JP6868015B2 - 母性脳反応性抗体に対するおとり抗原を使用する自閉スペクトラム症の抑制 - Google Patents
母性脳反応性抗体に対するおとり抗原を使用する自閉スペクトラム症の抑制 Download PDFInfo
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Description
本出願は、2015年10月5日付けで出願された米国仮出願第62/237,150号(その内容は引用することにより本明細書の一部をなす)の利益を主張するものである。
本発明は、アメリカ国防総省により与えられた助成番号AR130137及びアメリカ国立衛生研究所により与えられた助成番号MH106195による政府支援によりなされたものである。アメリカ合衆国政府は、本発明に関し一定の権利を有する。
序論
自閉スペクトラム症(ASD)は、67件の出生のうち1件に起こり、支障を来すほどの金銭的費用及び感情的なコストをもたらす。病理生物学的メカニズムの理解の進展により、ASD発生において母性脳反応性抗体が関係づけられている。
ASDの子の母親の、事前に脳反応性ポリクローナル抗体を有することが分かっている血液試料から、モノクローナル抗体を作製した。これらの血液試料は罹患した子供の出生の何年も後に取得されたので、ヒト胎児脳溶解物中に存在する抗原に対して反応性であったメモリー(CD27陽性)B細胞に着目した。これらの細胞の検出を可能にするために、ヒト胎児脳溶解物の断片をビオチン化し、B細胞と一緒にインキュベートした。胎児脳の断片に結合した、ストレプトアビジン結合によって検出された個々のCD19陽性CD27陽性B細胞を単離した。免疫グロブリンの重鎖可変領域及び軽鎖可変領域の遺伝子を、PCRによって増幅させ、ヒト胚腎細胞(HEK 293)においてIgG1−κ抗体としてin vitroで発現させた(13)。
独自のヒト血液リソース(サイモン・シンプレックス・コレクション、自閉症遺伝学的リソース、及びファインスタイン医学研究所のGAP登録)を利用して、抗脳抗体の頻度が、コントロール群(2%、p<0.0001)と比較してASDの子の母親の血液において有意により高い(11%)ことを実証した。脳反応性モノクローナル抗体を同定し、単細胞をASDの子の母親からクローニングした(セルソーティングされたメモリーB細胞由来のIgGドメインの単一細胞発現クローニング)。簡潔には、末梢血から単離されたB細胞を、ビオチンで事前に標識されたヒト胎児脳溶解物と一緒にインキュベートし、そしてB細胞−脳抗原複合体を、アビジンクロマトグラフィーを使用して単離した。血液は、ASDの子をもたらした妊娠から何年も後に取得されたので、記憶コンパートメントにおけるB細胞だけに重要性がおかれるものと推論された。幸いにも、そのようなメモリーB細胞は、ヒトにおいては何年から何十年にもわたり存続するため、何年も前に起こった妊娠の間に存在していたかもしれない自己反応性における機会を与えることができる。したがって、後続工程で蛍光マーカー及びフローサイトメトリーを使用して、個々のメモリーB細胞を単独のウェル中にソーティングした。Nussenzweigらによって初めて記載された技術を使用して、IgG重鎖可変領域及び軽鎖可変領域を、ヒト構築物中にクローニングした(34)。次いでこれらのシーケンシングを行い、発現のためにHEK 293T細胞中に同時トランスフェクションさせた。脳に対する免疫反応性を、胎児マウス脳及び成体マウス脳に免疫組織化学を用いて検証し、関心が持たれるモノクローナル抗体を発現させ、プロテインGクロマトグラフィーで精製した。20種の脳反応性モノクローナル抗体のライブラリを作製した。メモリーB細胞の選択と一致して、これらのモノクローナル抗体のほとんどは、胚中心反応により成熟されて、メモリー細胞コンパートメントに入ったB細胞の特徴である可変領域の大規模な体細胞超変異を含む。推定抗原は、プールされた抗原調製物を全長ヒトタンパク質アレイでスクリーニングした後に、抗体の選択のためにイムノブロットを行うことによって同定した。
調査被験体: ASDの子を持つ母親からの血漿を、サイモン・シンプレックス・コレクション(SSC、sfari.org/resources/simons-simplex-collection)から取得した(35)。妊娠可能年齢の女性からのコントロール血漿を、ノース・ショア・LIJ・ヘルス・システムの臨床研究所及びファインスタイン医学研究所の登録(www.gapregistry.org)における参加者から取得した。両方のコホートは、以前(36)に記載されたものとした。全ての個人から、適切な治験審査委員会を通じてインフォームドコンセントを得た。
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Claims (6)
- Caspr2に対する抗体に結合する作用物質であって、該作用物質はCaspr2の細胞外部分の配列を含むペプチドを含む作用物質を含む、胎児又は小児における自閉スペクトラム症の抑制又は発生減少のため、妊娠した母親における使用のための組成物であって、前記組成物は、
胎児を身ごもっている母親若しくは胎児が小児として産まれる前の母親に、Caspr2に対する抗体に結合する作用物質を前記母親が妊娠中に投与することによって使用されるか、又は
胎児を身ごもっている母親(i)若しくは胎児が小児として産まれる前の母親(ii)の血液を、Caspr2に対する抗体に結合する作用物質と体外で接触させることでCaspr2に対する抗体の血中レベルを減少させ、こうして処理された血液を、前記母親に戻して再循環させることによって使用される、
前記組成物。 - 前記Caspr2がヒトCaspr2の配列を有する、請求項1に記載の組成物。
- 前記作用物質は、Caspr2の細胞外部分の配列を含むペプチドを含む融合タンパク質を含む、請求項1又は2に記載の組成物。
- 前記融合タンパク質は、免疫グロブリンFc配列を含む、請求項3に記載の組成物。
- 前記免疫グロブリンは、IgGである、請求項4に記載の組成物。
- 前記胎児は雄である、請求項1〜5に記載の組成物。
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CA2900366A1 (en) * | 2013-02-08 | 2014-08-14 | University Of Iowa Research Foundation | Diagnostic tools to predict onset of preeclampsia |
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