JP2020526747A - 固形腫瘍の診断用のバイオマーカーの絶対定量の方法および装置 - Google Patents
固形腫瘍の診断用のバイオマーカーの絶対定量の方法および装置 Download PDFInfo
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Abstract
【選択図】図5
Description
本発明は、免疫ブロット法を用いて臨床診断のためにバイオマーカー(biomarker)を組織レベルで定量的に検出する方法および装置に関する。
具体的に、本発明は、定量ドットブロット(QDB:quantitative dot blot)分析を用いて、バイオマーカーの発現レベルを検出し、参照データベースと組み合わせた場合、固形腫瘍の診断および予後を提供するための方法および装置に関する。
QDBによる定量
絶対的検出
バイオマーカー
参照データベース
絶対的量に基づく診断法
材料および方法
凍結組織およびホルマリン固定パラフィン包埋(FFPE)切片の両方を、IHCスコア(0、1+、2+または3+)を含むそれらの臨床情報と共に地元の病院から取得された。そのうちの一部はFISHの結果でした。MCF−7およびBT−474細胞株は、中国科学院のセルバンク(中国、上海)から取得され、これら2つの細胞株から調製した溶解物をHER2陰性対照および陽性対照として使用した。
細胞培養に使用されるすべての一般的な試薬は、細胞培養培地および培養皿を含むThermo Fisher Scientificics(米国マサチューセッツ州ウォルサム)から購入された。プロテアーゼ阻害剤は、Sigma Aldrich社(米国ミズーリ州セントルイス)から購入された。他の全ての化学物質は、中国北京国薬集団化学試剤有限公司(Sinopharm Chemicals、中国、北京市)から購入された。組換えヒトHER2/ErbB2/CD340(676−1255)タンパク質は、Sino Biological Inc.(北京、中国)から購入された。QDBプレートは、煙台、Yantai Zestern Biotechnique Co. Ltd.(中国煙台市)によって製造された。
凍結組織については、約150mgの組織を組織生検から切り出し、そしてプロテアーゼ抑制剤(2μg/mLのロイペプチン、2μg/mLのアプロチニン、1μg/mLのペプスタチン、2mMのPMSF、2mMのNaF)を加えた300μLの溶解緩衝液(50mM HEPES、137mM NaCl、5mM EDTA、1mM MgCl2、10mM Na2P2O7、1%TritonX−100、10%グリセロール)中にハンドヘルド組織ホモジナイザーを用いて30秒処理した後、12000×gで5分間遠心分離した。免疫ブロット分析のために上清を集めた。総タンパク質濃度は、製造元の取扱説明に従って、Pierce BCAタンパク質アッセイキットを用いて検出された。MCF−7およびBT−474細胞から溶解物を調製するために、プロテアーゼ阻害剤を含む溶解緩衝液(lysis buffer)中で細胞を50回上下にピペッティングすることによって溶解させた。遠心分離後に上清を回収し、総タンパク質濃度をBCAタンパク質アッセイキットによって検出した。
図に示すように精製HER2タンパク質を段階希釈し、FFPE切片から抽出した全タンパク質と共に膜上にスポットした。これらのサンプルは、Li−CorのC−Digit Westernブロットスキャナーを使用して画像が取り込まれるまで、典型的なドットブロット法で処理された。Li−Cor社に由来のImageQuantiプログラムを使用して画像をデジタルに変換し、そしてタンパク質標準曲線を確立して、患者サンプルからの画像収集をバイオマーカーレの絶対ベルに変換した。
特異的抗体(HER2についてはEP3または4B5クローン、Ki67についてはMIB1、エストロゲン受容体(ER)についてはSP1)の線形範囲は、これらのバイオマーカーについてそれぞれ陽性と試験された患者からの全溶解物を使用することによって決定した。溶解物は、乳癌または胃癌組織3〜4個から調製された等量の組織溶解物を最初に混合することによって調製された。混合した溶解物を0〜2μgまで段階希釈してQDB分析の線形範囲を決めた。市販されているか、または社内で自己発現および精製されたタンパク質標準品も0〜500pgまで段階希釈してQDB分析の線形範囲を決定するために使用された。
統計的有意性についての一般的な検定には、とりわけ、t検定、ANOVA、クラスカル−ウォリスKruskal−Wallis、ウィルコクソンWilcoxon、マン−ホイットニーMann−Whitney、およびオッズ比が含まれる。バイオマーカーは、単独でまたは組み合わせて、被験体が標的表現型の状態に属するという相対的確率の尺度を提供する。それ自体、バイオマーカーは、例えば疾患、薬物の治療有効性などのためのマーカーとしての用途を見出すことができる。したがってバイオマーカーは、診断などを容易にするアッセイにおける分析物である。
Claims (20)
- サンプルの定量分析方法であって、
(a)サンプルの1つまたは複数の特徴を表す単一のマーカーを提供するステップであって、前記サンプルは前記マーカーの単一ユニットの集団を含む、ステップと、
(b)ドットブロット分析を用いて前記マーカーを検出するステップであって、定量的結果はサンプル中の前記マーカーの単一ユニットの集団の絶対量であり、サンプル体積またはサンプル重量によって正規化される、ステップと、
(c)前記マーカーの定量的結果に基づいて、前記サンプルの1つ以上の特徴の客観的測定を得るステップと、を含む
サンプルの定量分析方法。 - 前記ステップ(b)には、定量ドットブロット(QDB)分析により前記マーカーを検出することを含む、請求項1に記載の定量分析方法。
- 前記ステップ(b)には、
(b1)結合因子を含む溶液と共にサンプルをインキュベートするステップであって、前記結合因子は、前記マーカーの単一ユニットに特異的に結合することができ、且つ、前記結合因子は、前記ドットブロット分析によって定量化することができる、ステップと、
(b2)前記結合因子のQDB分析により前記マーカーを検出するステップと、を含む、請求項2に記載の定量分析方法。 - 前記マーカーはタンパク質マーカーであり、そして前記結合因子は抗体である、請求項3に記載の定量分析方法。
- 前記抗体は分析物特異的試薬(analyte specific reagent:ASR)抗体である、請求項4に記載の定量分析方法。
- 前記抗体はインビトロ診断(in vitro diagnostics:IVD)抗体である、請求項4に記載の定量分析方法。
- 前記抗体は免疫組織化学でアッセイすることができる、請求項4に記載の定量分析方法。
- 前記サンプルは被検対象からの生検組織である、請求項1に記載の定量分析方法。
- 前記生検組織はホルマリン固定およびパラフィン包埋のものである、請求項8に記載の定量分析方法。
- 被検対象は癌患者である、請求項8に記載の定量分析方法。
- (d)マーカーの定量的結果に基づいて患者を評価するステップをさらに含む、請求項10に記載の定量分析方法。
- 前記ステップ(d)において、患者を評価することは、患者に対して癌の診断および予後を含む、請求項11に記載の定量分析方法。
- 前記癌の診断および予後は、無病生存率、全生存率、ハザード比、および治療案の予測を含む、請求項12に記載の定量分析方法。
- 患者からの生検組織サンプル中のマーカーの定量分析に基づき、患者の癌を診断するための参照データベースであって、
複数の参照プロフィールを含み、前記複数の参照プロフィールのそれぞれは、
(a)確定診断された癌患者からの生検組織サンプルを提供するステップと、
(b)定量ドットブロット(QDB)分析により前記マーカーを検出するステップであって、定量的結果は、生検組織サンプル中の前記マーカーの絶対量であり、生検組織サンプルの体積または生検組織サンプルの重量によって正規化される、ステップと、
(c)前記定量的結果を癌患者の確定診断と関連づけることにより参照プロフィールを得るステップとによって得られる、
参照データベース。 - 前記ステップ(b)には、
(b1)前記生検組織サンプルを、前記マーカーに特異的に結合する結合因子を含む溶液と共にインキュベートするステップと、
(b2)前記結合因子のQDB分析により前記マーカーを検出するステップとを含む、請求項14に記載の参照データベース。 - 前記マーカーはタンパク質マーカーであり、そして前記結合因子は抗体である、請求項15に記載の参照データベース。
- 患者の癌を診断するための方法であって、
請求項14に記載の参照データベースを提供するステップと、
患者から生検組織サンプルを得るステップと、
QDB分析法により患者の前記生検組織サンプルにおいて前記参照データベースに使用されるマーカーの含有量を検出するステップであって、検出結果が前記生検組織サンプルにおける前記マーカーの絶対量である、ステップと、
前記生検組織サンプルにおける前記マーカーの定量的結果を、前記参照データベースに記憶された参照プロフィールのそれぞれに比較するステップと、
前記参照データベースから、前記生検組織サンプルにおける前記マーカーの定量的結果とのベストマッチを有する参照プロフィールを検索し、検索された参照プロフィールに関連する既知の診断結果を出力するステップとを含む、方法。 - 前記癌は固形腫瘍癌である、請求項17に記載の方法。
- 請求項14に記載の参照データベースを含む、患者の癌を診断するためのキット。
- インターネットを介して請求項14に記載の参照データベースにアクセスするように構成されているユニットを含む、患者の癌を診断するためのキット。
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US20210011010A1 (en) | 2021-01-14 |
US20190004037A1 (en) | 2019-01-03 |
KR102502745B1 (ko) | 2023-02-23 |
US10788484B2 (en) | 2020-09-29 |
SG11201908865WA (en) | 2019-10-30 |
CA3101968A1 (en) | 2019-01-03 |
CN110753845B (zh) | 2023-08-22 |
KR20200020906A (ko) | 2020-02-26 |
JP7194128B2 (ja) | 2022-12-21 |
WO2019006156A1 (en) | 2019-01-03 |
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