JP2020156498A - 抗rho gtpaseコンホーメーションシングルドメイン抗体及びその使用 - Google Patents
抗rho gtpaseコンホーメーションシングルドメイン抗体及びその使用 Download PDFInfo
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Abstract
Description
本発明は、抗Rho GTPaseコンホーメーションシングルドメイン抗体、ならびに特に、治療及び診断分野におけるその使用に関する。
Rho GTPaseは、アンドラッガブルタンパク質と主に考えられているRasに相同な20個の低分子量GTPaseのファミリーに属する。その生理活性は、そのグアニンヌクレオチド三リン酸ヒドラーゼの非常に遅い触媒活性よりも、スイッチIとスイッチIIとの高度に保存されたドメインのコンホーメーション変化にある。したがって、低分子量Gタンパク質は、不活性なGDP結合状態と活性なGTP結合コンホーメーションとの間をサイクルする分子スイッチである。Rhoサブファミリーは、85%超の配列同一性を共有するRhoA、RhoB、及びRhoCを含み、広い範囲の主な細胞プロセスに関与する多面的なタンパク質である。同細胞プロセスには、アクトミオシン細胞骨格の制御、細胞接着、細胞質分裂、細胞遊走、ストレス応答、及び細胞生存又はアポトーシスが含まれる。これらのGTPaseは、細胞膜へのそのアンカーに必須であるカルボキシ末端イソプレノイド基の付加により、翻訳後に修飾される。この場合、GTPaseは、グアニンヌクレオチド交換因子(GEF)により触媒されるヌクレオチド交換による種々の刺激に基づいて活性化することができる。ついで、活性化工程は、GTPase活性化タンパク質(GAP)により向上されるGTP加水分解によりつり合わせられる。したがって、活性型Rhoの細胞プールは、細胞膜において、限られたプールに維持される。主な画分は、膜から抽出され、グアニンヌクレオチド解離阻害剤(GDI)により、細胞質中に捕捉される。これらの大型のタンパク質は、そのアミノ末端部分により、Rhoのスイッチドメインと相互作用するため、GDPの放出を妨害し、そのカルボキシ末端部によっても、イソプレニル基に対して、Rhoタンパク質の可溶性を維持するが、膜から締め出すために、この疎水性部分を遮断する。
本発明者らは、一般的には、camelidae由来のシングルドメインVHと呼ばれる、ヒト化ナノボディの完全な合成ライブラリを生成した。この新規なファージディスプレイライブラリは、安定性について最適化された固有のスキャホールドに基づいており、非常に機能的な結合分子の系統的な選択が可能である。同分子は、ヒト化合成シングルドメイン抗体(hs2dAb)に相当する。このため、本発明者らは、特に、種々のターゲットに対して、複数の機能的な細胞内抗体を選択した。それらの中でも、活性なGTP結合状態のRhoタンパク質の1つのコンホーメーションセンサは、H12 hs2dAbと呼ばれるクローンである。H12 hs2dAbは、RhoサブファミリーメンバーRhoA、RhoB、及びRhoC間を区別せず、Rasのホモログである低分子量Gタンパク質に近いRac1ファミリーのメンバーにも結合するpanRhoバインダーであることが証明された。さらに、本発明者らは、より競合的な選択スキームを使用することにより、Rhoサブファミリーに対してより特異性を有する、すなわち、Rac1又は他の低分子量Gタンパク質を認識しない、複数の活性なRho選択的hs2dAb分子を単離した。これらのhs2dAbの一部は、Rhoの構成的に活性なリコンビナントL63変異体に対して、ナノモル濃度未満の親和性を有したことが証明された。これらの分子の細胞内発現により、アクチン細胞骨格の明確な再構築がもたらされる。このことから、これらの分子は、培養細胞におけるRhoシグナル伝達の強力な細胞内阻害剤として機能することが示唆される。ついで、本発明者らは、同じ戦略を、そのGTP結合状態にあるRhoBを特異的に認識するシングルドメイン抗体を選択するのに適用した。特に、本発明者らは、活性なRhoBタンパク質ノックダウンを誘導することができる、機能的な細胞内抗体の視覚的な細胞内スクリーニングを確立した。このタンパク質ノックダウンは、選択されたシングルドメイン抗体に遺伝的に融合されたFボックスドメインの使用に基づいていた。同使用により、結合したターゲットのユビキチン化及びその後のプロテアーゼ依存性分解が誘導される。二重の困難性は、RhoBを最も近いホモログから生理学的に区別することができ、活性なGTP結合状態に選択的であることができる細胞内抗体を特定することであった。種々のRho変異体を発現する細胞株を使用して、本発明者らは、その活性状態に選択的な、遺伝的にコードされた堅牢なRhoB阻害剤を選択するのに成功し、内因性RhoB活性画分をノックダウンし、その基底活性を枯渇させるだけでなく、成長因子処理後のその細胞内活性化もブロックする、この固有のツールの効率性を証明した。さらに、原理証明の研究において、本発明者らは、巧妙なRhoB活性ノックダウンがRhoBの全細胞画分を置換えなかったが、ヒト気管支上皮細胞の遊走及び浸潤においてRNAiと同様の表現型を誘導したことを証明した。したがって、本発明は、抗Rho GTPaseコンホーメーションシングルドメイン抗体、ならびに特に、治療及び診断分野におけるその使用に関する。
ディスプレイ技術を使用する完全にin vitroでの免疫化の主な利点の1つは、所望のアウトカムに対して選択させるための、抗原のコンホーメーション及び濃度の制御である。例えば、選択スキームは、低いオフレート速度論を備えた、高い親和性バインダーの回復を改善し、特異的なエピトープをターゲットにし、又は、コンホーメーション感受性バインダーを特定するように策定することができる。リンコンビナント抗体フラグメントライブラリスクリーニングにより、例えば、活性なコンホーメーションの低分子量GTPaseを選択的にターゲットにする、複数のバインダーが提供されてきた。(国際出願第EP2014/073713号に記載された)本発明者らの合成ライブラリは、選択的なコンホーメーションバインダーの特定を可能にするのに十分な多様性及び機能性を有したと仮定した。Rhoサブファミリーから、低分子量GTPaseに対するコンホーメーション特異的抗体を選択するために、減法パニングを行った。低分子量GTPaseは、GDP又はGTPヌクレオチドそれぞれに結合した場合、不活性状態と活性状態との間をサイクルする分子スイッチである。活性又は不活性なコンホーメーションを安定的にとる低分子量GTPaseの変異体を設計することができる。構成的に活性な変異体(例えば、RhoA Q63L、RhoB Q63L、又はRhoC Q63L)を、ベイトとしてHEK293中で発現させ、ついで、そのネイティブなコンホーメーションを保存するパニングのために新鮮にプルダウンさせた。GTP結合RhoAに特異的なファージ中で濃縮するために、枯渇工程を、GDP結合RhoAタンパク質を使用する2回目のラウンドのパニングから導入して、活性変異体に対する選択前に、汎用バインダーを除去した。4回のラウンドの選択後に、クローンを、ファージELISAを使用し、GTPγS(GTPの非加水分解性類似物)ロードRho GTPase又はGDPロードRho GTPaseのいずれかに対して分析した。選択されたシングルドメイン抗体の基本的な特徴を、表1に示す。
クローンH12を、ELISAにより更に分析した。本事例では、大腸菌中でGST融合物として発現された複数の精製Rhoタンパク質について、可溶型の抗体を使用する。H12 hs2dAbは、構成的に活性な変異体であるRhoAL63及びGTPγSでロードされた野生型RhoAに効率的に結合したことが示された。対照的に、不活性なRhoAN19変異体又はGDPロード野生型RhoAへの結合は観察されなかった(図1A)。ついで、H12がGTPロードRhoAを哺乳類の細胞抽出物から特異的にプルダウンすることができたかどうかを試験した。大腸菌中で発現させたCBDタグ付きH12構築物を、キチンビーズに固定し、GTPγS又はGDPのいずれかで予め処理されたHeLa細胞抽出物と共にインキュベーションした。GSTに融合されたRhotekinのRho結合ドメイン(GST−RBD)を、対照として使用した。このドメインは、活性なコンホーメーションのRho GTPaseに結合するのが公知であり、現時点でRho活性をアッセイするのに標準的な方法である。H12 hs2dAbは、GTPγSでロードされたRhoに非常に選択的であり、GDPロード抽出物ではシグナルを与えないことが見出された(図1B)。次に、H12により、RhoA活性コンホーメーションを免疫蛍光において特異的に検出したかどうかを試験した。GFP−RhoAL63活性変異体又は不活性なGFP−RhoAN19を発現しているHeLa細胞を固定し、H12 hs2dAbで染色した。不活性な変異体であるGFP−RhoAN19の過剰発現は、RhoA経路においても、又は、細胞の形状においても、ドミナントネガティブな作用を有さず、トランスフェクションされていない細胞のバックグラウンドを上回って増大されたシグナルをもたらさなかった。対照的に、強力な染色が、GFP−RhoAL63活性変異体を発現している細胞において、選択的に得られた。これらの細胞は、束ねられたアクチンストレスファイバーを示すことに留意。この特徴的な表現型は、向上したRhoA活性に関連付けられる(図1B)。要するに、これらの結果から、H12 hs2dAbは、その活性なコンホーメーションにあるRhoに選択的であることが示された。
蛍光タンパク質ノックダウンの視覚的スクリーニングによる細胞内抗体の直接選択
細胞内抗体を使用して細胞内でのRhoB活性に干渉する目的で、ファージディスプレイ選択で開始し、続けて、機能的な阻害性細胞内抗体の特定を目的として細胞内をスクリーニングする戦略が確立された。過去10年間に、Rhoタンパク質のGTPコンホ―メーションを区別するバインダーを単離するために、精緻なファージディスプレイ選択スキームが確立された。選択中にRhoBのネイティブなコンホ―メーションを保持するために、ベイト抗原を、哺乳類細胞中で発現させ、新鮮に抽出し、NaLi−H1ライブラリファージとのインキュベーション中に、ナノモル濃度範囲で使用した。競合的パニング選択を、過剰のGDPロード野生型RhoBの存在下における事前洗浄工程後に、構成的に活性な変異体であるRhoBL63を使用して行い、その最も近いホモログより、RhoBに対して選択的なバインダーを濃縮した。2回のラウンドの濃縮後に、5モル濃度過剰のRhoAL63及びRhoCL63を加えて、ベイトと更に競合させた。細菌により発現され、精製されたGST−RhoBL63に対する結合ファージの陽性濃縮をファージELISAにおいて制御した後に、RhoB細胞内抗体についての直接スクリーニングの開発が望まれた。このようなモノクローナル結合ドメインの有効性は、非常にアッセイ法依存的である場合がある、すなわち、ELISAスクリーニングにおいて陽性のものが免疫蛍光においては作用しない、又は、その逆もある場合があることを、リコンビナント抗体技術における過去の経験から学んだ。また、ターゲットに対するナノボディの蛍光融合物の共局在に基づく選択スキームも使用して、細胞内抗体を単離した。ついで、1セットのこれらのトラッキング細胞内抗体を機能化し、抗原を分解するために、GFPをプロテアソームターゲットドメインにより置き換えた時点では、驚くべきことに、最良のトラッカーと最良のデグレーダーとの間の相関関係は明らかではなかった。したがって、特定のアッセイ法において作用する細胞内抗体を特定する最良の方法は、最終的なフォーマットにおいて直接スクリーニングすることであろうと判断した。
Fボックスドメインのペプチド又は細胞内抗体への融合が、種々の細胞環境におけるプロテアソームによるターゲット分解を媒介することが報告されている。Fボックスドメインの存在が分解を担うかどうかを確認するために、hs2dAbを単独で、Hm及びHmB細胞株中で発現させたが、mCherry蛍光の減少は観察されなかった(図3B)。次に、MG132プロテアソーム阻害剤を使用して、観察された分解がプロテアソーム依存性であったことの対照実験を行った。フローサイトメトリーにより定量された4つのF−Ib誘導蛍光減衰をわずかに減少させるDMSO処理と比較して、36時間の間の1μM MG132の処置により、mCherry蛍光は、ほぼ対照レベルに回復した(図3C)。最後に、蛍光減衰が、トランスフェクションにおけるプラスミド濃度を2μgから0に減少させた後に蛍光を定量することにより、F−Ib発現の直接的な作用であったかどうかを分析した。用量応答性の直接的な作用が、プラスミド濃度が低いほど、蛍光シグナルが大きくなるように、効果的なF−H12及びF−B6について観察された(データを示さず)。これらの結果と共に、直接的な視覚的スクリーニングにより選択されたF−Ibが特異的にターゲッティングし、プロテアソーム依存法において、クロマチンで濃縮されたRhoBL63デルタCAAXタンパク質を分解することが証明された。
H12 hs2dAbは、コンホーメーションセンサであり、RhoA、RhoB、RhoCホモログ間を区別しないGTPロードRhoタンパク質のブロッキング細胞内抗体であり、近くの関連するGTPaseであるRac1及びCDC42をも認識する。本研究において、H12 hs2dAbが再度濃縮され、選択されたという事実は、以前のパニングにおいて、その提示がRhoAL63での3回目のラウンドのパニングにおいてクローンの50%を上回ったように、その濃縮が初期のラウンドの選択において非常に高かったため、驚くべきことではなかった。ここで、活性なRhoA及びRhoCにより競合を導入したにも関わらず、H12は、総じて、選択から排除されなかった。このことは、他の新たに選択されたhs2dAbも、panRhoであった場合があることを示唆している。それにも関わらず、H12濃縮は非常に低かった。このことは、新たな減法選択が、少なくとも部分的に効果的であったことを示唆している。選択されたF−hs2dAbの選択性を決定するために、H2B−mCherry−RhoBL63以外で、同じ基礎において種々の安定した細胞株を生成した。H2B−mCherry−RhoAL63及びH2B−mCherry−RhoCL63のトランスフェクションでは、安定した細胞株を生成することができず、一過性発現の不均一性は、蛍光減衰の決定的な定量をもたらさなかった(データを示さず)。しかしながら、類似する細胞株の生成は、H2B−mCherry−Rac1L61によって可能であった。Rac1は、主にスイッチドメインにおいて、Rhoサブファミリーの最も近いホモログである。予想通りに、F−H12は、後者の細胞株において、蛍光減衰を誘導した。他の選択されたF−Ibの中でも、F−B5は、H2B−mCherry−Rac1L63の蛍光レベルにも影響を及ぼしたが、F−6B及びF−B15は、活性型Rac1を分解することができなかった(図3D)。この点において、hs2dAb5又はそのF−5機能化なしに、研究を続行したが、hs2dAb H12を、pan活性なRho対照として維持した。ついで、同じ変異が他のRasホモログに結合するヌクレオチドにおいてGTPase欠損をもたらすため、主に不活性であると考えられているRhoBN19変異体に対するその作用を比較することにより、残りのF−Ibのコンホーメーション選択性に取り組んだ。F−Ibとして発現させたhs2dAbのコンホーメーション選択性を、蛍光減衰アッセイ法において決定するために、H2B−mCherry−RhoBN19の安定した細胞株を生成した。FACS分析後に、全ての効果的なF−Ibは、RhoBの活性な変異体のみを分解し、不活性型を分解しなかった(図3E)。これらの結果から、F−B6及びF−B15は、その活性なコンホーメーションにあるRhoBを優先的に認識するコンホーメーションhs2dAbであることが示される。
ついで、これらの細胞内抗体が、内因性の活性型RhoBを分解できたかどうかを調査した。この目的を達成するために、顕著な量のRhoBタンパク質を検出可能な基底レベルの活性なRhoBを伴って発現する一般的な細胞株であるHeLa S3細胞を使用した。Rho GTPase活性をアッセイするための標準的な方法は、GST−RBDを使用するプルダウンに基づいている。RBDは、GTP結合Rhoとのみ相互作用する3つのRhoの共通するエフェクターであるRhotekinからのRho結合ドメインである。F−Ibの一過性トランスフェクションの48時間後、RhoB基底活性画分のプルダウンは、対照であるF−B20及びF−NRより、F−B6、F−B15、又はF−H12によりトランスフェクションされた細胞において低かった。RhoA及びRhoCの検出から、それらの基底活性も影響を受けたかどうかを評価することが可能であった。予想通りに、F−H12は、3つ全てのRho活性画分のレベルの強力な低下を誘導した。しかしながら、3つの活性なRhoのレベルは、F−B15及びF−B6の発現について、等しく低下しなかった。このことから、これらは、F−H12と同じ選択性を有さないことが示唆される。活性なRhoB及びRhoAの両方の分解を誘導したF−B15 hs2dAbとは対照的に、F−B6は、RhoA又はRhoCプルダウン画分の明らかなモデュレーションを誘導しなかった(図4A)。定量から、F−B6は、この細胞環境及びアッセイ条件において、RhoB活性のみを低下させることが示された(図4B)。この結果は、それらのGTPロード状態にあるRhoBとRhoAとを区別し、その細胞内タンパク質分解を可能にするであろう分子の最初の例である。
本願全体を通して、種々の参考文献が、本発明が属する分野の水準を説明している。これらの参考文献の開示は、参照により本開示に組み入れられる。
Claims (17)
- CDR1−IMGT、CDR2−IMGT、及びCDR3−IMGTのアミノ酸配列が、表Bで定義されたシングルドメイン抗体(hs2dAb)H12、B6、4P75、4SP1、4SNP36、4SNP61、5SP10、5SP11、5SP58、5SNP47、5SNP48、5SNP65、B20、B15、B5、B71、E3、A6、G12、NB61、212B、111B、又は404FのCDR1−IMGT、CDR2−IMGT、及びCDR3−IMGTのアミノ酸配列に対して少なくとも90%の同一性を有する、
シングルドメイン抗体。 - シングルドメイン抗体(hs2dAb)H12、B6、4P75、4SP1、4SNP36、4SNP61、5SP10、5SP11、5SP58、5SNP47、5SNP48、5SNP65、B20、B15、B5、B71、E3、A6、G12、NB61、212B、111B、又は404FのCDR1−IMGT、CDR2−IMGT、及びCDR3−IMGTを含む、請求項1記載のシングルドメイン抗体。
- 配列番号:1に対して少なくとも90%の同一性を有するフレームワーク領域FR1を含む、請求項1記載のシングルドメイン抗体。
- 配列番号:2に対して少なくとも90%の同一性を有するフレームワーク領域FR2を含む、請求項1記載のシングルドメイン抗体。
- 配列番号:3に対して少なくとも90%の同一性を有するフレームワーク領域FR3を含む、請求項1記載のシングルドメイン抗体。
- 配列番号:4に対して少なくとも90%の同一性を有するフレームワーク領域FR4を含む、請求項1記載のシングルドメイン抗体。
- 配列番号:62〜80及び配列番号:93〜96で表わされるアミノ酸配列に対して少なくとも70%の同一性を有するアミノ酸配列を含む、請求項1記載のシングルドメイン抗体。
- 配列番号:62〜80及び配列番号:93〜96で表わされるアミノ酸配列からなる群より選択されるアミノ酸配列を含む、請求項1記載のシングルドメイン抗体。
- 異種ポリペプチドに融合して、融合タンパク質を形成している、請求項1記載のシングルドメイン抗体。
- 免疫グロブリンドメイン、シグナルドメイン抗体、キャリアポリペプチド、蛍光ポリペプチド、酵素、融合タンパク質の精製もしくは単離を容易にするポリペプチド、細胞透過性ペプチド、又はユビキチンリガーゼドメインに融合している、請求項1記載のシングルドメイン抗体。
- Fボックスドメインに融合している、請求項1記載のシングルドメイン抗体。
- 請求項1記載のシングルドメイン抗体をコードする、核酸分子。
- 請求項12記載の核酸分子を含む、ベクター。
- 請求項12記載の核酸分子によりトランスフォーメーションされている、ホスト細胞。
- 少なくとも1つの活性型Rho GTPaseの存在を検出する方法であって、
i)対象からサンプルを得る工程と、
ii)in vitroにおいて、サンプルを請求項1記載のシングルドメイン抗体と接触させる工程と、
iii)前記シングルドメイン抗体の前記サンプルへの結合を検出する工程と、
iv)工程(iii)で検出された結合を標準と比較する工程とを含み、
前記サンプルに対する結合の差が、活性型Rho GTPaseの存在を示す、
方法。 - 医薬として使用するための、請求項1記載のシングルドメイン抗体又は請求項12記載の核酸分子。
- ガンの処置を必要とする対象において、ガンを処置するための方法であって、治療的に有効量の、請求項1記載のシングルドメイン抗体又は請求項12記載の核酸分子を、対象に投与することを含む、
方法。
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Family Cites Families (11)
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US7563443B2 (en) | 2004-09-17 | 2009-07-21 | Domantis Limited | Monovalent anti-CD40L antibody polypeptides and compositions thereof |
EP2287197A1 (en) * | 2009-08-21 | 2011-02-23 | Pierre Fabre Medicament | Anti-cMET antibody and its use for the detection and the diagnosis of cancer |
CN102399288B (zh) * | 2011-10-19 | 2013-06-05 | 山西德丰信成生物科技有限公司 | 针对免疫球蛋白Fc段的单域重链抗体 |
JP6871866B2 (ja) * | 2015-02-03 | 2021-05-19 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 抗rho gtpaseコンホーメーションシングルドメイン抗体及びその使用 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009538600A (ja) * | 2006-05-12 | 2009-11-12 | ザ クイーンズ ユニヴァーシティ オブ ベルファスト | 癌治療の標的としてのdub3 |
WO2014195713A1 (en) * | 2013-06-06 | 2014-12-11 | David J Rowlands | Single domain antibody display |
Non-Patent Citations (3)
Title |
---|
CHAISEMARTIN, L. ET AL.: "Synthesis and Application of a N-1' Fluorescent Biotinyl Derivative Inducing the Specific Carboxy-Te", BIOCONJUGATE CHEM, vol. 20, JPN6019039838, 6 April 2009 (2009-04-06), pages 847 - 855, ISSN: 0004779194 * |
CHINESTRA, P. ET AL.: "Generation of a Single Chain Antibody Variable Fragment(scFv) to Sense Selectively RhoB Activation", PLOS ONE, vol. Vol.9m Issue 11, e111034, JPN6019039835, 3 November 2014 (2014-11-03), pages 1 - 11, ISSN: 0004779192 * |
GOFFINET, M. ET AL.: "Identification of a GTP-bound Rho specific scFv molecular sensor by phage display selection", BMC BIOTECHNOLOGY, vol. 8, no. 34, JPN6019039836, 31 March 2008 (2008-03-31), pages 1 - 14, ISSN: 0004779193 * |
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CN114133450B (zh) | 2023-09-22 |
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US11319381B2 (en) | 2022-05-03 |
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CN114133450A (zh) | 2022-03-04 |
US10544210B2 (en) | 2020-01-28 |
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JP6871866B2 (ja) | 2021-05-19 |
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