JP7499566B2 - 質量タグ及び二次イオン質量分析計を用いた組織の多重化イメージング - Google Patents
質量タグ及び二次イオン質量分析計を用いた組織の多重化イメージング Download PDFInfo
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- 238000012800 visualization Methods 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
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Description
本願は、2013年9月13日に出願された米国仮特許出願第61/877,733号、及び2014年3月26日に出願された米国仮特許出願第61/970,803号の利益を主張するものであり、これらの出願は、参照によりその全体が本明細書に組み込まれる。
本発明は、アメリカ国立衛生研究所により与えられた契約番号CA034233、AI057229、CA130826、EY018228、HHSN272200700038C、1K99 GM104148-01の下での政府支援に基づいてなされたものである。米国政府は、本発明に一定の権利を有するものである。
本明細書で他に断らない限り、本明細書で使用される全ての技術及び科学上の用語は、本発明が属する分野の当業者により通常理解されるものと同様の意味を持つ。本明細書に記載の方法及び材料と同様のまたは同等の方法及び材料を、本発明の実施または試験のために使用することができるが、好ましい方法及び材料が本明細書に記載される。
試料を分析するシステムも提供する。このシステムは、a)試料を含む基板を保持するホルダを含む二次イオン質量分析法(SIMS)システムであって、(i)試料を一次イオンビーム(例えば、酸素、セシウム、金、アルゴン、ビスマス、キセノン、C60、SF6、またはガリウムイオン、またはその任意の混合物、例えば、酸素とキセノンイオンの混合物ビーム)で走査し、試料に結合されている特異的結合試薬の質量特異的存在量の測定値を含むデータセットを生成し、(ii)データセットを出力するように構成さるシステム、及び、b)データセットを処理して試料の画像を生成する画像分析モジュールを含むコンピュータを具備していてもよい。ホルダは、走査しやすくするために少なくともx及びy方向(試料の平面内である)に制御可能に移動する(例えば、段付けされるかまたは連続的に移動する)ことが可能な可動ステージ内にある。画像分析モジュールは、上述の方法の多くのステップを行うようにプログラミングすることができる。例えば、いくつかの実施形態では、画像分析モジュールは、画像を分割して、個別細胞の境界、必要に応じて、個別細胞の細胞内特徴を画像内で識別してもよい。場合によっては、画像分析モジュールは、画像内の個別細胞の各々またはその細胞内特徴のデータを統合し、必要に応じて、細胞の各々について得られた統合データに基づいて、個別細胞をカテゴリー分けしてもよい。画像分析モジュールは、組織試料の画像を表示してもよく、細胞及び/またはその細胞内特徴は、それらのカテゴリーによって色分けされる。上述したように、画像のいずれの1つのピクセルにおいても、ピクセルの色の強度は、SIMSシステムによって得られたそのピクセルについて得られた信号の大きさと相関している。特定の実施形態では、システムは、四重極、次いでイオンパルサー、次いで飛行時間(TOF)管と結合しているDCイオン源(即ち、動的ソース)を含んでいてもよい。SIMSシステムは、動的または静的であってもよい。NanoSIMSは、高出力のDC一次イオン源を用いるので動的とみなされ、NanoTOFは、低出力パルス源を用いるので静的とみなされる。
上述の方法を用いて、対象からの細胞を分析し、例えば、細胞が正常であるかどうかを判定し、または細胞が治療に応答しているかどうか判定することができる。一実施形態では、本方法を用いて、がん細胞の異形成の度合いを判定してもよい。これらの実施形態では、細胞は、多細胞生物または微生物からの試料であってもよい。生物学的試料は、個体(例えば軟組織もしくは体液)から、またはインビトロで増殖された細胞培養物から単離してもよい。生物学的試料は、脳、副腎、皮膚、肺、脾臓、腎臓、肝臓、脾臓、リンパ節、骨髄、膀胱、胃、小腸、大腸また筋肉等などの軟組織から作ることができる。体液には、血液、血漿、唾液、粘液、痰、脳脊髄液、胸膜液、涙液、乳糜管液、リンパ液、喀痰、脳脊髄液、滑液、尿、羊水、及び***等が含まれる。生物学的試料には、インビトロでの培養下で増殖された細胞が含まれる。細胞は、組織生検、擦り取った細胞または洗浄細胞の細胞であってもよい。特定の実施形態では、細胞は、ホルマリン固定パラフィン包埋(FFPE)試料中の細胞であってもよい。特定の場合では、本方法を用いて、FFPE試料中の異なる種類のがん細胞を区別してもよい。
基板調製:シリコンウェーハ(Silicon Valley Microelectronics)を18mm2片に角切りにし、メタノールで2回濯ぎ、綿先端アプリケーターで研磨した。次いで、洗浄した基板を2%ポリ-l-リシン溶液(Sigma-Aldrich)に10分間浸し、60℃で1時間焼成した。
抗体:抗体、レポーター同位体、及び濃度の要約が、下の表S1に見出される。製造者推奨のプロトコルに従って、MaxPAR抗体結合キット(DVS Sciences、Toronto、Canada)を用いて金属結合一次抗体を一度につき100μgで調製した。標識後、抗体をCandor PBS抗体安定化溶液(Candor Bioscience GmbH、Wangen、Germa血球発現)で0.4mg/mLに希釈し、4℃で長期保存した。
MIBIの性能評価:MIBIのワークフローは、免疫蛍光(IF)及び発色IHCアッセイと比較可能である(図1)。フルオロフォアまたは酵素結合試薬の代わりに、生物学的標本を、同位体的に純粋で安定的なランタニドに結合した一次抗体とともにインキュベートする(図1)。一次抗体は、標本との同時インキュベーションのために、溶液中で混合される。MIBI用に調製した標本を試料ホルダにマウントし、ラスタライズ化された酸素デュオプラズマトロン一次イオンビームに曝した。このイオンビームが試料に衝突することで、結合抗体のランタニド付加物を二次イオンとして遊離させる。この試験では、二次イオンを複数の光電子増倍管を備えた磁場型質量分析計を介して次に分析し、複数のランタニド同位体(質量ベースレポーター)を並列検出させる。得られたデータは、各ランタニドの元素分布、したがって、各抗体とその対応しているエピトープの二次元マップを生成する。
Claims (34)
- 試料の分析方法であって、
複数の異なる非生物元素を用いて試料中の個別の標的タンパク質を標識することであって、この標識することが、各標的タンパク質を、前記標的タンパク質を特異的に結合し、複数の異なる非生物元素に単一分子連結部分を介して結合している捕捉剤を含むプローブと接触させることを含み、前記プローブの少なくとも1つが、少なくとも1つのキレートした非生物元素を含むものである、標識することと、
前記試料の表面にわたって一次イオンビームを走査して、前記試料上の複数の場所の各々で前記非生物元素から生じる二次イオンの集団を生成することと、
前記試料上の複数の場所の各々について、前記二次イオンの対応する集団を測定することによって、試料中の前記標的タンパク質の1つまたは複数について存在量の情報を判断することと、
を含む、方法。 - 前記非生物元素の少なくとも1つが、1つまたは複数の金属原子を含む、請求項1に記載の方法。
- 前記1つまたは複数の金属原子が、1つまたは複数のランタニド原子を含む、請求項2に記載の方法。
- 前記1つまたは複数の金属原子が、1つまたは複数の貴金属原子を含む、請求項2に記載の方法。
- 前記捕捉剤の少なくとも1つが、染料である、請求項1に記載の方法。
- 前記捕捉剤の少なくとも1つが抗体を含む、請求項1に記載の方法。
- 前記複数の非生物元素が、
各々が第1の標的タンパク質を特異的に結合する第1型の捕捉剤に結合されている、第1群の非生物元素と、
各々が、第1の標的タンパク質とは異なる第2の標的タンパク質を特異的に結合する第2型の捕捉剤に結合されている、第2群の非生物元素と、
を含む、請求項1に記載の方法。 - 前記第1群の非生物元素の各メンバーが同じである、請求項7に記載の方法。
- 前記第2群の非生物元素の各メンバーが同じである、請求項8に記載の方法。
- 前記複数の非生物元素が、各々が第3の標的タンパク質を特異的に結合する第3型の捕捉剤に結合されている、第3群の非生物元素を含み、前記方法がさらに、前記試料中の領域の1つまたは複数で、前記第1群、第2群および第3群の非生物元素から生じる二次イオンの集団を測定することによって試料中の特徴を区別することを含む、請求項7に記載の方法。
- 前記連結部分の少なくとも1つがポリマーであり、前記ポリマーの複数の単位が少なくとも1つの金属キレート基を含む、請求項1に記載の方法。
- 前記金属キレート基の少なくとも1つがポリキラント配位基である、請求項11に記載の方法。
- 前記金属キレート基の各々がポリキラント配位基である、請求項12に記載の方法。
- さらに、前記第1および第2の非生物元素から生じる二次イオンの集団を測定することによって試料中の特徴を区別することを含む、請求項7に記載の方法。
- 測定した二次イオンの集団に基づいて、細胞膜、ミトコンドリア、小胞体、ゴルジ体、核膜、およびサイトゾル画分からなる群から選択される少なくとも1つのメンバーを識別することを含む、請求項14に記載の方法。
- さらに、前記試料中の細胞の集団を識別することと、前記集団中の各細胞について、前記細胞に対応する試料中の場所で測定した二次イオンの統合した存在量値を判断することとを含む、請求項1に記載の方法。
- さらに、前記細胞に対応する統合した存在量値に基づいて、前記集団中の少なくとも1つの細胞をカテゴリー分けすることを含む、請求項16に記載の方法。
- 試料を分析するためのシステムであって、
パルス状の一次イオン源と
前記パルス状の一次イオン源と同期された飛行時間検出器と
を具備し、
プローブの各々が、標的タンパク質を特異的に結合する捕捉剤に単一分子連結部分を介して結合している複数の異なる非生物元素を含む複数のプローブであって、少なくとも1つのプローブが少なくとも1つのキレートした非生物元素を含むものである複数のプローブを用いて標識された試料を受け取り、
前記試料の表面にわたって一次イオン源により生成された一次イオンビームを走査して、前記試料上の複数の場所の各々で前記非生物元素から生じる二次イオンの集団を生成し、
前記試料上の複数の場所の各々について、前記飛行時間検出器を用いて前記二次イオンの対応する集団を測定することによって、試料中の1つまたは複数の標的タンパク質について存在量の情報を判断するように構成されている、システム。 - 前記非生物元素が、1つまたは複数の金属原子を含む、請求項18に記載のシステム。
- 前記1つまたは複数の金属原子が、1つまたは複数のランタニド原子を含む、請求項19に記載のシステム。
- 前記1つまたは複数の金属原子が、1つまたは複数の貴金属原子を含む、請求項19に記載のシステム。
- 前記捕捉剤の少なくとも1つが、染料である、請求項18に記載のシステム。
- 前記捕捉剤の少なくとも1つが抗体を含む、請求項18に記載のシステム。
- 前記複数の非生物元素が、
各々が第1の標的タンパク質を特異的に結合する第1型の捕捉剤に結合されている、第1群の非生物元素と、
各々が、第1の標的タンパク質とは異なる第2の標的タンパク質を特異的に結合する第2型の捕捉剤に結合されている、第2群の非生物元素と、
を含む、請求項18に記載のシステム。 - 前記第1群の非生物元素の各メンバーが同じである、請求項24に記載のシステム。
- 前記第2群の非生物元素の各メンバーが同じである、請求項25に記載のシステム。
- 前記複数の非生物元素が、各々が第3の標的タンパク質を特異的に結合する第3型の捕捉剤に結合されている、第3群の非生物元素を含み、前記システムがさらに、前記試料中の領域の1つまたは複数で、前記第1群、第2群および第3群の非生物元素から生じる二次イオンの集団を測定することによって試料中の特徴を区別するように構成されている、請求項24に記載のシステム。
- 前記連結部分の少なくとも1つがポリマーであり、前記ポリマーの複数の単位が少なくとも1つの金属キレート基を含む、請求項18に記載のシステム。
- 前記金属キレート基の少なくとも1つがポリキラント配位基である、請求項28に記載のシステム。
- 前記金属キレート基の各々がポリキラント配位基である、請求項29に記載のシステム。
- さらに、処理装置を具備し、前記飛行時間検出器を用いて前記第1および第2の非生物元素から生じる二次イオンの集団を測定するように構成され、前記処理装置が、前記第1および第2の非生物元素から生じる測定された二次イオンの集団に基づいて試料中の特徴を区別するように構成されている、請求項24に記載のシステム。
- 前記処理装置が、測定した二次イオンの集団に基づいて、細胞膜、ミトコンドリア、小胞体、ゴルジ体、核膜、およびサイトゾル画分からなる群から選択される少なくとも1つのメンバーを識別するように構成されている、請求項31に記載のシステム。
- さらに、処理装置を具備し、前記処理装置が、前記試料中の細胞の集団を識別し、前記集団中の各細胞について、前記細胞に対応する試料中の場所で測定した二次イオンの統合した存在量値を判断するように構成されている、請求項18に記載のシステム。
- 前記処理装置が、前記細胞に対応する統合した存在量値に基づいて、前記集団中の少なくとも1つの細胞をカテゴリー分けするように構成されている、請求項33に記載のシステム。
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