JP2015512247A - 光線力学的療法に使用するための新規光免疫複合体 - Google Patents
光線力学的療法に使用するための新規光免疫複合体 Download PDFInfo
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Abstract
Description
クロリンe6(C34H36N4O6)
EGFR特異的scFV−425抗体断片10、および異なった抗原(CD30)と結合するコントロール断片(scFV−Ki4)17をコードする配列をpMS−SNAPバイシストロニックベクターに導入して、(図1a)に示すように完全なscFV−425−SNAPカセットおよびscFV−Ki4−SNAPカセットを作製した。これらのコンストラクトをHEK−293T細胞に形質導入により導入して、安定的に形質転換された細胞をゼオシン選択および緑色蛍光タンパク質(GFP)活性のモニタリングにより同定した。融合タンパク質を(C末端His6タグを用いた)アフィニティークロマトグラフィーにより培養上清から分離して最終純度約90%とし、最終収量は上清中のタンパク質が18mg/Lであった(図1b)。
光増感剤クロリンe6(Ce6)を、N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩(EDC)、ヒドロキシスルホスクシンイミドのナトリウム塩(sulfo−NHS)、およびBG−PEG24−NH2リンカーを用いて修飾することに成功した。Ce6のカルボキシ基をBG基に修飾し、反応効率をHPLCにより決定した(データ示さず)。高純度のBG−PEG24−Ce6は質量分析により確認した。Ce6、BG−PEG24−NH2、およびBG−PEG24−Ce6の正確な質量は、Micromass QTOFII質量分析器で検出し、連結されたCe6とBG−PEG24−NH2について計算された理論質量と同じ質量を精製BG−PEG24−Ce6が有することを確認した(図2a)。
SNAPタグの機能性をBG修飾蛍光色素とカップリングすることにより調査し、室温で2時間インキュベーション後の標識化効率が85〜90%であることが明らかになった(データ示さず)。反応は、BG修飾Ce6を用いて繰り返した。光増感剤は融合タンパク質中の活性SNAPタグとのみ反応し、反応は、1.5倍モル過剰量のBG−Vista Greenとの後インキュベーションによって示されるように、ブロモテニルプテリジン(BTP)で不可逆的に阻害することができた。CRi Maestroイメージングシステムを用いた分析では、予め阻害された融合タンパク質と関連した蛍光は示されなかった(図2b、c)。
標識化scFV−425−SNAP融合タンパク質の活性を決定するために、BG−Vista GreenまたはBG−Ce6のいずれかで標識化したタンパク質を用いてフローサイトメトリー分析を行った。全ての標識化タンパク質は、氷上で30分間のインキュベーション後、相当する標的細胞株(A431、MDA−MB−231、MDA−MB−468、およびSiHa)上で強い蛍光シグナルを示したが、コントロール細胞(L540およびCHO−K1)上では示さなかった。予想通り、標識化scFV−Ki4−SNAPはL540上で強い蛍光シグナルを示したが、A431細胞およびCHO−K1細胞上では示さなかった(図3)。
scFV−425−SNAP−Ce6および複合体化していないBG−Ce6の濃度依存的細胞毒性効果を、4系統のEGFR+細胞株およびネガティブコントロールとしてCHO−K1を用いて、XTTに基づいた比色細胞増殖アッセイにより評価した。scFV−425−SNAP−Ce6で処理したA431細胞、MDA−MB−231細胞、MDA−MB−468細胞、およびSiHa細胞の生存率は、光活性化に続く24時間のインキュベーション後、濃度依存的に著しく減少した。IC50値は、48nM(A431)、220nM(MDA−MB−231)、38nM(MDA−MB−468)、および218nM(SiHa)であった。CHO−K1細胞は800nMの複合体化融合タンパク質に暴露した場合であっても影響されないままであり、コントロールコンストラクトであるscFV−Ki4−SNAP−Ce6はA431細胞およびCHO−K1細胞のいずれにおいてもほとんど影響を及ぼさなかった。対照的に、複合体化していないCe6はすべての細胞株に対して有毒であり、IC50値は、16nM(A431)、22nM(MDA−MB−231)、22nM(MDA−MB−468)、26nM(SiHa)、および18nM(CHO−K1)であった。これらのデータを(図5a、c)に示す。
細胞培養
EGFR+細胞であるA431細胞、MDA−MB−231細胞、MDA−MB468細胞、およびSiHa細胞、ならびにEGFR−細胞であるL540細胞、CHO−K1細胞、およびHEK−293T細胞を含む全ての細胞株は、ヒト由来であった。A431細胞、L540細胞、CHO−K1細胞、およびHEK−293T細胞は、2mMのL−グルタミン、10%(v/v)のウシ胎児血清(FBS)、および100U/mlのペニシリン−ストレプトマイシンを添加したRPMI−1640培地中で培養した。MDA−MB−231細胞、MDA−MB468細胞、およびSiHa細胞は、10%(v/v)のウシ胎児血清(FBS)および100U/mlのペニシリン−ストレプトマイシンを添加したDMEM培地中で培養した。全ての細胞は、5%CO2雰囲気中、37℃で培養した。全ての培地および添加物は、インビトロジェン社(ドイツ、ダルムシュタット)から入手した。
各scFvの配列を、N末端の結合リガンド(scFv−425またはscFv−Ki4)およびC末端のO6−アルキルグアニン−DNAアルキルトランスフェラーゼ(SNAPタグ)配列を与える発現カセット中に挿入した。TGA終止コドンはHis6タグ配列の直下に作成した。His6タグ標識された融合タンパク質は、無細胞上清からNi−NTA金属アフィニティークロマトグラフィーにより精製した。より多くの容量は、Akta FLPCシステム上で、4×緩衝液(200mM NaH2PO4、1.2M NaCl、40mM イミダゾール、pH8)で平衡化後に5mLのNi−NTA Superflowカートリッジ(キアゲン社、ドイツ、ヒルデン)を用いて精製した。結合したHisタグ標識化タンパク質は、50mM NaH2PO4、300mM NaCl、250mM イミダゾール、pH8)中に溶出した。溶出後、タンパク質を1mM ジチオエリスリイトール(Carl Roth社、ドイツ、カールスルーエ)を含むリン酸緩衝食塩水(PBS)に対して4℃で一晩透析した。エクトイン凍結保存材を50mMの最終濃度になるよう添加し、アリコートを−20℃で保存した。
ジメチルホルムアミド中で2mgのCe6を5倍モル過剰量のEDCおよびsulfo−NHS(シグマアッルドリッチ社、ミズーリ州、セントルイス)と室温で30分間混合することにより、Ce6(Porphyrin Products社、ユタ州、ローガン)のカルボキシ基をベンジルグアニンで修飾した。次に活性化混合物を4倍モル過剰量のベンジルグアニンリンカーであるBG−PEG24−NH2(Covalys Biosciences社、スイス、ヴィッタースヴィル)と暗所にて室温で一晩混合した。修飾Ce6は、Shimadzu Prominence HPLCシステム、および2.5μm(4.6×50mm)のWater XBridge(登録商標) OSTC18カラム(Waters社、マサチューセッツ、ミルフォード)を用いたHPLCにより、流速1mL/分で精製した。分離は、100%の0.1M TEAAから100%のアセトニトリルまで20分の勾配で行い、280nmおよび410nmでモニタリングした。Ce6、BG−PEG24−NH2、およびBG−PEG24−Ce6の質量は、Micromass QTOFII質量分析器を、エレクトロスプレーイオン源であるAdvion Nanomate(Advion社、米国、ニューヨーク州、イサカ)を用い、7μlのサンプル容量、1.4kVで確認した。正確な質量は、MaxEnt3(登録商標)アルゴリズム(Micromass社)を400〜2000Daの範囲で用いた300〜2500m/zの範囲における質量スペクトルから得た。
精製SNAPタグ融合タンパク質は、BG修飾色素(covalys Biosciences社、スイス、ヴィッタースヴィル)またはBG修飾Ce6と、暗所で1.5〜3倍モル過剰量の色素と室温で2時間インキュベーションすることにより複合体化した。残存する色素をzeba spin脱塩カラム7K MWCO(サーモフィッシャーサイエンティフィック社、イリノイ州、ロックフォード)を用いたゲル濾過クロマトグラフィーにより除去した。結合効率は、相当する色素の吸光係数および融合タンパク質の理論上の吸光係数を用いて測光的に決定した。標識化タンパク質はSDS−PAGEで分離後に、UVトランスイルミネーターGel Doc XRゲルドキュメンテーション(バイオラッドラボラトリー社、ドイツ、ミュンヘン)または青色および黄色のフィルターセットを用いたCRi Maestroイメージングシステム(CRi社、米国、マサチューセッツ、ウォバーン)のいずれかで可視化した。
標識化融合タンパク質および未標識融合タンパク質の結合効果は、FACSCalibur(ベクトン・ディッキンソン社、ドイツ、ハイデルベルク)およびCellQuestソフトウエアを用いたフローサイトメトリーにより決定した。EGFR+細胞株であるA431、MDA−MB−231、MDA−MB468、およびSiHaを用いてscFv−425−SNAPの結合効果を試験し、EGFR−細胞株であるL540およびCHO−K1をネガティブコントロールとして用いた。コントロール融合タンパク質であるscFv−Ki4−SNAPは抗原であるCD30を認識するため、L540細胞に結合するが他の細胞株には結合しないはずである。約4×105細胞を、0.5μgの標識化タンパク質を含む200μLのPBS中で、氷上、20分間インキュベーションした。その後、細胞を1.8mLのPBSを用いて通常の細胞洗浄器で2回洗浄し、フローサイトメトリーで分析した。
画像はTCS SP5共焦点顕微鏡(ライカマイクロシステムズ社、ドイツ、ウェッツラー)で可視化した。細胞はフローサイトメトリー用に記載した ように調製した。結合効率は、細胞を標識化融合タンパク質と氷上で30分間インキュベートすることにより決定した。内部移行は、細胞を標識化融合タンパク質と37℃で30分間インキュベートすることによりモニタリングした。
上記のようにインキュベートしたA431細胞、MDA−MB−231細胞、MDA−MB468細胞、SiHa細胞、およびCHO−K1細胞のアリコート(2×104個)をPBS中で2回洗浄した後、Ce6、scFv−425−SNAP−Ce6、またはKi4−scFv/SNAP−Ce6のいずれかの濃度を増加させて処理して37℃で3時間インキュベートした。コントロールのインキュベート物は、光増感剤の代わりに500μg/mLのゼオシンとともにインキュベートした。その後、7mmの水キュベットおよびオレンジフィルターOG590、580〜1400nmの範囲のスペクトルでHydrosunタイプ505(Hydrosun Medizintechnik社、ドイツ、ミュールハイム)を用いて24J/cm2の広帯域の可視/近赤外光を細胞に照射し、5%CO2雰囲気中、37℃でさらに24時間インキュベートした。
統計学的分析および曲線近似はGraphPad Prismソフトウエア(GraphPad社、カリフォルニア州、サンディエゴ)を用いて行った。データは平均±MESで示す。スチューデントt−検定および二元分散分析を用いて、独立実験の有意性を評価した。基準p<0.05を用いて統計的有意性を決定した。
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Claims (19)
- 抗体またはその誘導体もしくはその断片、scFvなどの合成ペプチド、ミモトープからなる群より選択され、CD抗原、サイトカイン受容体、インターロイキン受容体、ホルモン受容体、成長因子受容体、特にErbBファミリーのチロシンキナーゼ成長因子受容体、と結合したタンパク質と共有結合した光増感剤を含み、
該光増感剤が修飾ヒトDNA修復タンパク質であるO6−アルキルグアニン−DNAアルキルトランスフェラーゼ(hAGTm)を介して該結合タンパク質と結合している化合物。 - 内部移行性且つ疾患特異的な細胞表面受容体を特異的に標的とする、請求項1に記載の化合物。
- 前記チロシンキナーゼ成長因子受容体に結合するタンパク質がscFv抗体断片、特に配列番号2のポリヌクレオチド配列によりコードされる配列番号1のscFv抗体断片である、請求項1または請求項2に記載の化合物。
- 配列番号4のポリヌクレオチド配列によりコードされる配列番号3のアミノ酸配列を有する、請求項1〜請求項3に記載の化合物。
- 前記光増感剤がO6−アルキルグアニン−DNAアルキルトランスフェラーゼの活性部位と結合している、請求項1〜請求項4に記載の化合物。
- 前記光増感剤がポルフィリン、クロロフィル、および色素からなる群から選択される、請求項1〜請求項4に記載の化合物。
- 抗体またはその誘導体もしくはその断片、scFvなどの合成ペプチド、ミモトープからなる群から選択される結合タンパク質を含み、該結合タンパク質が、CD抗原、サイトカイン受容体、インターロイキン受容体、ホルモン受容体、成長因子受容体、特にErbBファミリーのチロシンキナーゼ成長因子受容体、と結合し、O6−アルキルグアニン−DNAアルキルトランスフェラーゼ(hAGTm)と称される修飾ヒトDNA修復タンパク質と共有結合している化合物。
- 前記結合タンパク質がscFv抗体断片、特に配列番号1および/または配列番号3のscFV抗体断片である、請求項7に記載の化合物。
- 特に配列番号2および/または配列番号4を含む、請求項7に記載の化合物をコードするポリヌクレオチド配列。
- 請求項1に記載の化合物をコードする、配列番号5のヌクレオチド配列のポリヌクレオチド。
- O6−アルキルグアニン−DNAアルキルトランスフェラーゼ(hAGTm)を、抗体またはその誘導体もしくはその断片、scFvなどの合成ペプチド、ミモトープからなる群から選択される結合タンパク質と融合するステップを含み、該結合タンパク質が、CD抗原、サイトカイン受容体、インターロイキン受容体、ホルモン受容体、成長因子受容体、特にErbBファミリーのチロシンキナーゼ成長因子受容体、と結合する、請求項7に記載の化合物を製造する方法。
- 真核生物発現ベクターpMS−SNAPのSifIおよびNotIによる消化部位にscFv−425配列が挿入されて、N末端結合リガンド(scFv−425)およびC末端SNAPタグ配列を与える、請求項11に記載の方法。
- 前記scFv−425−SNAP融合タンパク質が、ヒト胎児腎臓細胞株、特にHEK−293T細胞(ATCC:CRL−11268)で発現する、請求項11または請求項12に記載の方法。
- 前記scFv−425−SNAP融合タンパク質がアフィニティークロマトグラフィー、特にNi−NTAアフィニティークロマトグラフィーにより無細胞上清から精製される、請求項11〜請求項13のいずれか1項に記載の方法。
- 請求項7の化合物と結合した、以下の式のポルフィリン誘導体。
- クロリンe6などのポルフィリン光増感剤のカルボキシ基の少なくとも一部を、活性化エステルへと、またはカップリング剤により、反応させ、続いてO6−ベンジルグアニン、O2−ベンジルシトシン、またはコエンザイムA(CoA)と反応させる、請求項15に記載の化合物の製造方法。
- O6−ベンジルグアニン、O2−ベンジルシトシン、またはコエンザイムA(CoA)が、PEG−24−NH2などのリンカー分子と結合しており、および/または、前記活性化エステルが、NHSなどのスクシンイミドから形成されるか、または前記カップリング剤がEDC、EDAC、およびDCCなどのカルボジイミドからなる群から選択される、請求項16に記載の方法。
- 請求項1〜請求項8の少なくとも1項に記載の化合物と、光免疫療法と関連した薬学的効果を改善または可能にする薬学的に許容可能なアジュバントと、を含む医薬。
- 光免疫療法により癌を治療するための、請求項1〜請求項8の少なくとも1項に記載の化合物の使用。
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CA2866933C (en) | 2020-08-18 |
US9872904B2 (en) | 2018-01-23 |
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IN2014DN06866A (ja) | 2015-05-22 |
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