JP5690048B2 - 血液性癌の分析および臨床管理のための、細胞抗原および標的シグナル伝達タンパク質の複合プロフィール - Google Patents
血液性癌の分析および臨床管理のための、細胞抗原および標的シグナル伝達タンパク質の複合プロフィール Download PDFInfo
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Description
白血病は、骨髄及び血液の悪性癌である。白血病は、異常な白血球の過剰産生により、骨髄及び/又は末梢血が過密になることを特徴とする。これにより、正常な血球の産生及び機能が低下する。慢性リンパ球性白血病(CLL)は、ヒトにおいて発症する白血病の主な4種類の1つであり、その他には急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、及び急性リンパ球性白血病(ALL)がある。
本発明は、腫瘍性病態を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する方法を対象とする。本発明の複合マーカープロフィールは、予後及び治療に関連する腫瘍性病態の亜群の同定、及び個体の臨床経過の予測を可能にする。本発明の方法は、危険群を決定する方法、再発の危険性の増大を予測する方法、二次的合併症を発症する危険性の増大を予測する方法、個体の治療を選択する方法、個体の治療応答を予測する方法、個体の治療効果を判定する方法、及び個体の予後を判定する方法を含めた、腫瘍性病態に罹患した個体の治療を選択するのに有用なツールを提供する。具体的には、本発明の方法は、個体の腫瘍性病態の経過が進行性であるか、遅進性であるかを予測する予後指標の役割を果たし、それによって臨床医が患者を管理し、使用する治療法を評価するのに役立つ、複合マーカープロフィールを作成する方法を開示する。
本発明は、腫瘍性病態を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する方法を対象とする。本発明の複合マーカープロフィールは、予後及び治療に関連する腫瘍性病態の亜群の同定、及び個体の臨床経過の予測を可能にする。本発明の方法は、危険群を決定する方法、再発の危険性の増大を予測する方法、二次的合併症を発症する危険性の増大を予測する方法、個体の治療を選択する方法、個体の治療効果を判定する方法、及び個体の予後を判定する方法を含めた、腫瘍性病態に罹患した個体の臨床管理に有用なツールを提供する。
本実施例は、B細胞慢性リンパ球性白血病(C−LL)を有する疑いのある個体の複合プロフィールを作成するための試料の調製を示す。
本参考例は、複合プロフィールを作成するためのフローサイトメトリーによる試料分析を示す。
図5は、AML試料のmTORによるS6活性化を示すフローサイトメトリーの図を示す。
Claims (31)
- 腫瘍性病態を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する方法であって、
(a)生体試料を、個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体と反応させる手順であって、マーカーのレベル及びマーカーの組み合わせによって前記試料に内在する正常及び腫瘍性細胞集団を同定する、手順;
(b)前記試料に内在する前記正常及び腫瘍性細胞集団を同定するマーカーのレベル及びマーカーの組み合わせを検出することにより、前記試料に内在する前記正常及び腫瘍性細胞集団の存在を同定する手順;
(c)前記試料に内在する正常および腫瘍性細胞集団における標的タンパク質の発現レベルを測定する手順であって、前記標的タンパク質は、活性化リン酸化シグナル伝達タンパク質、増殖マーカー、及びアポトーシスマーカーからなる群より選択される、手順;並びに
(d)前記正常及び腫瘍性細胞集団のそれぞれにわたる、前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカーのレベル及びマーカーの組合せを、前記試料に内在する前記腫瘍性細胞集団における前記標的タンパク質の前記発現レベルの、前記試料に内在する前記標的タンパク質について陽性である前記正常細胞集団における前記標的タンパク質の発現レベルに対する標準化に基づいて、前記標的タンパク質の発現レベルと関連付け、腫瘍性病態を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する手順、
を含み、
ここで、前記腫瘍性病態が、慢性リンパ球性白血病(CLL)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、及び急性リンパ球性白血病(ALL)からなる群から選択され、
試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、
方法。 - 前記標的タンパク質が活性化リン酸化シグナル伝達タンパク質である、請求項1に記載の方法。
- 標的タンパク質修飾の決定も更に含む、請求項1に記載の方法。
- 前記細胞集団関連マーカーが、CD3、CD5、CD10、CD11b、CD13、CD14、CD15、CD16、CD19、CD22、CD23、CD56、CD45、CD33、CD34、MPL(ミエロペルオキシダーゼ)、CD64、CD79a、CD79b、及びCD117(c−kit受容体)からなる群から選択される細胞表面マーカーを含む、請求項1に記載の方法。
- 前記腫瘍性病態がB細胞慢性リンパ球性白血病(B−CLL)である、請求項1に記載の方法。
- 前記標的タンパク質が、ZAP−70、活性化誘導性C型レクチン(AICL)、リポタンパク質リパーゼ、及びIM68532からなる群から選択される、請求項5に記載の方法。
- 前記B細胞慢性リンパ球性白血病(B−CLL)がIg突然変異型B−CLLである、請求項5に記載の方法。
- 前記細胞集団関連マーカーが、CD3、CD5、CD19、CD23、CD38、CD56、CD79b、及びfmc7からなる群から選択される、請求項5に記載の方法。
- 前記白血病B細胞がZAP−70陽性である、請求項8に記載の方法。
- 前記細胞集団の1つ以上がZAP−70陰性細胞集団を含む、請求項8に記載の方法。
- 前記ZAP−70陰性細胞集団が顆粒球を含む、請求項10に記載の方法。
- 個体のIg非突然変異型B細胞慢性リンパ球性白血病(CLL)の臨床経過を予測する方法であって、
(a)前記個体由来の生体試料を提供する手順;
(b)前記生体試料を、CD5、CD19及びCD56からなる群より選択される個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体と反応させる手順であって、マーカーのレベル及びマーカーの組み合わせによって、前記試料に内在する正常及び腫瘍性細胞集団を同定する、手順;
(c)前記試料に内在する前記正常及び腫瘍性細胞集団を同定するマーカーのレベル及びマーカーの組み合わせを検出することにより、前記試料に内在する前記正常及び腫瘍性細胞集団の存在を同定する手順;
(d)前記試料に内在する正常および腫瘍性細胞集団における少なくとも1つのシグナル伝達タンパク質の発現レベルを測定する手順であって、前記少なくとも1つのシグナル伝達タンパク質はZAP70を含む、手順;
(e)前記正常及び腫瘍性細胞集団のそれぞれにわたる、前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカーのレベル及びマーカーの組合せを、前記試料に内在する前記腫瘍性細胞集団における前記標的タンパク質の前記発現レベルの、前記試料に内在する前記標的タンパク質について陽性である前記正常細胞集団における前記標的タンパク質の発現レベルに対する標準化に基づいて、前記少なくとも1つのシグナル伝達タンパク質の存在と関連付け、B細胞慢性リンパ球性白血病(B−CLL)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する手順であって、前記複合マーカープロフィールが前記シグナル伝達タンパク質のレベルの相対的な定量化を表す、手順;並びに
(f)前記複合マーカープロフィールを1つ以上の基準複合マーカープロフィールと比較する手順であって、前記比較によってIg非突然変異型B細胞慢性リンパ球性白血病(CLL)の臨床経過の予測が可能となる、手順、
を含み、
前記試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、方法。 - 慢性骨髄性白血病(CML)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する方法であって、
(a)前記生体試料を、個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体と反応させる手順であって、マーカーのレベル及びマーカーの組み合わせによって前記試料に内在する正常及び腫瘍性細胞集団を同定する、手順;
(b)前記試料に内在する前記正常及び腫瘍性細胞集団を同定するマーカーのレベル及びマーカーの組み合わせを検出することにより、前記試料に内在する前記正常及び腫瘍性細胞集団の存在を同定する手順;
(c)前記試料に内在する正常および腫瘍性細胞集団における少なくとも1つの標的タンパク質の発現レベルを測定する手順であって、前記少なくとも1つの標的タンパク質は、活性化リン酸化シグナル伝達タンパク質、増殖マーカー、及びアポトーシスマーカーからなる群から選択される、手順;並びに
(d)前記正常及び腫瘍性細胞集団のそれぞれにわたる、前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカー及びマーカーの組合せのレベルを、前記試料に内在する前記腫瘍性細胞集団における前記標的タンパク質の前記発現レベルの、前記試料に内在する前記標的タンパク質について陽性である前記正常細胞集団における前記標的タンパク質の発現レベルに対する標準化に基づいて、前記少なくとも1つの標的タンパク質の発現レベルと関連付け、慢性骨髄性白血病(CML)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する手順、
を含み、
前記試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、方法。 - 前記細胞集団関連マーカーが、CD45、CD34、CD11b、CD13、CD15、CD14、CD33、CD79a、CD79b、CD22、CD10、CD16、Bcr/Abl、及びTdTからなる群から選択される、請求項13に記載の方法。
- 前記標的タンパク質が活性化リン酸化シグナル伝達タンパク質である、請求項13に記載の方法。
- 前記活性化リン酸化シグナル伝達タンパク質が、Abl、CRKL、Hck、STAT1、STAT3、STAT5、Akt/PKB、及びS6からなる群から選択される、請求項15に記載の方法。
- 前記標的タンパク質が増殖マーカー又はアポトーシスマーカーである、請求項13に記載の方法。
- 前記標的タンパク質が、サイクリンD1及びサイクリンA2からなる群から選択される増殖マーカーである、請求項17に記載の方法。
- 前記標的タンパク質がカスパーゼ−3及びBcl−Xlからなる群から選択されるアポトーシスマーカーである、請求項17に記載の方法。
- 急性骨髄性白血病(AML)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する方法であって、
(a)生体試料を、個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体と反応させる手順であって、マーカーのレベル及びマーカーの組み合わせによって前記試料に内在する正常及び腫瘍性細胞集団を同定する、手順;
(b)前記試料に内在する前記正常及び腫瘍性細胞集団を同定するマーカーのレベル及びマーカーの組み合わせを検出することにより、前記試料に内在する前記正常及び腫瘍性細胞集団の存在を同定する手順;
(c)前記試料に内在する正常および腫瘍性細胞集団における少なくとも1つの標的タンパク質の発現レベルを測定する手順であって、前記少なくとも1つの標的タンパク質は、活性化リン酸化シグナル伝達タンパク質、増殖マーカー、及びアポトーシスマーカーからなる群より選択される、手順;並びに
(d)前記正常及び腫瘍性細胞集団のそれぞれにわたる、前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカーのレベル及びマーカーの組合せを、前記試料に内在する前記腫瘍性細胞集団における前記標的タンパク質の前記発現レベルの、前記試料に内在する前記標的タンパク質について陽性である前記正常細胞集団における前記標的タンパク質の発現レベルに対する標準化に基づいて、前記少なくとも1つの標的タンパク質の存在と関連付け、急性骨髄性白血病(AML)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する手順、
を含み、
前記試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、方法。 - 前記細胞集団関連マーカーが、CD45、CD33、CD34、CD11b、CD13、CD14、CD15、CD16、MPL(ミエロペルオキダーゼ)、CD64、及びCD117(c−kit受容体)からなる群から選択される、請求項20に記載の方法。
- 前記細胞集団関連マーカーが、白血病顆粒球又は白血病単球を含む細胞集団を同定する、請求項21に記載の方法。
- 前記標的タンパク質が活性化リン酸化シグナル伝達タンパク質である、請求項20に記載の方法。
- 前記活性化リン酸化シグナル伝達タンパク質が、Abl、CRKL、Hck、STAT1、STAT3、STAT5、Akt/PKB、及びS6からなる群から選択される、請求項20に記載の方法。
- 前記標的タンパク質が増殖マーカー又はアポトーシスマーカーである、請求項20に記載の方法。
- 前記標的タンパク質がサイクリンD1及びサイクリンA2からなる群から選択される増殖マーカーである、請求項25に記載の方法。
- 前記標的タンパク質がカスパーゼ−3及びBcl−Xlからなる群から選択されるアポトーシスマーカーである、請求項25に記載の方法。
- 個体の急性骨髄性白血病(AML)の臨床経過を予測する方法であって、
(a)前記個体から得られた生体試料を、CD34、CD45、及びCD117からなる群より選択される個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体と反応させる手順であって、マーカーのレベル及びマーカーの組み合わせによって前記試料に内在する正常及び腫瘍性細胞集団を同定する、手順;
(b)前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカーのレベル及びマーカーの組み合わせを検出することにより、前記試料に内在する前記正常及び腫瘍性細胞集団の存在を同定する手順;
(c)前記試料に内在する正常および腫瘍性細胞集団における少なくとも1つの標的タンパク質の発現レベルを測定する手順であって、前記少なくとも1つの標的タンパク質は、ERKおよびS6からなる群より選択される、手順;並びに
(d)前記正常及び腫瘍性細胞集団のそれぞれにわたる、前記試料に内在する前記正常及び腫瘍性細胞集団を同定する前記マーカーのレベル及びマーカーの組合せを、前記試料に内在する前記腫瘍性細胞集団における前記標的タンパク質の前記発現レベルの、前記試料に内在する前記標的タンパク質について陽性である前記正常細胞集団における前記標的タンパク質の発現レベルに対する標準化に基づいて、前記少なくとも1つの標的タンパク質の発現レベルと関連付け、急性骨髄性白血病(AML)を有する疑いのある個体由来の試料の複合マーカープロフィールを作成する手順;並びに
(e)前記複合マーカープロフィールを1つ以上の基準複合マーカープロフィールと比較する手順であって、前記比較によって急性骨髄性白血病(AML)の臨床経過の予測が可能となる、手順、
を含み、
前記試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、方法。 - 請求項1に記載の複合マーカープロフィールを作成するためのキットであって、
(a)個別の細胞集団関連マーカーに特異的な2つ以上の結合分子群を含有する結合分子の集合体であって、マーカーのレベル及びマーカーの組み合わせによって、前記試料に内在する正常及び腫瘍性細胞集団を同定する、結合分子の集合体;並びに
(b)腫瘍性病態を有する疑いのある個体由来の試料の複合マーカープロフィールを作成するための、活性化リン酸化シグナル伝達タンパク質、増殖マーカー、及びアポトーシスマーカーからなる群から選択される標的タンパク質に特異的な少なくとも1つの結合分子、
を含み、
前記試料は、白血病B細胞、正常B細胞、T細胞、NK細胞、正常な末梢血「前」B細胞、顆粒球又は単球の細胞集団を含む、キット。 - 前記細胞集団関連マーカーが細胞表面マーカーを含む、請求項29に記載のキット。
- 前記細胞表面マーカーが、CD3、CD5、CD10、CD11b、CD13、CD14、CD15、CD16、CD19、CD22、CD56、CD45、CD33、CD34、MPL(ミエロペルオキシダーゼ)、CD64、CD79a、CD79b、及びCD117(c−kit受容体)からなる群から選択される、請求項30に記載のキット。
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CN103399150A (zh) | 2013-11-20 |
JP2009515170A (ja) | 2009-04-09 |
EP1943516B1 (en) | 2015-01-07 |
EP1943516A2 (en) | 2008-07-16 |
CN103399150B (zh) | 2018-07-13 |
DK1943516T3 (en) | 2015-03-16 |
US20070105165A1 (en) | 2007-05-10 |
ES2531168T3 (es) | 2015-03-11 |
WO2007056192A2 (en) | 2007-05-18 |
WO2007056192A3 (en) | 2007-07-05 |
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