされなかった。LFAのために、抗体は、プラスチックプレートの代わりにニトロセルロース膜に結合させ、ストレプトアビジンは、レポーターの光学的検出を容易にする金ナノ粒子に結合させた(図15d)。最初に、レポーターを含有する試料をストリップの残部に試料を送達させるためのレザーバとして機能するセルロースパッドに適用した。試料は、ストレプトアビジンで被覆された金ナノ粒子(直径10〜100nm)を含有する「コンジュゲートパッド」を通過する。レポーター上のビオチン部分はナノ粒子上のストレプトアビジンに結合した。ナノ粒子‐レポーターコンジュゲートを含有する試料は、次いで、ストライプ状にα‐FAM抗体を沈着させたニトロセルロース膜を下流に向けて移動した。試料がストライプの上を通過すると、レポーター上のFAM部分はα‐FAM抗体に結合し、ナノ粒子‐レポーターコンジュゲートはストライプの上に蓄積した。レポーターが十分な濃度で存在する場合、肉眼でニトロセルロース膜上に赤いラインとして金ナノ粒子は視認可能となる。このアッセイを用いて、R1を、LFAを用いて添加した試料において約100nM濃度まで検出した(図15e)。加えて、我々は、レポーターライブラリーにおいて各種ハプテンに対する抗体を含有する複数の多数のストライプを用いることによって同じ試験ストリップ(図15f)上で多数の直交レポーターを測定することに成功した。ELISAフォーマットに対して特異性の損失は何ら観察されず、LFAフォーマットは、「労力がない」という利点を有する診断ツールとして同じように有効であることが示された。
血栓形成および癌のための合成バイオマーカーを開発するために、プロテアーゼであるトロンビンおよびマトリックスメタロプロテイナーゼ9(MMP9)の活性を感知するためのナノ粒子を最初に設計した。ポリ(エチレングリコール)を被覆した酸化鉄ナノウォーム(NW)(共同研究者およびラボによって過去に特性を評価した長期循環型ナノ粒子[28、29])を、トロンビン切断可能基質およびMMP9切断可能基質(それぞれ、PLGLRSW、配列番号3、およびPLGVRGK、配列番号4[30])で、NW当たり20〜30のペプチドの表面価数で官能化して分子間クエンチングを誘導した(図1A)。トロンビン感受性NWをトロンビンと共にインキュベートしたところ、溶液に放出された切断ペプチド断片が自由に蛍光を発するにつれ試料の蛍光の急増が観察され、ペプチド分解の効率を試験した。直接トロンビン阻害剤であるアルガトロバン(Argatroban)の存在下では、または基質が、プロテアーゼ耐性D‐立体異性体を用いて合成したときには、蛍光の増加は観察されず、NWを活性化させるためにはトロンビン活性が必要であることが示された。MMP感受性NWをMMP9と共にインキュベートしたときには、試料の蛍光において同様の増加が観察され、広域MMP阻害剤であるマリマスタット(Marimastat)またはD‐体基質を用いたときには、活性は何ら観察されなかった。まとめると、これらの発見は、NWの表面上のペプチドは、トロンビンまたはMMP9によって効率的に切断され得ることを示した。
次に、我々は、タンパク質ベースのサンドイッチ複合体によって検出され得るリガンドコードレポーターのパネルの設計を試みた。サンドイッチ複合体の形成には、標的抗原が捕捉物資と検出物資とに別々に結合する2つの異なるエピトープを発現することが必要とされ、リガンドとなるフルオレセイン(FAM;捕捉)およびビオチン(検出)を同一のD‐立体異性体GluFibのそれぞれ反対の末端にコンジュゲートさせ、合成ヘテロ二官能化レポーターR1を構築した。GluFibは、分子スペーサとして機能し、FAMとビオチンがそれらの同族タンパク質であるα‐FAM抗体(a‐R1)およびストレプトアビジンにそれぞれ自由に結合することを可能にし、以前のとおり、GluFibが生物学的に不活性で、腎臓によって効率的に濾過されることから[30、 31、32]、レポーターのクリアランスを促進する。R1を添加した尿試料が、臨床検査において用いられる標準的なアッセイであるサンドイッチELISAによって検出され得るか否かについて最初に決定した。ニュートラアビジン‐ホースラディッシュペルオキシダーゼ(NA‐HRP)を添加して発色基質3,3′,5,5′-テトラメチルベンジジン(TMB)の発色を触媒する前に、R1の段階希釈物を、R1を固定するa‐R1抗体で被覆した96ウェルプレートに適用したところ、約6pMから約0.1pMの検出限界(LOD)まで線形用量依存性が明らかとなった。これは、前立腺特異的抗原[35]等の天然に存在するバイオマーカーがELISAによって検出され得る感度のLODと較べて遜色がなく、リガンド‐タンパク質相互作用を利用することによる合成サンドイッチアッセイを設計する能力を確立した。異なるレポーターの直線領域の分析は、以下の表3に見出すことができる。
家庭用の妊娠試験としてヒト絨毛性ゴナドトロピンを検出する、20年よりも前に開発されたペーパーベースのLFAは、それ以来、病原体、薬物、ホルモンおよび代謝物質を検出する多様なセッティングの用途に拡張されている[37]。LFAは、サンドイッチ複合体によって抗原を検出するものであり、捕捉抗体が、ニトロセルロース膜等の高度に多孔質の試験ストリップに吸着されており、その試験ストリップは、サンプルパッドから捕捉領域に液体を移動させ、分析物を輸送する働きをする。固定された分析物は、次いで、酵素的な増幅なしに肉眼で検出可能な着色ラインを作り出すナノ粒子(典型的には金またはラテックスのナノスフィア)に結合させた検出剤によって視覚化される。
尿濃度は、多くのホストおよび環境要因(例えば、食物、活動レベル、病歴、サーカディアンリズム)に依存するものであり、それゆえ、我々は、試験に関する正規化ストラテジーの開発を試みた。同時投与された遊離レポーターは、疾患状態とは独立して尿中に入り、プロテアーゼ活性によって放出されるレポーターのレベルを正規化するのに用いられ得ることが仮説として立てられた。遊離R4およびトロンビン感受性NW(R3で標識)の混合物を健常コホートまたは血栓症コホートのマウスに注入し、注入後30m間、すべての尿を採集し、このアプローチを調査した。R4の尿中の濃度は、ELISAによれば、2つの群の間で統計的に同等であり、遊離レポーターの偏りのないクリアランスが示された(p=0.25)。対照的に、トロンビン活性のレポーターであるR3の尿レベルは、独立に定量したときには(p<10−4)またはR4に対して正規化したときには(p<10−4)、血栓を保有するマウスで顕著に増加した。多数の捕捉抗体を印刷したペーパーストリップを用いてR3およびR4の尿レベルを同時に分析したところ、同様に、健常コントロールと比較して疾患尿試料ではR3/R4の比において統計的に優位な増加が観察された(p=0.0015)。真陽性(感度)および偽陽性(1−特異性)の比を、受信者操作特性(receiver-operating characteristic;ROC)曲線によって分析したところ、多重化ペーパー試験は、曲線下面積(area under the curve,a.u.c)が0.92となり、コントロールマウスに対して血栓形成マウス由来の尿を正確に区別した(p=0.0015)。
Claims (14)
- バイオマーカーナノ粒子を投与されている対象からの生体試料を用いること、ここで、バイオマーカーナノ粒子は、酵素感受性ドメインを介してヘテロ二官能化検出可能マーカーに連結したキャリアドメインを含み、ヘテロ二官能化検出可能マーカーは、リンカーによって接続された捕捉リガンドと検出リガンドとを含み、さらにヘテロ二官能化検出可能マーカーは、酵素に暴露されたときにバイオマーカーナノ粒子から放出される;および
生体試料における検出可能マーカーの存在が対象内に活性型で存在する酵素を示す、検出可能マーカーの存在を検出するために捕捉アッセイを使用して生体試料をインビトロで分析すること
を含み、ここで、捕捉リガンドおよび検出リガンドが、別個のハプテンである、インビトロ方法。 - 生体試料が、検出可能マーカーをバイオマーカーナノ粒子から放出する身体部位から離れた身体部位から採取され、生体試料が尿である、請求項1に記載のインビトロ方法。
- 対象が、複数のバイオマーカーナノ粒子を投与されており、ここで複数のバイオマーカーナノ粒子は、複数の検出可能マーカーを含み、その結果、各酵素感受性ドメインが特定の検出可能マーカーに関連する、請求項1または2に記載のインビトロ方法。
- 分析することが、生体試料を物品に導入することを含み、
該物品が、検出試薬が結合する規定領域を有する膜と、生体試料が膜に送達され、かつ膜に沿って移動するように、導入された生体試料を膜と接触させて収容するリザーバーと、膜上にコンジュゲートパッドとを含むハウジング(housing)を含み、
コンジュゲートパッドが、捕捉リガンドに結合するアフィニティ剤を含み、生体試料が妊娠タンパク質を含まない、請求項1に記載のインビトロ方法。 - アフィニティ剤が金ナノ粒子に結合したストレプトアビジンであり、捕捉リガンドがビオチンである、請求項4に記載のインビトロ方法。
- 検出試薬が検出リガンドに特異的な抗体であり、任意に、抗体がα−FAM抗体である、請求項4に記載のインビトロ方法。
- 酵素感受性ドメインを介してヘテロ二官能化検出可能マーカーに連結したキャリアドメインを含むバイオマーカーナノ粒子を投与されている対象からの生体試料を用いること、これにより、検出可能マーカーが、酵素に暴露されたときに、バイオマーカーナノ粒子から放出され、かつ検出可能マーカーがリンカーによって接続された捕捉リガンドと検出リガンドとを含み、生体試料が、検出可能マーカーをバイオマーカーナノ粒子から放出する身体部位から離れた身体部位から採取される;および
生体試料における検出可能マーカーの存在が対象内に活性型で存在する酵素を示す、検出可能マーカーの存在を検出するために捕捉アッセイを用いて生体試料をインビトロで分析すること
を含み、ここで、捕捉リガンドおよび検出リガンドが、別個のハプテンである、インビトロ方法。 - 捕捉アッセイが、捕捉リガンドと結合する基質上の一次抗体、および、検出リガンドに連結している酵素結合二次抗体を用いるELISAアッセイを含む、請求項7に記載のインビトロ方法。
- 捕捉アッセイがアフィニティ剤に対する捕捉リガンドの結合を含む、請求項7に記載のインビトロ方法。
- 捕捉リガンドがタンパク質である、請求項9に記載のインビトロ方法。
- リンカーが、ポリマーである、請求項7に記載のインビトロ方法。
- 酵素感受性検出可能マーカーが、疾患または状態に関連しないが正常状態に関連するプロテアーゼによる切断に感受性がある、請求項7に記載のインビトロ方法。
- 対象に投与された遊離レポーターに基づいて検出シグナルを正規化することをさらに含む、請求項7に記載のインビトロ方法。
- バイオマーカーナノ粒子を含む組成物であって、バイオマーカーナノ粒子が、酵素感受性ドメインによって、リンカーによって接続された捕捉リガンドと検出リガンドとを含む検出可能マーカーに連結したキャリアドメインを有するモジュール構造を含み、検出可能マーカーが、検出リガンドが酵素に暴露されたときにバイオマーカーナノ粒子から放出された後に、捕捉リガンドと検出リガンドを介してELISAまたはラテラルフローアッセイにおいて検出されることができ、ここで、捕捉リガンドおよび検出リガンドが、別個のハプテンである、前記組成物。
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