JP2019537029A - 合成分類指標の同定のためのシステムおよび方法 - Google Patents
合成分類指標の同定のためのシステムおよび方法 Download PDFInfo
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Abstract
Description
発明の要旨
[0005]本発明は、合成分類指標の同定のためのシステムおよび方法を提供することによって、前述の欠点を克服する。
[0012]方法の別の側面において、第一の複数のペプチドにおけるペプチドは、1アミノ酸〜4アミノ酸の間でタイリングされる。
[0014]方法の別の側面において、変異体ペプチドの各1つは天然存在ペプチドに対応し、そして変異体ペプチドの各1つは、少なくとも1つのアミノ酸位に関して、対応する天然存在ペプチド配列と異なる配列を有する。
[0021]方法の別の側面において、第一の複数のペプチドにおけるペプチドは、1アミノ酸〜4アミノ酸の間でタイリングされる。
[0035]本出願において、文脈から別に明らかでない限り、(i)用語「a」は、「少なくとも1つ」を意味すると理解可能であり;(ii)用語「または(оr)」は、「および/または(and/or)」を意味すると理解可能であり;(iii)用語「含む(comprising)」および「含まれる(including)」は、それらのみ、あるいは1またはそれより多いさらなる構成要素または工程とともに提示されるかいずれであっても、箇条書きされた構成要素または工程を含むと理解可能であり;そして(iv)用語「約」および「およそ」は、一般の当業者によって理解されるであろうような標準的な変動を可能にすると理解可能であり;そして(v)範囲が提供される場合、終点が含まれる。
[0048]やはり上に論じるように、多様な状況において、特定の状態、疾患等に関して、被験体を正確に診断するための方法を提供することが有用でありうる。診断の性質に応じて、方法または試験は、初期の検出を可能にすることも可能であり、治療等に関して計画する改善された機会を潜在的に生じる。しかし、所定の病気は、特に、検出可能な症状が、より容易に検出可能な方式では明らかになっていない可能性がある、分子レベルでの変化(例えばゲノム突然変異、タンパク質凝集、核酸またはタンパク質の発現レベルの変化等)に制限されている初期には、正確に診断することが困難でありうる。例えば、アルツハイマー病(AD)は、記憶喪失、錯乱、および判断力の低下または劣った判断力のような外からわかる徴候が含まれうる、慢性神経変性疾患である。しかし、ADの原因はほとんど理解されていない一方、タンパク質ミスフォールディングを含む生化学的変化が、疾患進行に寄与すると仮定されている。したがって、現在、より明確な診断には、脳組織の検査が必要である。すなわち、ADのような疾患の診断は、主観的であるか、または状態進行の初期には検出が困難でありうる、行動特性または他の外からわかる徴候とは対照的に、ペプチド、タンパク質、または核酸などのバイオマーカーに焦点を当てた診断から利益を受ける可能性もある。
実施例1:
[0061]関節リウマチ(RA)は、身体の多数の関節(例えば5より多い関節)において現れる、全身性炎症性疾患である。炎症プロセスは、主に、関節の裏打ち(滑膜)に影響を及ぼすが、他の臓器にもまた影響を及ぼしうる。炎症滑膜は、軟骨および骨の侵食、ならびにときに関節変形を導く。関節リウマチは自己免疫疾患であるため、リウマチ因子(RF)などの自己抗体が、しばしば、RA患者から単離された血清試料中に存在する。1990年代後期、アルギニンのシトルリン化、そしてより最近、リジンのホモシトルリン化が、RA患者の血清から単離された自己抗体の抗原性決定基と同定されてきている(Prujinら, 2015. Citrullination and carbamylation in the pathophysiology of rheumatoid arthritis, Front Immunol. vol. 6, iss. 192もまた参照されたい)。RAの典型的な第一選択治療には、疾患修飾性抗リウマチ薬(DMARDS)の使用が含まれる。
[0069]高密度ペプチドアレイ産生のためのマスクレスアレイ合成プラットフォームの使用、ペプチド分類指標発見、およびそれに続く、リードペプチドの体系的なアミノ酸置換を通じた増進を適用して、健康な対照、第一選択治療に反応する疾患患者、および第一選択治療に不応性である疾患患者の間を区別する合成ペプチド分類指標を生成可能である。
Claims (17)
- 合成分類指標を同定するための方法であって:
少なくとも第一の試料および第二の試料を、第一の複数のペプチドと接触させ、該第一の試料は第一のコホート群に由来し、該第二の試料は第二のコホート群に由来し、該第一の群は該第二の群とは異なり、そして該第一の複数のペプチドの少なくとも部分は少なくとも1つの天然存在アミノ酸配列を定義し;
該第一の複数のペプチドから第一のペプチドサブセットを選択し;
該第一の試料および該第二の試料を、第二の複数のペプチドと接触させ、該第二の複数のペプチドの少なくとも部分は、該第一のペプチドサブセットの複数の変異体ペプチドを含み、該複数の変異体ペプチドは各々、対応する該第一のペプチドサブセットの1つに対して、置換、欠失、挿入、伸長、および修飾の少なくとも1つを有し;そして
該第二の複数のペプチドから第二のペプチドサブセットを選択し、該第二のペプチドサブセットは、該複数の変異体ペプチドの少なくとも1つを含み、該第二のペプチドサブセットは合成分類指標を少なくとも部分的に定義し、該合成分類指標は、該第一の群に由来する試料および該第二の群に由来する試料の間を区別する
ことを含む、前記方法。 - 前記合成分類指標が、前記第一の群に由来する試料および前記第二の群に由来する試料の間を、前記第一のペプチドサブセットから選択されるペプチドからなる天然分類指標よりも、より優れた感度およびより優れた特異性の少なくとも1つで区別する、請求項1の方法。
- 前記第一の複数のペプチドおよび前記第二の複数のペプチドにおけるペプチドが各々、長さ約12アミノ酸〜約16アミノ酸の間である、請求項1の方法。
- 前記第一の複数のペプチドにおけるペプチドが、1アミノ酸〜4アミノ酸の間でタイリングされる、請求項1の方法。
- 前記合成分類指標が、診断分類指標および予後診断分類指標の1つである、請求項1の方法。
- 前記変異体ペプチドの各1つが天然存在ペプチドに対応し、そして該変異体ペプチドの各1つが、少なくとも1つのアミノ酸位に関して、該対応する天然存在ペプチド配列と異なる配列を有する、請求項1の方法。
- 前記合成分類指標における複数の変異体ペプチドの少なくとも1つが、前記第一の群および前記第二の群のいずれかと関連する天然存在ペプチド配列のいずれとも異なる配列を有する合成ペプチドである、請求項1の方法。
- 前記第一の試料および前記第二の試料の各々と前記第一の複数のペプチドの相互作用に特徴的な、第一のシグナル出力を検出し;
該第一のシグナル出力に基づいて、前記第一のペプチドサブセットを選択し;
該第一の試料および該第二の試料の各々と前記第二の複数のペプチドの相互作用に特徴的な、第二のシグナル出力を検出し;そして
該第二のシグナル出力に基づいて、前記第二のペプチドサブセットを選択する
ことをさらに含む、請求項1の方法。 - 合成分類指標を同定するための方法であって;
少なくとも第一の試料および第二の試料を、第一の複数のペプチドと接触させ、該第一の試料は第一のコホート群に由来し、該第二の試料は第二のコホート群に由来し、該第一の群は該第二の群とは異なり、そして該第一の複数のペプチドは:
i)少なくとも1つの天然存在アミノ酸配列を定義する第一のペプチドサブセット、および
ii)該第一のペプチドサブセットの複数の変異体ペプチドを定義する第二のペプチドサブセットであって、該複数の変異体ペプチドには、該第一のペプチドサブセットの各1つに関して、対応する該第一のペプチドサブセットの1つに対して、置換、欠失、挿入、伸長、および修飾の少なくとも1つを有する変異体ペプチドが含まれる、前記の第二のペプチドサブセット;
該第二のペプチドサブセットから該複数の変異体ペプチドの少なくとも1つを選択し;そして
該複数の変異体ペプチドの少なくとも1つを含む合成分類指標を定義し、該合成分類指標が該第一の群に由来する試料および該第二の群に由来する試料の間を区別する
ことを含む、前記方法。 - 前記第一の複数のペプチドの少なくとも部分が、ターゲットプロテオームの少なくとも約90%に相当し、該ターゲットプロテオームがウイルスおよび生物から選択される、請求項9の方法。
- 前記合成分類指標が、前記第一の群に由来する試料および前記第二の群に由来する試料の間を、前記第一のペプチドサブセットより選択されるペプチドからなる天然分類指標よりも、より優れた感度およびより優れた特異性の少なくとも1つで区別する、請求項9の方法。
- 前記第一の複数のペプチドにおけるペプチドが各々、長さ約12アミノ酸〜約16アミノ酸の間である、請求項9の方法。
- 前記第一の複数のペプチドにおけるペプチドが、1アミノ酸〜4アミノ酸の間でタイリングされる、請求項9の方法。
- 前記変異体ペプチドの各1つが天然存在ペプチドに対応し、そして該変異体ペプチドの各1つが、少なくとも1つのアミノ酸位に関して、該対応する天然存在ペプチド配列と異なる配列を有する、請求項9の方法。
- 前記合成分類指標における前記複数の変異体ペプチドの少なくとも1つが、前記第一の群および前記第二の群のいずれかと関連する天然存在ペプチド配列のいずれとも異なる配列を有する合成ペプチドである、請求項9の方法。
- 前記第一の試料および前記第二の試料の各々と前記第一の複数のペプチドの相互作用に特徴的な、第一のシグナル出力を検出し;そして
該第一のシグナル出力に基づいて、前記第一のペプチドサブセットを選択する
ことをさらに含む、請求項9の方法。 - 複数の合成ペプチドを含む組成物であって、該合成ペプチドの各々が、少なくとも1つの天然存在アミノ酸配列を定義する対応するペプチドに対して、置換、欠失、挿入、伸長、および修飾の少なくとも1つを有し、該合成ペプチドが、少なくとも部分的に合成分類指標を定義し、該合成分類指標が請求項1〜14記載の方法によって同定されており、そして第一のコホート群に由来する試料および第二のコホート群に由来する試料の間を区別する、前記組成物。
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