JP2017515108A - 肉腫の転移を検出するための方法およびバイオマーカー - Google Patents
肉腫の転移を検出するための方法およびバイオマーカー Download PDFInfo
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Abstract
Description
本出願は、その全体が参照により本明細書に援用される「method and biomarker for detecting metastasis of sarcoma」という表題で2014年4月22日に出願されたPCT出願第PCT/CN2014/075944号および「method and biomarker for detecting metastasis of sarcoma」という表題で2014年4月23日に出願されたPCT出願第PCT/CN2014/076048号に関し、それに基づく優先権の利益を主張する。
本出願の第1の態様は、対象における肉腫転移を評価するための方法を提供する。この方法は、対象の生体サンプルを得ること、およびこの生体サンプル中におけるモエシンのN末端セグメントのレベルを検出することを含む。対象の生体サンプルで検出されたモエシンのN末端セグメントのレベルは、この対象が肉腫の転移を発症していること、またはこの対象が肉腫の転移を発症する可能性が高いことを示す。
本出願の別の態様は、モエシンのN末端セグメントから本質的になる、肉腫転移を評価するためのバイオマーカーを提供する。
本出願の別の態様は、対象における肉腫転移を治療するための方法に関する。この方法は、モエシンのN末端セグメントの機能を特異的に調節する試薬と、薬学的に許容される添加剤とを含む医薬組成物の有効量を対象に投与することを含む。
モエシンのN末端セグメントに対するモノクローナル抗体を、従来のハイブリドーマ法を使用して調製することができる。配列番号3の配列を有するモエシンのN末端セグメントを生成するために、PCRを使用して、図3に示す配列番号3に記載のN末端セグメントに対応するcDNA断片を増幅させる。
様々なステージの肉腫を有する患者から血清サンプルまたは血漿サンプルを採取し、化学発光酵素免疫アッセイを使用して、N末端セグメント(アミノ酸残基1〜297)およびC末端セグメント(アミノ酸残基471〜577)等のヒトモエシンの特異的セグメントの存在に関して試験した。簡潔に言うと、セグメントに特異的に結合する抗体をコーティングしたプレートへの結合を競合させるために、ビオチン標識N末端セグメントまたはビオチン標識C末端セグメントでサンプルを希釈した。次いで、酵素(西洋ワサビペルオキシダーゼ)標識ストレプトアビジンを添加してビオチンに結合させた。洗浄後、発光シグナルを発現させて、プレートに結合した酵素標識ストレプトアビジンを測定した。この発光シグナルは、サンプル中のN末端セグメントまたはC末端セグメントの濃度に反比例していた。
最初に、天然状態で抗体を保存することができる条件下で、ポリスチレンマイクロウェルプレートのウェルに、モエシンタンパク質のN末端セグメントまたはC末端セグメントに対する高純度の抗体をコーティングした。具体的には、ELISAプレート(LUMITRAC(商標)600 96−ウェルの白色の免疫プレート、Greiner 655074)の各マイクロウェルを、12〜16時間にわたり2℃〜8℃にて、モエシンのN末端セグメントまたはC末端セグメントに対する抗体 約100ngと共にインキュベートした。次いで、このプレートをPBSで1回洗浄した後、保存して後に使用するために、ブロッキング溶液でブロックして真空乾燥した。
図4および表1に示すように、転移性肉腫の患者からのサンプルは、健康な個体と比べて有意に高い濃度のN末端モエシンセグメントを含んでいた(p<0.05)。これに対して、非転移性肉腫の患者でのN末端モエシンセグメントの濃度は健康な個体と比べて有意に高くはなく(p=0.11)、転移性肉腫の患者および非転移性肉腫の患者の両方でのC末端モエシンセグメントは、健康な個体と比べて有意に高かった(p<0.001)。これらのサンプルでは、完全長のモエシンタンパク質を検出しなかった。したがって、N末端モエシンセグメントの存在を、転移性肉腫のバイオマーカーとして使用することができる。
Claims (29)
- 対象における肉腫転移を評価するための方法であって、
対象の生体サンプルを得ること、
生体サンプル中におけるモエシンのN末端セグメントのレベルを検出すること
を含み、
対象の生体サンプルで検出されたモエシンのN末端セグメントのレベルが、対象が肉腫の転移を発症していること、または対象が肉腫の転移を発症する可能性が高いことを示す、方法。 - N末端セグメントがヒトモエシンのアミノ酸残基1〜297からなる、請求項1に記載の方法。
- モエシンが、配列番号2に記載のアミノ酸配列を有するヒトモエシンである、請求項2に記載の方法。
- N末端セグメントが、ヒトモエシンのアミノ酸残基1〜297の領域からの少なくとも20個の連続したアミノ酸残基を含む、請求項1に記載の方法。
- N末端セグメントが、ヒトモエシンのアミノ酸残基1〜297の領域からの少なくとも50個の連続したアミノ酸残基を含む、請求項1に記載の方法。
- 生体サンプル中におけるモエシンのN末端セグメントのレベルが、前記サンプルとモエシンのN末端セグメントに特異的に結合する試薬とを接触させることにより検出される、請求項1に記載の方法。
- 前記試薬が、モエシンのN末端セグメントに結合する抗体またはこの抗体断片である、請求項6に記載の方法。
- 前記抗体がモノクローナル抗体である、請求項7に記載の方法。
- 対象の生体サンプルで検出されたモエシンのN末端セグメントのレベルが、参照サンプルから検出したモエシンのN末端セグメントの参照レベルと比較される、請求項1に記載の方法。
- モエシンのN末端セグメントの参照レベルと比べて、生体サンプルで検出されたモエシンのN末端セグメントのレベルが高いことが、対象が肉腫の転移を発症していること、または対象が肉腫の転移を発症する可能性が高いことを示す、請求項8に記載の方法。
- 生体サンプルで検出されたモエシンのN末端セグメントのレベルが、モエシンのN末端セグメントの参照レベルの少なくとも2倍である、請求項9に記載の方法。
- 生体サンプルで検出されたモエシンのN末端セグメントのレベルが、モエシンのN末端セグメントの参照レベルの少なくとも5倍である、請求項9に記載の方法。
- 参照サンプルが、腫瘍を有さない対象または腫瘍が非転移性である対象に由来する、請求項10に記載の方法。
- 生体サンプルが、全血、血清および血漿からなる群から選択される、請求項1に記載の方法。
- 肉腫が、骨肉腫、ユーイング肉腫、非ホジキンリンパ腫、多発性骨髄腫、軟骨肉腫、巨細胞腫、脂肪肉腫または平滑筋肉腫である、請求項1に記載の方法。
- モエシンのN末端セグメントから本質的になる、肉腫転移を評価するためのバイオマーカー。
- ヒトモエシンのアミノ酸残基1〜297の内の少なくとも20個の連続したアミノ酸残基を含む、請求項16に記載のバイオマーカー。
- ヒトモエシンのアミノ酸残基1〜297の内の少なくとも50個の連続したアミノ酸残基を含む、請求項16に記載のバイオマーカー。
- モエシンのN末端セグメントがヒトモエシンのアミノ酸残基1〜297からなる、請求項16に記載のバイオマーカー。
- ヒトモエシンのアミノ酸残基1〜297をコードする、単離ヌクレオチド配列またはそのバリアント。
- モエシンのN末端セグメントに特異的に結合する試薬を含む、対象における肉腫転移を評価するためのキット。
- 前記試薬が抗体である、請求項21に記載のキット。
- 対象における肉腫転移を評価するためのバイオマーカーとしてのモエシンのN末端セグメントの使用。
- 対象における肉腫転移を評価するための検出剤を製造するための、モエシンのN末端セグメントの使用。
- 対象における肉腫転移を治療する方法であって、モエシンのN末端セグメントの機能を特異的に調節する試薬と、薬学的に許容される添加剤とを含む医薬組成物を対象に投与することを含む方法。
- 前記試薬がモエシンのN末端セグメントに特異的に結合する、請求項25に記載の方法。
- 前記試薬が抗体である、請求項26に記載の方法。
- 前記試薬がモノクローナル抗体またはその断片である、請求項27に記載の方法。
- 対象における肉腫転移を治療するための薬剤を製造するためのモエシンのN末端セグメントの使用。
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PCT/CN2015/077163 WO2015161793A1 (en) | 2014-04-22 | 2015-04-22 | Method and biomarker for detecting metastasis of sarcoma |
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US20170059570A1 (en) | 2017-03-02 |
AU2015251315A1 (en) | 2016-11-03 |
US10365282B2 (en) | 2019-07-30 |
EP3134429B1 (en) | 2019-06-19 |
EP3134429A1 (en) | 2017-03-01 |
WO2015161793A1 (en) | 2015-10-29 |
CN106459166B (zh) | 2020-03-10 |
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