JP2011510272A - 改善された質量分析法分析のための組成物およびプロセス - Google Patents
改善された質量分析法分析のための組成物およびプロセス Download PDFInfo
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- JP2011510272A JP2011510272A JP2010542434A JP2010542434A JP2011510272A JP 2011510272 A JP2011510272 A JP 2011510272A JP 2010542434 A JP2010542434 A JP 2010542434A JP 2010542434 A JP2010542434 A JP 2010542434A JP 2011510272 A JP2011510272 A JP 2011510272A
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Classifications
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6848—Methods of protein analysis involving mass spectrometry
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
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- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/25125—Digestion or removing interfering materials
Landscapes
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Abstract
Description
この特許出願は、2008年1月15日に出願された米国仮特許出願第12/014,671号(すなわち、出願人としてThomas Becker、表題COMPOSITIONS AND PROCESSES FOR IMPROVED MASS SPECTROMETRY ANALYSIS、そして代理人番号SEQ−6015−UTによって指定される)の利益を主張する。この特許出願の全体は、全ての文字および図面を含めて、このような実施を可能にする範囲内で参考として本明細書に援用される。
本発明は一般的に、質量分析法とともに用いるための組成物および方法に関する。
本発明は、たとえば核酸(例、オリゴヌクレオチドおよびポリヌクレオチド)、タンパク質、ペプチドおよび脂質など、ならびにそれらの特定の類似体および結合体、たとえば糖タンパク質またはリポタンパク質などを含む分析物の質量分析法に基づく分析の改善を可能にする。本教示内でMALDI分析に適用できるその他の物質は、小さな分子、代謝産物、天然生成物および医薬品である。本発明の方法および組成物は、多数のグアニンおよびチミンを含むポリヌクレオチドに対して特に有用である。なぜならこれらのポリヌクレオチドはアンモニア付加物形成をより起こしやすいためである。
本明細書において用いられる「サンプル」とは、分析される分析物を含有する組成物を示す。特定の実施形態において、サンプルは「生物学的サンプル」からのものである。一般的に生物学的材料は、生きた供給源(例、ヒト、動物、植物、バクテリア、真菌、原生生物、ウイルス))から得られるあらゆる材料と考えられる。生物学的サンプルは、固体材料(例、組織、細胞ペレットおよび生検)および生物学的流体(例、尿、血液、唾液、羊水および(頬側細胞を含有する)口腔洗浄薬)を含むあらゆる形であってもよい。好ましくは、固体材料は流体と混合される。
マトリックス材料は、たとえばMALDI分析法など、特定の形の質量分析法において使用される。マトリックス材料は、分析物分子を互いに分離し、レーザー光子によって与えられたエネルギーを吸収し、そのエネルギーを分析物分子に移すことによって分析物分子の脱離およびイオン化をもたらす働きをする。一旦分析物がイオン化されると、飛行時間(TOF)分析計などの質量分析計を用いてイオン質量を測定できる。
本明細書において用いられる「付加物低減添加剤」という用語は、質量分析法による分析に必要なあらゆる1つまたはそれ以上の構成要素または試薬に添加される物質である。これらの構成要素または試薬は、サンプル、分析物、マトリックス材料、基体、またはその組合せを含む。特定の実施形態において、付加物低減添加剤はアスコルビン酸か、または実質的に等しい付加物低減効果を有するアスコルビン酸のあらゆる誘導体である。
R1およびR2は独立にOH、ハロゲン、R3、OR3、アジド、シアノ、CH2R3、CHR3R4、SR3、NR3R4であり;
R3およびR4は独立にH、アルキル、アセチレンもしくはシアノ、または任意に置換されたアリール環状炭素、アリール複素環、非アリール環状炭素もしくは非アリール複素環である。本発明において用いられるアスコルビン酸類似体は一般的にフリーラジカル消去剤(scavenging agents)であり、アスコルビン酸類似体のフリーラジカル消去活性は、当業者によって決定され得る(例、2,6-ジクロロフェノール-インドフェノール(2,6−dichlorophenol−indophenol:DCPIP)、ヨウ素、ヨウ素酸塩およびヨウ化物の混合物またはN‐ブロモスクシンイミドなどの酸化剤による滴定)。
本明細書において用いられる「基体(substrate)」とは不溶性の支持を示し、その上に分析物を堆積させて分析する。基体は、シリカ、ガラス(例、ガラス、制御細孔ガラス(controlled−pore glass:CPG))、ナイロン、Wang樹脂、Merrifield樹脂、セファデックス、セファロース、セルロース、磁気ビーズ、Dynabeads、金属面(例、鋼、金、銀、アルミニウム、シリコンおよび銅)、プラスチック材料(例、ポリエチレン、ポリプロピレン、ポリアミド、ポリエステル、ポリビニリデンジフルオリド(polyvinylidenedifluoride:PVDF))または、プレートを有するかもしくは有さないウエハ(例、シリコンウエハ)などの平坦面のピット中のビーズまたはピン(例、組合せの合成または分析に好適なピンのアレイを含んでもよいが、これらに限定されない。固体支持は、以下を含むがこれらに限定されないあらゆる所望の形であってもよい:ビーズ、チップ、毛細管、プレート、膜、ウエハ、コーム、ピン、ピットを有するウエハ、実質的に平坦な表面、ピットもしくはナノリットルウェルのアレイ、ならびに当業者に公知のその他のジオメトリおよび形。好ましい支持は、サンプルを別々の位置に受取るかまたは結合するように設計された平坦面である。最も好ましいのは、サンプルを受取るか、含有するか、結合するための親水性の位置を囲む疎水性の領域を有する平坦面である。基体材料は、装置の動作に対して、またはMALDI質量分析法の典型的なマトリックス材料および溶媒を含む、この手順において用いられる試薬に対して不活性であってもよい。
本明細書において用いられる「標的部位」という用語は、たとえばマトリックス材料、マトリックス材料と添加剤、または分析物などの材料を堆積および保持できる、基体上の特定の位置を示す。基体は1つまたはそれ以上の標的部位を含有していてもよく、その標的部位はランダムに配置されてもよいし、規則的なアレイまたはその他のパターンであってもよい。MALDI分析などの質量分析法分析のために用いられるときには、標的部位または堆積された材料によってもたらされる部位は、脱離をもたらすために基体上に焦点合せされるレーザースポットのサイズに等しいか、またはそれより小さいことが好ましい。よって標的部位は、たとえば固体支持の表面に位置決めされるウェルもしくはピット、ピンもしくはビーズ、または物理的障壁、またはそれらの組合せ、たとえばチップ上のビーズ、ウェル中のチップなどであってもよい。標的部位は基体上に物理的に置かれてもよいし、基体の表面にエッチングされてもよいし、ある位置の周囲をエッチングした後に残る「タワー」であってもよいし、たとえば相対的な親水性、疎水性などの物理化学的パラメータ、または中もしくは上に液体を保持するあらゆるその他の界面化学によって定められてもよい。
本発明の方法および組成物は、以下を含むあらゆるイオン化源とともに用いられてもよい:大気圧化学イオン化(Atmospheric Pressure,Chemical Ionisation:APCI)、化学イオン化(CI)、電子衝撃(Electron Impact:EI)、エレクトロスプレーイオン化(Electrospray Ionisation:ESIまたはES)、高速原子衝撃(Fast Atom Bombardment:FAB)、電界脱離/電界イオン化(Field Desorption/Field Ionisation:FD/FI)、マトリックス支援レーザー脱離イオン化法(MALDI)、および熱スプレーイオン化(Thermospray Ionisation:TSP)。特定の実施形態において、イオン化源はMALDIまたはESである。
分析物に対する添加剤
以下の実施例において、Sequenom iPLEX(商標)反応からの分析物を、ナノ純水またはアスコルビン酸添加剤のいずれかと混合して、付加物形成に対する添加剤の影響を定めた。どちらもこれにより引用により援用されるJurinke,C.,Oeth,P.,van den Boom,D.,MALDI−TOF mass spectrometry:a versatile tool for high−performance DNA analysis.Mol.Biotechnol.26,147−164(2004);およびOeth,P.et al.,iPLEXTM Assay:Increased Plexing Efficiency and Flexibility for MassARRAY(登録商標)System through single base primer extension with mass−modified Terminators.SEQUENOM Application Note(2005)に記載されるとおりのSequenom iPLEX(商標)プロトコルに続いて、プレートは並行して処理された。希釈/条件付けステップの際に、標準的なプロトコルの指示どおりに9□lの分析物溶液を25□lのナノ純水と混合する一方で、他方のプレートをアスコルビン酸と混合して20mMの最終アスコルビン酸濃度を得た。
マトリックスに対する添加剤
以下の実施例において、アスコルビン酸(ascorbic acid:AA)を含む新たなマトリックス組成物が、付加物形成を低減することによってスペクトル品質を改善することが示された。
以下のストック溶液およびナノ純水からマトリックスの組合せを調製した(異なるマトリックス構成要素のストック溶液は、その構成要素の官能基に従って陽イオン交換樹脂で処理した−酸はH+形の交換樹脂で、アンモニア塩はNH4+形の樹脂で処理した):
3-HPA:30%の水性アセトニトリル中に350mM。
表1のマトリックスに直接スポットされた合成オリゴヌクレオチドを用いて2つの実験を行なった。第1の実験において、17mer合成オリゴヌクレオチド(GTG GTG GTG GTG GTG GT)を、「古い」樹脂処理したマトリックスと、「新しい」アスコルビン酸で変更したマトリックスの両方でテストした。図1(古いマトリックス)においてはアンモニア付加物が明らかに存在する(ピークの高さは5335Daにおける親ピークの約12%)のに対し、図2(新しいマトリックス)においてはアンモニア付加物が存在しない。この新しいマトリックスは代替的に「マトリックス63C」と呼ばれることもある。
付加物形成スコア=
=(閾値を超えるパッドの相対度数)*(平均付加物ピーク高さ)
基体上の「パッド」および「スポット」という用語は、互いに交換可能である。平均付加物ピーク高さに対する標準偏差はすべてのマトリックスに対して低くて同等であり、表中には報告されていない。
RhDおよびAMG遺伝子における多型性に向けられた、検証されたSequenom遺伝子型同定アッセイを用いて、付加的な実験を行なった。これらのアッセイはiPLEX(商標)アッセイおよびMassARRAY(登録商標)技術を用いて行なわれた(Jurinke,C.,Oeth,P.,van den Boom,D.,MALDI−TOF mass spectrometry:a versatile tool for high−performance DNA analysis.Mol.Biotechnol.26,147−164(2004);およびOeth,P.et al.,iPLEXTM Assay:Increased Plexing Efficiency and Flexibility for MassARRAY(登録商標)System through single base primer extension with mass−modified Terminators.SEQUENOM Application Note(2005)、どちらもこれにより引用により援用される)。簡単には、SNPを囲む標的領域が最初にPCRによって増幅される。その後、PCR産物にオリゴヌクレオチドプライマーをアニーリングし、4つのターミネーターヌクレオチドの混合物とDNAポリメラーゼとを用いて、対立遺伝子特異的に単一ヌクレオチドだけ伸長させる。伸長産物を小型化したチップアレイに移し、MALDI−TOF質量分析法によって分析する。伸長産物の分子量を決定することによって、サンプル中に存在するSNP対立遺伝子の明確な同定が可能になる。質量シグナルのピーク面積比によって、所与のサンプル中の対立遺伝子の相対的存在量の推定が可能になる。
付加物形成を低減して疑陽性コールを排除することの重要性は、RHD−4−psi3−i遺伝子型同定アッセイの結果を示す図3および図4に明瞭に示されている。7626Daのピークは、標準マトリックスに対して報告されるような挿入(図3)ではなく、7571Daの伸長産物に対する55Da(NH3+K)付加物である。この付加物は新しいマトリックスにおいては明瞭に除去されている(図4)。
マトリックスおよび分析物に対する添加剤
新しい、アスコルビン酸で変更したマトリックスを、分析物溶液(8289DaのAMGプライマー伸長産物)に加えられたアスコルビン酸とも組合せてテストした。実施例1および実施例2の表2〜6にみられるとおり、アスコルビン酸を分析物に加えるか、または標準マトリックスと組合せることによって、アンモニアおよびナトリウム付加物が大きく低減した。下の表7を参照。標準マトリックスにおいてはアスコルビン酸処理分析物に対して43%の減少があり、新しいマトリックス上に堆積されたアスコルビン酸処理分析物に対しては57%の減少があった(未処理マトリックス上に分配された未処理分析物との比較)。
安定性テスト
6ヵ月の期間にわたり、4つの安定性テストを行なって、時間によるアスコルビン酸の付加物低減特性を定めた。テストされたマトリックスの性能が時間経過によって減少することは示されなかった。その代わりに、アンモニアおよびアルカリ付加物に対して得られたSNRおよび一定の付加物形成スコアから、アスコルビン酸と組合せた3−HPAおよびその添加剤DAC、NH4−オキサレートの安定性が確認された。
Claims (46)
- 質量分析法によって分析される分析物を含むサンプルにおける付加物形成を低減させるための方法であって、質量分析法による該分析物の分析の前に、アスコルビン酸またはその塩、互変異性体もしくは類似体を含む付加物低減添加剤を該サンプルに加えるステップを含む、方法。
- 前記付加物低減添加剤はシュウ酸アンモニウムをさらに含む、請求項1に記載の方法。
- 前記分析物は核酸である、請求項1に記載の方法。
- 前記核酸はデオキシリボ核酸である、請求項3に記載の方法。
- 前記核酸はリボ核酸である、請求項3に記載の方法。
- 質量分析法による前記分析は、マトリックス支援レーザー脱離/イオン化飛行時間型(MALDI−TOF)質量分析法、レーザー脱離質量分析法(LDMS)、エレクトロスプレー(ES)質量分析法、イオンサイクロトロン共鳴(ICR)質量分析法、およびフーリエ変換質量分析法からなる群より選択される、請求項1に記載の方法。
- 質量分析法によって分析される分析物を含むサンプルにおける付加物形成を低減させるための方法であって、質量分析法による該分析物の分析の前に、アスコルビン酸またはその塩、互変異性体もしくは類似体を含む付加物低減添加剤をマトリックスに加えるステップを含む、方法。
- 質量分析法による前記分析物の分析の前に、前記付加物低減添加剤を該分析物にも加えるステップをさらに含む、請求項7に記載の方法。
- 前記付加物低減添加剤はシュウ酸アンモニウムをさらに含む、請求項7または8に記載の方法。
- 前記マトリックス組成物は3-ヒドロキシピコリン酸(3-HPA)を含む、請求項7または8に記載の方法。
- 前記マトリックス組成物はクエン酸ジアンモニウム(DAC)を含む、請求項7または8に記載の方法。
- 前記分析物は核酸である、請求項7または8に記載の方法。
- 質量分析法において用いるために好適な基体を調製するための方法であって、付加物低減添加剤を含むマトリックス材料を該基体上に堆積させるステップを含み、該付加物低減添加剤はアスコルビン酸またはその塩、互変異性体もしくは類似体を含む、方法。
- 前記基体を密封するステップをさらに含む、請求項13に記載の方法。
- 酸化を最小限にするために薬剤またはガスによって前記基体を処理するステップをさらに含む、請求項13に記載の方法。
- 前記基体はシリカを含む、請求項13に記載の方法。
- 前記付加物低減添加剤はシュウ酸アンモニウムをさらに含む、請求項13に記載の方法。
- 質量分析法によって分析される組成物であって、分析物と付加物低減添加剤とを含む、組成物。
- 前記付加物低減剤は、アスコルビン酸またはその塩、互変異性体もしくは類似体を含む、請求項18に記載の組成物。
- シュウ酸アンモニウムをさらに含む、請求項19に記載の組成物。
- マトリックス組成物と、アスコルビン酸またはその塩、互変異性体もしくは類似体とを含む、組成物。
- マトリックス組成物と、アスコルビン酸またはその塩、互変異性体もしくは類似体と、シュウ酸アンモニウムとを含む、組成物。
- 質量分析法による分析に好適な組成物であって、分析物と付加物低減添加剤とを含み、該添加剤はアスコルビン酸またはその塩、互変異性体もしくは類似体と、シュウ酸アンモニウムとを含む、組成物。
- 質量分析法のための標的部位であって、基体と、アスコルビン酸またはその塩、互変異性体もしくは類似体およびシュウ酸アンモニウムを含む付加物低減添加剤とを含む、標的部位。
- マトリックス材料をさらに含む、請求項24に記載の標的部位。
- 質量分析法分析のための分析物を調製するための方法であって、
分析物を含む溶液を、アスコルビン酸またはその塩、互変異性体もしくは類似体を含む組成物と接触させることによって、質量分析法分析のためのサンプルを調製するステップと;
該サンプルを質量分析計に導入するステップと
を含む、方法。 - 前記組成物はシュウ酸アンモニウムを含む、請求項26に記載の方法。
- 前記分析物は核酸である、請求項26に記載の方法。
- 前記核酸はデオキシリボ核酸である、請求項28に記載の方法。
- 前記核酸はリボ核酸である、請求項28に記載の方法。
- 前記質量分析法分析は、マトリックス支援レーザー脱離/イオン化飛行時間型(MALDI−TOF)質量分析法、レーザー脱離質量分析法(LDMS)、エレクトロスプレー(ES)質量分析法、イオンサイクロトロン共鳴(ICR)質量分析法、およびフーリエ変換質量分析法からなる群より選択される、請求項26に記載の方法。
- 質量分析法によって分析物を分析するための方法であって、
サンプルを質量分析計に導入するステップであって、該サンプルは分析物と、アスコルビン酸またはその塩、互変異性体もしくは類似体とを含む、ステップ、ならびに
質量分析法によって該サンプルを分析するステップ
を含む、方法。 - 前記サンプルはシュウ酸アンモニウムをさらに含む、請求項32に記載の方法。
- 前記分析物は核酸である、請求項32に記載の方法。
- 前記核酸はデオキシリボ核酸である、請求項34に記載の方法。
- 前記核酸はリボ核酸である、請求項34に記載の方法。
- 前記質量分析法分析は、マトリックス支援レーザー脱離/イオン化飛行時間型(MALDI−TOF)質量分析法、レーザー脱離質量分析法(LDMS)、エレクトロスプレー(ES)質量分析法、イオンサイクロトロン共鳴(ICR)質量分析法、およびフーリエ変換質量分析法からなる群より選択される、請求項32に記載の方法。
- スポットのアレイを含む基体であって、各スポットは(i)マトリックス支援レーザー脱離/イオン化(MALDI)質量分析法のためのマトリックスと、(ii)アスコルビン酸またはその塩、互変異性体もしくは類似体とを含む、基体。
- 各スポットはシュウ酸アンモニウムをさらに含む、請求項38に記載の基体。
- 前記スポットの1つまたはそれ以上は分析物をさらに含む、請求項38に記載の基体。
- 前記分析物は核酸である、請求項40に記載の基体。
- 前記核酸はデオキシリボ核酸である、請求項41に記載の基体。
- 前記核酸はリボ核酸である、請求項41に記載の基体。
- 前記マトリックスは3-ヒドロキシピコリン酸を含む、請求項38に記載の基体。
- 前記基体はチップである、請求項38に記載の基体。
- 前記チップはシリコンチップである、請求項45に記載の基体。
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