JP2022153460A - 膀胱がんのバイオマーカーとしてのケラチン17 - Google Patents
膀胱がんのバイオマーカーとしてのケラチン17 Download PDFInfo
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Abstract
Description
本出願は、その内容が全体として参照により本明細書に組み込まれている、2016年8月5日出願の米国特許仮出願第62/371,286号の優先権の利益を主張するものである。
は、免疫組織化学的染色、若しくは免疫細胞化学的分析によって、又はmRNA検出によって決定される。
て、試料中のK17発現のレベルは、ELISAによって決定される。本方法の他の実施形態において、K17発現レベルは、膀胱細胞又は尿中のK17 mRNAの量を検出することによって決定される。
本開示で使用される「ペプチド」又は「タンパク質」という用語は、隣接するアミノ酸残基のアルファアミノ基とカルボキシ基との間のペプチド結合によって互いに連結した、直鎖状に連続するアミノ酸残基を指す。一実施形態において、タンパク質はケラチン17(K17)である。
本開示は、膀胱がんのバイオマーカーとしてケラチン17使用するための方法を説明する。ここでは、様々な診断カテゴリー(すなわち、非癌性膀胱粘膜、低悪性度乳頭状尿路上皮新生物(PUNLMP)、低異型度乳頭状尿路上皮癌(LG)、及び高異型度乳頭状尿路上皮癌(HG)、又は移行尿路上皮がん)について、ホルマリン固定パラフィン包埋試料又は尿細胞診試料から得た顕微解剖組織切片中で、K17 RNA又はタンパク質の発現を免疫組織化学、免疫細胞化学、溶液若しくは固相タンパク質アッセイ(例えば、ELISA、マイクロ流体、フローサイトメトリー、質量分析)によって検出、又は(例えば、Q-RTPCRなどのRT-PCR方法論によって)K17 mRNAを検出若しくはK17 mRNAのレベルを測定した。データは、K17が、対照(良性)試料とPUNLMP試料との間で発現に約30倍の差異;対照試料とLG膀胱がん試料との間で発現に15倍の差異;及び対照試料とHG膀胱がん試料との間でK17発現に13倍の差異を示したことを示す。したがって、本開示は、K17発現は、測定することができ、膀胱がんの診断のための診断バイオマーカーとして使用することができることを示すものである。
材料及び方法。
実施した試験は、84例のホルマリン固定パラフィン包埋した外科的組織塊(Table 1 (表1))の分析を含んだ。外科的組織塊は全て、膀胱がんを有することが疑わしい対象(患者)から得た。これらの試験の症例は、次の診断カテゴリー:良性の尿路上皮、(n=12)、低悪性度乳頭状尿路上皮新生物(PUNLMP)(n=9)、低異型度乳頭状尿路上皮癌(n=23)、高異型度乳頭状尿路上皮癌(n=14)、移行/尿路上皮癌(n=26)を含む。ある症例において、組織塊は、病理学者によって、経尿道的切除術(TURBT)、膀胱生検、又は膀胱切除標本のいずれかからのヘマトキシリン-エオジン染色した切片を、当初報告された診断組織が残余組織塊に十分に提示されていることを確認する組織学的再調査(DCM)を行って、選択した。残余組織が不足している、又は診断に用いた組織が後の臨床使用のために保存できなかった症例は、本試験に含めなかった。膀胱がんは、全内容が参照により本明細書に組み込まれているEdge SB及びCompton CC. Annals of surgical oncology. (2010) 17:1471~4頁に記載の(i)臨床病期、並びに(ii)腫瘍異型度(Table 1 (表1))によって分類した。
膀胱がんの診断方法としての免疫組織化学的染色細胞におけるケラチン17検出。
早期の膀胱がんの1つ又は複数の診断カテゴリーにおけるK17の診断値を決定するために、保管していた、良性の膀胱粘膜(良性の)、低悪性度乳頭状尿路上皮新生物(PUNLMP)、低異型度乳頭状尿路上皮癌(LG)、高異型度乳頭状尿路上皮癌(HG)、及び尿路上皮がんの4つの診断カテゴリーからの膀胱がん患者の組織試料の組織に対して、K17についての免疫組織化学的染色(Table 1 (表1))を行った。
自動装置ベースの検出方法による細胞中のケラチン17検出。
尿細胞診試料の免疫染色に加えて、尿細胞診試料中のK17陽性細胞は、蛍光的にタグ付けされたタンパク質を検出することができる、フローサイトメトリー及びマイクロ流体装置システムによって検出が可能である。ここでは、K17が陽性であることが既知である標識されたがん細胞(HeLa、図8A)、及びK17陰性である対照細胞(C33、図8B)を単離し、K17抗体で蛍光標識し、上述の通り、K17発現をマイクロ流体検出装置上で分析した。図8A~8Bにみられるように、対照のC33細胞(K17陽性は35.1%)と比較して、HeLa中ではK17標識細胞が有意に多い(K17陽性は90.4%)。まとめると、これらのデータは、K17陽性細胞の検出が、K17免疫染色とマイクロ流体装置とを併用して効率的に達成しうることを示している。
無細胞K17ベースの診断方法。
Table 4 (表4)及びTable 5 (表5)に示したように、膀胱細胞を欠く自然尿からなる検査試料をK17タンパク質発現について分析して、対象が膀胱がんを有するかどうかを判定することができる。例えば、Table 4 (表4)は、ELISAベースのK17検出方法を用いて得られた結果を示す。ここでは、既知量のK17タンパク質を有する対照試料(すなわち、標準物質)を分析して、無細胞試料のELISAシステム検査の感度を決定した。増加したK17タンパク質発現のカットオフ値は、検出可能なシグナルを陰性対照の平均からのブランクの3倍の標準偏差とした陰性対照(ゼロ標準物質)から決定した。例えば、次式を用いた:陰性対照のELISAの読み取りの平均+[陰性対照の3倍の標準偏差]。データに基づくと、ELISAの感度の限界は、K17タンパク質、約1ng/1mLである。
Claims (25)
- 対象のケラチン17発現を検出するための方法であって、
対象から試料を受け取る工程であって、前記試料が複数の膀胱細胞を含む、工程と、
前記試料中のケラチン17(K17)タンパク質発現を検出する工程であって、前記検出が前記細胞を抗K17抗体と接触させる工程、及び細胞中の前記K17タンパク質と抗K17抗体との間の結合を免疫組織化学分析によって検出する工程と、
K17染色によりK17発現について前記細胞をスコアリングする工程であって、K17染色が2+であるならば、前記対象が膀胱がん細胞を有する、工程と
を含む、方法。 - 前記試料を加工する工程を更に含み、前記加工する工程が、試料を解体して細胞を単離する工程と、尿素を含む溶解溶液中で単離した細胞を溶解する工程と、溶解溶液からタンパク質を単離する工程と、トリプシンを含む消化溶液中で単離したタンパク質を消化する工程と、得られた混合物を、ペプチドを目的とした遠心分離に供する工程とを含む、請求項1に記載の方法。
- 前記試料が、膀胱組織及び尿からなる群から選択される、請求項1に記載の方法。
- 前記膀胱組織が、生検組織、又はホルマリン固定パラフィン包埋組織試料である、請求項3に記載の方法。
- 前記複数の膀胱細胞が、移行上皮細胞、結合組織細胞、筋肉細胞、脂肪細胞、又はそれらの組合せである、請求項1に記載の方法。
- 対象の膀胱がんを診断する方法であって、
対象から試料を受け取る工程であって、前記試料が複数の膀胱細胞を含む、工程と、
前記試料の前記膀胱細胞中のK17タンパク質発現を検出する工程であって、前記検出が、前記細胞を抗K17抗体と接触させる工程、及び細胞中のK17タンパク質と抗K17抗体との間の結合を検出する工程を含む、工程と、
複数の膀胱細胞を含む対照尿試料を受け取る工程と、
前記対照尿試料中のK17タンパク質発現を検出する工程であって、前記検出が前記対照尿試料を抗K17抗体と接触させる工程、及び前記対照尿試料中のK17と抗K17抗体との間の結合を検出する工程と、
前記対照尿試料中のK17発現の量と比較して、試料中でK17タンパク質発現の量の10倍~60倍の間の増加が検出される場合、対象が膀胱がんであると診断する工程と
を含む、方法。 - 前記膀胱がんが尿路上皮がんである、請求項6に記載の方法。
- 前記尿路上皮がんが、低悪性度乳頭状新生物、低異型度乳頭状尿路上皮がん、高異型度乳頭状尿路上皮がん、又は移行尿路上皮がんである、請求項7に記載の方法。
- 前記抗K17抗体が、抗ヒトK17マウスモノクローナル抗体[E3]である、請求項6に記載の方法。
- 前記試料が尿試料である、請求項6に記載の方法。
- 前記試料が、膀胱組織、又はホルマリン固定パラフィン包埋膀胱組織である、請求項6に記載の方法。
- 試料中のK17タンパク質発現が、免疫組織化学、組織マイクロアレイ、免疫細胞化学的分析、ウエスタンブロッティング、フローサイトメトリー、マイクロ流体検出、及びELISAからなる群から選択される方法によって検出される、請求項6に記載の方法。
- 試料中のK17タンパク質発現が、免疫組織化学、又は免疫細胞化学的分析によって検出される、請求項12に記載の方法。
- 請求項6に記載の方法を実施するために構成された構成要素を含む、対象を膀胱がんと特定するためのキット。
- 対象を膀胱がんであると診断するための方法であって、
対象から尿試料を受け取る工程であって、前記尿試料が複数の膀胱細胞を含む、工程と、
前記試料の前記膀胱細胞中のケラチン17(K17)タンパク質発現を検出する工程であって、前記検出が前記細胞を抗K17抗体と接触させる工程、及び前記尿試料中のK17タンパク質と抗K17抗体との間の結合を、免疫組織化学分析または酵素結合免疫吸着アッセイ(ELISA)によって検出する工程と、
複数の膀胱細胞を含む対照尿試料を受け取る工程と、
前記対照尿試料中のK17タンパク質発現を検出する工程であって、前記検出が前記対照尿試料中の前記細胞を抗K17抗体と接触させる工程、及び前記対照尿試料中のK17タンパク質と抗K17抗体との間の結合を、免疫組織化学分析またはELISAによって検出する工程と、
前記対照尿試料中のK17タンパク質発現の量と比較して、試料中でK17タンパク質発現の量の10倍~60倍の間の増加が検出される場合、対象が膀胱がんであると診断する工程と
を含む、方法。 - 前記K17タンパク質発現がELISAによって検出される、請求項15に記載の方法。
- 前記抗K17抗体が、抗ヒトK17マウスモノクローナル抗体[E3]である、請求項15に記載の方法。
- 請求項15に記載の方法を実施するために構成された構成要素を含む、哺乳動物の対象を膀胱がんであると診断するためのキット。
- 対象の膀胱がんを診断する方法であって、
対象から尿試料を受け取る工程であって、前記試料が複数の膀胱細胞を含む、工程と、
定性的又は定量的検出方法を使用して前記試料の前記膀胱細胞中のK17タンパク質の量を検出する工程であって、
対照尿試料のK17発現の量と比較して、前記尿試料中でK17タンパク質発現の量の10倍~60倍の間の増加が、前記対象が膀胱がんを有することを示す、工程と
を含む、方法。 - 前記試料に対して細胞回収工程が行われる、請求項19に記載の方法。
- 前記検出方法が定量的アッセイである、請求項19に記載の方法。
- 複数のK17タンパク質の量を複数の尿試料において同時に検出する、請求項19に記載の方法。
- 前記検出する工程が自動装置の使用を含む、請求項19に記載の方法。
- 前記自動装置がK17以外のバイオマーカーについてタンパク質のアッセイを行うことができる、請求項23に記載の方法。
- 前記検出する工程が、手持ち式又は可動式検出装置の使用を含む、請求項19に記載の方法。
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