JP5312684B2 - 癌のマーカーとしてのdppiv/セプラーゼの使用 - Google Patents
癌のマーカーとしてのdppiv/セプラーゼの使用 Download PDFInfo
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- JP5312684B2 JP5312684B2 JP2012508930A JP2012508930A JP5312684B2 JP 5312684 B2 JP5312684 B2 JP 5312684B2 JP 2012508930 A JP2012508930 A JP 2012508930A JP 2012508930 A JP2012508930 A JP 2012508930A JP 5312684 B2 JP5312684 B2 JP 5312684B2
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Description
本発明は、癌の評価の補助方法に関する。本発明は、種々の癌型のユニバーサルマーカーとしての「可溶性DPPIV/セプラーゼタンパク質複合体」(=DPPIV/セプラーゼ)の使用を開示する。DPPIV/セプラーゼの測定値は、例えば癌の早期検出もしくは診断、または手術を受けた患者のサーベイランスに使用され得る。
a)腫瘍の外科切除、
b)化学療法、
c)放射線療法、
d)生物製剤、例えば抗腫瘍抗体または抗脈管形成抗体を用いた治療、および
e)上記方法の組み合わせ
である。
本発明は、液体試料中の液体試料中の、a)可溶性ジペプチジルペプチダーゼIV/セプラーゼタンパク質複合体(=DPPIV/セプラーゼ)、b)任意に癌の1つ以上の他のマーカーの濃度を測定する工程、ならびにc)工程(a)および任意に工程(b)の測定結果を癌の評価に使用する工程を含み、DPPIV/セプラーゼの濃度の低下が癌を示す、インビトロで癌を評価する方法に関する。
好ましい態様において、本発明は、試料中のDPPIV/セプラーゼの濃度を測定する工程、および測定結果、特に測定した濃度を癌の評価に使用する工程を含む、インビトロにおける癌の評価方法に関する。
スクリーニングは、疾患の表示、例えば癌の存在について、個体、例えばリスクのある個体を同定するための試験の体系的な適用として規定される。好ましくは、スクリーニング集団は、癌のリスクが平均より高いことが知られた個体で構成される。例えば、肺癌のスクリーニング集団は、喫煙者、元喫煙者、およびウラン、石英またはアスベスト曝露労働者などの肺癌のリスクが平均より高いことが知られた個体で構成される。
マーカーは、特定の臓器の良性疾患対悪性疾患の鑑別診断を補助するか、異なる組織学的腫瘍型の識別を補助するか、または手術前のベースラインマーカー値を確立するかのいずれかであり得る。
予後指標は、一定の尤度で疾患結果を予測する癌患者およびその腫瘍の臨床的、病理学的、または生化学的特徴と定義され得る。その主な使用は、患者管理の合理的な計画、すなわち、それぞれ急性進行性疾患の過少治療および進行が遅い疾患の過剰治療の回避を補助すべきである。Molina、R.,et al.,Tumor Biol. 24 (2003)209-218では、NSCLCにおいてCEA、CA 125、Cyfra 21-1、SSCおよびNSEの予後値が評価された。彼らの研究では、マーカーNSE、CEA、およびLDH(乳酸デヒドロゲナーゼ)の異常血清レベルは、短い生存を示すようであった。
Merle,P.,et al.,Int. J. of Biological Markers 19 (2004)310-315では、導入補助化学療法で治療された局所進行NSCLCを有する患者におけるCyfra21-1血清レベルの変化が評価された。彼らは、Cyfra21-1血清レベルの早期モニタリングが病期III NSCLC患者の腫瘍応答および生存の有用な予後ツールであり得ると結論づけた。また、報告により、LCを有する患者の治療のモニタリングにおけるCEAの使用が記載された(Fukasawa, T. et al., Gan to Kagku Ryoho 13 (1986) 1862-1867)。これらの研究のほとんどは、遡及的でランダムではなく、少数の患者を含んだ。Cyfra21-1での研究の場合のように、CEA研究は、a)化学療法を受けている間にCEAレベルが減少した患者は、一般的に、CEAレベルが減少しなかった患者よりも良好な結果を有し、(b)ほぼすべての患者で、CEAレベルの増加は疾患の進行と関連したことを示した。
癌性組織の完全な除去を目的とした外科的切除を受けるLC患者の大部分は、
後に再発性または転移性の疾患を発症する(Wagner, H. Jr., Chest 117 (2000) 110S-118S; Buccheri, G. et al., Ann. Thorac. Surg. 75 (2003) 973-980)。これらの再発のほとんどは、手術後最初の2〜3年以内に起こる。再発性/転移性疾患は、検出が遅すぎた場合は常に致死的であるため、相当な研究が、その初期ひいては潜在的に治療可能な病期での癌再発に焦点を当てている。
配列番号: 1は、ヒトセプラーゼタンパク質(アイソフォーム1); SwissProtデータベース受託番号Q12884のアミノ酸配列を示す。
配列番号: 2は、ヒトDPPIVタンパク質; SwissProtデータベース受託番号P27487のアミノ酸配列を示す。
配列番号: 3は、可溶性ヒトDPPIVタンパク質; Swissprotデータベース受託番号P27487の29〜766位のアミノ酸配列を示す。
配列番号: 4は、可溶性ヒトセプラーゼタンパク質; Swissprotデータベース受託番号Q12884の26〜760位のアミノ酸配列を示す。
ラットモノクローナル抗DPPIVおよび抗セプラーゼ抗体(それぞれ、クローンE26およびD28)は、Vitatex Inc. (Stony Brook、NY、USA)から購入した。該抗体は、以前に、Ghersi,G. et al. (J. Biol. Chem. 277 (2002) 29231-29241)およびPineiro-Sanchez,M.-L. et al. (J. Biol. Chem. 12 (1997) 7595-7601)によって記載されている。
モノクローナルラットIgG(クローンE26)を、10mM NaH2PO4/NaOH、pH7.5、30mM NaCl中で10mg/mlにした。IgG溶液1mlあたり50μlのビオチン-N-ヒドロキシスクシンイミド(DMSO中3.6mg/ml)を添加した。室温で30分後、試料をSuperdex 200上でクロマトグラフィー処理した(10mM NaH2PO4/NaOH、pH7.5、30mM NaCl)。ビオチン化IgG含有画分を回収した。
モノクローナルラットIgG(クローンD28)を10mM NaH2PO4/NaOH、30mM NaCl、pH7.5中で10mg/mlにした。IgG溶液1mlあたり50μlのジゴキシゲニン-3-O-メチルカルボニル-ε-アミノカプロン酸-N-ヒドロキシスクシンイミドエステル(Roche Diagnostics、Mannheim、Germany、カタログ番号1 333 054)(DMSO中3.8mg/ml)を添加した。室温で30分後、試料をSuperdex(登録商標)200(10mM NaH2PO4/NaOH、pH7.5、30mM NaCl)上でクロマトグラフィー処理した。ジゴキシゲニン化IgG含有画分を回収した。
ヒト血清および血漿試料中のDPPIV/セプラーゼの測定のためのELISA
ヒト血清または血漿中のDPPIV/セプラーゼの検出のため、サンドイッチELISAを開発した。抗原の捕捉および検出のため、等分量の抗DPPIV モノクローナル抗体E26と抗セプラーゼモノクローナル抗体D28 (実施例1参照)を、それぞれ、ビオチンおよびジゴキシゲニンとコンジュゲートした。
CRC試験集団
第1の試験において、48名の充分特徴付けされた結腸直腸癌の患者(表1に示されたUICC分類)由来の試料を使用した。
から得られた対照試料(=対照コホート)と比較して評価した。
DPPIV/セプラーゼ複合体は癌患者を健常対照と識別する
DPPIV/セプラーゼの血清濃度は、CRC患者と健常対照間で顕著に異なる(図1および2)。
LC試験集団
第1の試験とは完全に独立した第2の試験では、肺癌(正確には、非小細胞肺癌: NSCLC)、頭頸部癌および膵臓癌に焦点を当てた。NSCLCでは、その2つの主要な型、腺癌および扁平上皮癌に苦しむ患者を調査した。表3は、肺癌コホートの型および病期分布を示す。
DPPIV/セプラーゼはLC患者を健常対照と識別する
DPPIV/セプラーゼの血清濃度は、LC患者と健常対照間で顕著に異なる(図3)。癌患者コホートの平均濃度は対照コホートよりも有意に低い: 患者では35U/mlに対して対照では75U/ml。それぞれの対照コホートに対して95%特異性をもたらすカットオフ値では、肺癌の感度は77%である。
頭頸部試験集団
この試験では、頭頸部癌を有する充分特徴付けされた29名の患者由来の試料を使用した(表6に示すUICC分類)。試料を、既知の悪性疾患はなにもない明らかに健常な67名の個体から得た対照試料(=対照コホート)と比較して評価した。同じ対照コホートをLCおよび膵臓癌でのDPPIV/セプラーゼ試験の感度の評価に適用した。
DPPIV/セプラーゼは頭頸部癌患者を健常対照と識別する
DPPIV/セプラーゼの血清濃度は頭頸部癌患者と健常対照間で異なる(図3)。頭頸部癌患者コホートの平均濃度は対照コホートよりも有意に低い: 患者では44U/mlに対して対照では75U/ml。それぞれの対照コホートに対して95%特異性をもたらすカットオフ値では、頭頸部癌の感度は59%である。
膵臓癌試験集団
この試験では、膵臓癌を有する充分特徴付けされた44名の患者由来の試料を、対照コホートと比較して評価した。同じ対照コホートをLCおよび頭頸部癌でのDPPIV/セプラーゼ試験の感度の評価に適用した。表7は、膵臓癌コホートの型および病期分布を示す。
DPPIV/セプラーゼ複合体は膵臓癌患者を健常対照と識別する
DPPIV/セプラーゼの血清濃度は膵臓癌患者と健常対照間で顕著に異なる(図3)。膵臓癌患者コホートの平均濃度は対照コホートよりも有意に低い: 患者では41U/mlに対して対照では75U/ml。それぞれの対照コホートに対して95%特異性をもたらすカットオフ値では、膵臓癌の感度は59%である。
Claims (12)
- 血清または血漿試料中の
a) 可溶性ジペプチジルペプチダーゼIV/セプラーゼタンパク質複合体(=DPPIV/セプラーゼ)、
b) 任意に、癌の1つ以上の他のマーカー
の濃度を測定する工程、ならびに
c) 癌の評価において工程(a)および任意に工程(b)の測定結果を使用する工程を含み、ここで、DPPIV/セプラーゼの濃度の減少は癌を示す、
インビトロで癌を評価するための方法。 - サンドイッチイムノアッセイである、請求項1記載の方法。
- さらに、DPPIV/セプラーゼの一部としての可溶性ジペプチジルペプチダーゼIV (=可溶性DPPIV) に結合する第1の特異的結合剤、およびDPPIV/セプラーゼの一部としての可溶性セプラーゼタンパク質(=セプラーゼ)に結合する第2の特異的結合剤のそれぞれが使用されることを特徴とする、請求項2記載の方法。
- さらに、DPPIV/セプラーゼ複合体に結合するが可溶性DPPIVまたはセプラーゼのそれぞれには結合しない特異的結合剤が使用されることを特徴とする、請求項1または2記載の方法。
- さらに、それぞれ、第1の特異的結合剤または第2の特異的結合剤のいずれかが捕捉結合剤として使用され、前記第2の特異的結合剤または前記第1の特異的結合剤のいずれかが検出結合剤として使用されることを特徴とする、請求項2〜4いずれか記載の方法。
- さらに、肺、結腸、頭頸部、膵臓、食道、胃、胆管、腎臓、頸部、卵巣、乳房、膀胱、子宮内膜および前立腺の癌などの癌を評価するための方法であることを特徴とする、請求項1〜5いずれか記載の方法。
- さらに、工程(b)の前記1つ以上の他のマーカーが、Cyfra 21-1、CEA、FERR、OPN、抗p53自己抗体、セプラーゼ、NNMT、PSE3、S100A12、CYBP、ASC、NSE、CA19-9およびCA125からなる群より選択されることを特徴とする、請求項1〜6いずれか記載の方法。
- 癌の評価におけるDPPIV/セプラーゼの使用であって、DPPIV/セプラーゼの濃度の減少が癌を示し、DPPIV/セプラーゼが血清または血漿試料中において検出される、使用。
- 肺、結腸、頭頸部、膵臓、食道、胃、胆管、腎臓、頸部、卵巣、乳房、膀胱、子宮内膜および前立腺の癌からなる群より選択される癌の評価における、請求項8記載の使用。
- 癌の評価におけるDPPIV/セプラーゼおよび任意に癌の1つ以上の他のマーカーを含むマーカーパネルの使用であって、DPPIV/セプラーゼの濃度の減少が癌を示し、DPPIV/セプラーゼが血清または血漿試料中で検出される、使用。
- さらに、該任意に1つ以上の他のマーカーが、Cyfra 21-1、CEA、FERR、OPN、抗p53自己抗体、セプラーゼ、NNMT、PSE3、S100A12、CYBP、ASC、NSE、CA19-9およびCA125からなる群より選択されることを特徴とする、請求項10記載のマーカーパネルの使用。
- 肺、結腸、頭頸部、膵臓、食道、胃、胆管、腎臓、頸部、卵巣、乳房、膀胱、子宮内膜および前立腺の癌の評価における、請求項10または11記載のマーカーパネルの使用。
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