JP5128941B2 - 標的特異的コンポマー及び使用法 - Google Patents
標的特異的コンポマー及び使用法 Download PDFInfo
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Description
以下の説明には、本発明を理解するのに役立つ情報が含まれるが、当該情報が先行技術であること、若しくは本特許請求の発明に関連するものであること、又は明示的若しくは暗に引用されるすべての刊行物が先行技術であるということを認めるものではない。
生体分子(例えば、核酸、タンパク質、炭水化物及び脂質)の効率的で、信頼性の高い検出及び解析は、生物学における大きな課題である。これらの課題は、存在する異なる分子種の数という点からだけでなく、種々の特定種の分子の数に関しても極めて複雑な性質を持つ生体サンプルを解析するという状況において、特に重大である。この複雑性のため、妥当な、再現性のある結果を得るためには、極めて感度の高い、選択的方法が必要である。さらに問題を複雑にしているのは、そのような結果を、例えば、コスト、時間などの点で、商業的に実現可能な方法によって得なければならないということである。
本発明を詳細に記載する前に、本発明において用いるいくつかの用語を定義する。これらの用語に加え、他の用語も、必要に応じて、本明細書の他の場所で定義する。本明細書において特に定義しない限り、本明細書において用いる技術用語は、当該技術分野において理解されている意味を有する。
本発明は、サンプルが1種類以上の異種の標的分子を含むかどうかを決定するためのサンプルの効率的解析のための試薬及び方法を提供する。本発明によれば、サンプル中の1種類以上の特定標的分子種の検出は、その検出工程が標的分子の直接検出を必要としないという点から間接的に遂行される。代わりに、特定の標的と関連があるコンポマーを検出することによって特定の標的を検出する。本発明では、特定種の標的分子の間接検出を、アッセイ中にそれに対応するコンポマー種を生成させることによって行う。よって、コンポマー種は、それと関連がある標的分子がサンプル中に存在する場合のみ検出に利用できる。
広く、本発明は、サンプル、例えば、生体サンプル中の1種類以上の特定の標的分子種、例えば特定のポリペプチド又は核酸種を間接的に検出するための方法を提供する。特定の種の標的分子は、標的分子種と特に関連があるコンポマーを検出することによって間接的に検出される。コンポマーは、サブユニット、特に核酸塩基サブユニットで構成される線状重合体であり、それらは標的分子と特異的に結合する標的特異的分子と結合する鋳型から生成する。単一アッセイでの多様な標的分子種の平行解析を容易にするために、コンポマー種を、他のものと識別可能であるように設計する。コンポマー種間で異なる1つ以上の規定の特徴を通じて個別認識が行われる。定義することができるコンポマーの特徴としては、分子量、サブユニット配列及び長さと構造のみならず、異種間で識別がなされるように操作することができるその他の分子特徴も挙げられる。コンポマーの検出では、各コンポマーのもつ規定の特徴に応じて、好適なシステムを使用する。
本発明は、単一サンプルにおける1種類以上の標的分子の効率的な同時検出を提供する。本発明に従って解析することができるサンプルには、生体物質を含むかもしれないし、又は含まないかもしれない環境サンプルが含まれる。特に好ましいサンプルは、目的の生体分子種を含むことが分かっているか、又は含むことが疑われる生体サンプルである。解析用のサンプルは、任意の好適な供給源から得ることができる。サンプル取得後、検出すべき標的分子が、サンプル又はそのアリコート中に存在する場合には、本発明の標的検出試薬との相互作用を受けやすくする任意の好適な技術を用いてサンプルを処理する。
サンプル中に存在する目的の標的分子を検出するために、標的検出試薬を用いる。標的検出試薬は、図1に示すような、標的結合部分とコンポマー鋳型(又はその相補体)を含む合成分子である。標的結合部分とコンポマー鋳型は、単一反応で合成することができるし、又は異なる反応で合成した2個以上のサブユニットを組み合わせてそれらを結合してもよい。好ましい実施形態では、標的結合部分とコンポマー鋳型を別々に合成し、その後、必要に応じて要望どおりにそれらを結合することができる。コンポマー鋳型と標的結合部分の相互の配向は当業者の裁量に任せ、用途によって異なる。核酸成分からなる標的検出試薬の代表的な配向として、コンポマー鋳型が標的結合部分の5’又は3’に配置されたものが含まれる。同様に、他の任意の成分、例えば、プライマー結合部位(又はそれらの相補体)を含め、標的結合部分及び/又はコンポマー鋳型の上流又は下流(例えば、核酸に基づく成分の場合には、それぞれ、5’又は3’)に配置することができる。
本発明は、特定の標的分子を検出するための方法をさらに提供する。そのような方法は、(a)標的結合部分とコンポマー鋳型を含んでなる標的特異的な標的検出試薬を準備する工程;(b)標的分子を含むことが分かっているか又は疑われるサンプルを標的検出試薬と接触させて、試薬:標的複合体を作製する工程;(c)コンポマー鋳型からコンポマー(又は場合によっては、切断可能な基質)を生成させる工程;及び(d)アッセイで生成したコンポマー種を検出することにより、特定のコンポマー種と関連がある標的分子を間接的に検出するのに好適な検出技術を使用する工程を含む。そのような方法は、単一標的分子種、異なる標的分子種の小集団及び大量の異なる標的分子種に関して、多重形式により行い、例えば、数種類のコンポマー(各々が同じ標的分子と関連がある)の1種類以上を検出することができ、1種類以上のコンポマー種(それらの各々は2種類以上の異なる標的分子種と関連がある)を検出することができ、さらにコンポマー種(それらの各々は単一標的分子と関連がある)のライブラリーを使用することにより複数の異なる標的分子種を間接的に検出することができる。認められるように、異なるコンポマーを用いて、単一アッセイで数十、数百、数千もの異なる標的分子種(例えば、標的核酸)を同時に検出することができる。
コンポマーは、特定のアッセイで生成する可能性のある1種類以上のコンポマー種を検出するのに好適な任意の検出法を用いて検出することができるが、特定のアッセイにおいて可能な多重化のレベルは異なり得る。この目的に使用することができる検出システムの代表的な例としては、質量分析、電気泳動、クロマトグラフィー、核酸ハイブリダイゼーション及びNMRが挙げられる。コンポマー種の識別に有用な規定の特徴が質量に関係する場合には、質量分析が特に好ましい検出であるが、当業者ならば分かるように、当技術分野で公知の他の検出システムも、本明細書に基づいて本発明の実施用に容易に適合させることができる。このようなことから、以下の説明では質量に着目しているが、当然のことながら本発明の範囲は質量に基づく検出システム及び技術に限定されない。本発明において用いるのに好ましい質量分析計形式は、エレクトロスプレー(ES)、マトリックス支援レーザー脱離イオン化(MALDI)、イオンサイクロトロン共鳴(ICR)及びフーリエ変換である。ESでは、水又は揮発性バッファーに溶かしたサンプルを、大気圧イオン化インターフェース(API)に連続的又は不連続的に注入した後、四重極により質量を分析する。ES質量分析を用いて得ることができるイオンピークが多数出現すれば、質量決定の精度が高まる。特定の構造に関するさらに詳細な情報は、MS/MS四重極型の機器構成を用いることによって得ることができる。MALDI質量分析では、種々の質量分析装置、例えば、シングル又はトリプル四重極モード(MS/MS)の磁場/磁場偏向型装置、フーリエ変換型及び飛行時間型(TOF)の機器構成を使用することができる。脱離/イオン化法では、任意の好適なマトリックス/レーザー組み合わせを使用することができる。イオントラップ及びリフレクトロン型機器構成も使用することができる。現在のところ、MALDI-TOF質量分析がもっとも好ましい。質量分析やコンポマーを検出する他の方法については、例えば、米国特許第5,118,937号;同第5,202,561号;同第5,464,985号;同第5,547,835号;同第5,605,798号;同第5,622,824号;同第5,691,141号;同第5,777,324号;同第5,864,137号;同第5,869,242号;同第5,919,646号;同第5,922,542号;同第5,928,906号;同第6,024,925号;同第6,043,031号;同第6,051,378号;同第6,090,558号;同第6,104,028号;同第6,111,251号;同第6,194,144号;同第6,197,498号;同第6,207,370号;同第6,221,601号;同第6,221,605号;同第6,225,450号;同第6,235,478号;同第6,238,871号;同第6,258,538号;同第6,268,131号;同第6,268,144号;同第6,277,573号;同第6,300,076号;同第6,322,970号;同第6,379,917号;同第6,387,628号;同第6,423,966号;同第6,428,955号;同第6,436,635号;同第6,440,705号;同第6,458,945号;同第6,468,748号;同第6,475,736号;同第6,500,621号;同第6,500,650号;同第6,558,902号;同第6,566,055号;同第6,566,059号;同第6,582,923号;同第6,589,485号;同第6,602,662号;同第6,610,492号;同第6,635,452号;同第6,660,229号;同第6,706,530号;及び同第6,723,564号、並びに共同所有する米国特許出願番号第09/839,629号(公開番号20020155587)及び同第10/128,680号(公開番号20030033091)に記載されている。
標的検出試薬とそれらがコードするコンポマーには、種々の用途がある。例えば、標的結合部分は、タンパク質及び核酸などの特定の既知生体分子を標的とすることができる。特に好ましい標的分子は、疾患又は障害などの特定の状態の原因とまではいかなくても、その特定の状態と関係があることが分かっているものである。標的分子に特異的な標的検出試薬が標的分子と結合した後に、コンポマー鋳型からコンポマーを生成させることができる。その後、適合する検出システムを用いてコンポマーを検出することができ、その検出により、特定の標的分子の存在が間接的に示される。
Claims (8)
- サンプルが標的分子を含むかどうかを判定する方法であって、以下の:
a)反応条件下で、上記標的分子を含むことが疑われるサンプルを標的検出試薬と接触させて、試薬:標的複合体を形成させる工程、ここで当該標的検出試薬は、上記標的分子と特異的に反応する標的結合部分;及び当該標的結合部分に連結されたコンポマー鋳型、又はその相補体を含むものであり、ここで当該コンポマー鋳型は、コンポマーを含む切断可能な基質をコードする核酸分子であって、標的物質と関連があるが、当該標的分子と直接結合するわけではなく、かつ1、2又は3のサブユニットのみを含むコンポマーと、1又は複数のサブユニットを含む該切断可能な基質の他の部分とを供に含む、上記切断可能な基質をコードする核酸分子であり、ここで1又は複数のサブユニットのうち少なくとも1つは当該コンポマー内に存在せず、コンポマーがその位置で切断されて遊離可能であり;
b)形成したならば、試薬:標的複合体を用いて、コンポマー鋳型から切断可能な基質を生成させる工程、
c)該切断可能な基質を切断して、コンポマーを生成させる工程、そして
d)コンポマーが生成したかどうかを、質量分析法によりコンポマーを同定することによって判定し、それにより上記サンプルが上記標的分子を含むかどうかを判定する工程
を含む、前記方法。 - 前記切断基質が、化学的、物理的、及び酵素的プロセスからなる群から選ばれるプロセスにより切断される、請求項1に記載の方法。
- 前記コンポマー鋳型が、コンポマーを最低限コードするコード領域に作動可能なように連結されたプロモーター領域を含む転写ユニットを含む核酸分子を含む、請求項1又は2に記載の方法。
- 前記プロモーター領域が、細菌のプロモーター領域、バクテリオファージプロモーター領域、ウイルス及び真核プロモーター領域からなる群から選ばれる、請求項3に記載の方法。
- 前記プロモーター領域が、T7、SP6、及びT3プロモーター領域からなる群から選ばれるバクテリオファージプロモーター領域である、請求項4に記載の方法。
- 前記コンポマーが、2500〜10000ダルトンの分子量範囲で同定される、請求項1〜5のいずれか一項に記載の方法。
- 前記標的分子が、同一種のメンバー間で遺伝的バリエーションのソースからなる群から選ばれる核酸であり、かつ化学的に改変された核酸分子である、請求項1〜6のいずれか一項に記載の方法。
- 前記サブユニットが、核酸塩基サブユニットを指す、請求項1〜7のいずれか一項に記載の方法。
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EP1766092A4 (en) | 2009-10-28 |
HK1103107A1 (en) | 2007-12-14 |
US20090258793A1 (en) | 2009-10-15 |
CN101426932B (zh) | 2012-06-27 |
ES2406734T3 (es) | 2013-06-07 |
AU2005327980A1 (en) | 2006-08-31 |
CN101426932A (zh) | 2009-05-06 |
CA2569379A1 (en) | 2006-08-31 |
US7785843B2 (en) | 2010-08-31 |
EP1766092B1 (en) | 2013-03-20 |
WO2006091216A2 (en) | 2006-08-31 |
JP2008504028A (ja) | 2008-02-14 |
US20050287533A1 (en) | 2005-12-29 |
AU2005327980B2 (en) | 2011-08-18 |
WO2006091216A3 (en) | 2009-04-16 |
US7867714B2 (en) | 2011-01-11 |
CA2569379C (en) | 2015-10-13 |
EP1766092A2 (en) | 2007-03-28 |
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