JP2017148039A - 薬物スクリーニングおよび有効性アッセイ - Google Patents
薬物スクリーニングおよび有効性アッセイ Download PDFInfo
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Abstract
Description
別段に定義されていない限り、本明細書で使用されている技術的および科学的用語は、本発明が属する技術分野の当業者により一般的に理解されているのと同じ意味を有する。Principles of Tissue Engineering,3rd Ed.(R Lanza、R LangerおよびJ Vacanti編集),2007は、本出願において使用される用語の多くの一般的な指針を当業者に提供する。当業者には、本発明の実践に使用され得る、本明細書に記載の方法および材料と類似した、または等価の多くの方法および材料が認識される。実際に、本発明は、記載される方法および材料に決して限定されない。
腎臓疾患の治療における使用のための、すなわち、腎機能の安定化および/または改善および/または再生を提供する、特定の生物活性成分もしくは細胞型が濃縮された、および/または特定の不活性もしくは望ましくない成分もしくは細胞型が欠乏した腎細胞の単離された不均質集団、およびそれらの混合体は、以前に、2009年11月12日出願の米国特許出願公開第12/617,721号において記載されている。本発明は、健常個人と比較して細胞成分が欠落しているが、まだ治療特性を保持する、すなわち、腎機能の安定化および/または改善および/または再生を提供する単離腎細胞分画を使用して、試験薬剤をスクリーニングする方法を提供する。本明細書に記載の細胞集団、細胞分画、および/または細胞の混合体は、健常個体、腎臓疾患を有する個体、または本明細書に記載のような対象から得られてもよい。
本発明は、出発集団よりも優れた治療および再生結果を提供する、生物活性成分が濃縮され、不活性または望ましくない成分が欠乏した腎細胞の不均一集団のある特定の副分画を使用して、試験薬剤をスクリーニングする方法を企図する。本発明は、さらに、生物活性成分が濃縮され、不活性または望ましくない成分が欠乏した腎細胞の不均一集団のある特定の副分画を含むオルガノイドをさらに企図する。例えば、不活性または望ましくない成分、例えば、B1およびB5が欠乏した、本発明の生物活性成分、例えば、B2、B4、およびB3は、単独に、または混合されて、薬物スクリーニングにおける予想外の改善を提供する。不活性または望ましくない成分、例えば、B1およびB5が欠乏した、本発明の生物活性成分、例えば、B2、B4、およびB3を含む、および/またはそれらから形成されるオルガノイドは、単独に、または混合されて、生物活性成分のin vivoでの可能性のある再生生物活性(すなわち有効性)を決定するためのin vitro有効性アッセイにおいて驚異的に有用である。
本発明の発明者らは、驚くべきことに、B1が欠乏したB2、B3、B4およびB5の組み合わせのin vitro培養が、B5の欠乏をもたらすことを発見した。一実施形態において、B5は、少なくとも1回、2回、3回、4回または5回の継代後に欠乏する。他の一実施形態において、本明細書に記載の条件下で継代されたB2、B3、B4およびB5細胞分画の組み合わせは、継代細胞集団の約5%未満、約4%未満、約3%未満、約2%未満、約1%未満、または約0.5%未満のパーセンテージのB5を有する継代細胞集団を提供する。
本明細書に記載のように、本発明は、1つには、生物活性成分が濃縮され、不活性または望ましくない成分が欠乏した腎細胞の不均一集団のある特定の副分画が、出発集団よりも優れた治療および再生結果を提供し、さらに、in vivoまたは臨床毒性および効用をより正確に予測するための薬物スクリーニングの基盤を提供するという驚くべき発見に基づく。好ましい実施形態において、本発明の細胞集団は、B1および/またはB5細胞集団が欠乏している。例えば、B2、B3、およびB4’の2つ以上の混合体、B2、B3、およびB4’の濃縮細胞集団は、B1および/またはB5が欠乏していてもよい。
一態様において、本発明は、腎臓組織から単離および/または培養された細胞集団を使用して試験薬剤をスクリーニングする方法を提供する。別の態様において、本発明は、腎臓組織から単離および/または培養された細胞集団を含む、および/またはそれから形成されるオルガノイド、ならびに本発明のオルガノイドを形成する方法および使用する方法を提供する。本明細書において、腎細胞成分、例えば、スクリーニングアッセイにおいて使用される濃縮細胞集団を分離および単離するための方法が提供される。一実施形態において、細胞集団は、新しく分解された、すなわち機械的もしくは酵素的に分解された腎臓組織から、または哺乳動物腎細胞の不均一in vitro培養物から単離される。
Bertramらの米国特許出願公開第20070276507号に記載のように、ポリマーマトリックスまたは骨格は、任意の数の全体的システム、配置または空間制限を満たすために、任意の数の望ましい構成に成形されてもよい。一実施形態において、本発明のマトリックスまたは骨格は、三次元であってもよく、また器官または組織構造の寸法および形状に適合するように成形されてもよい。例えば、薬物スクリーニングにおける使用のためのポリマー骨格の使用において、三次元(3D)マトリックスが使用されてもよい。様々な異なる形状の3D骨格が使用され得る。当然ながら、ポリマーマトリックスは、異なるサイズの患者に適合するように異なるサイズおよび形状に成形されてもよい。ポリマーマトリックスはまた、患者の特別な要求に対応するために、他の様式で成形されてもよい。別の実施形態において、ポリマーマトリックスまたは骨格は、生体適合性の多孔質ポリマー骨格であってもよい。骨格は、開放気泡ポリ乳酸(OPLA(登録商標))、セルロースエーテル、セルロース、セルロースエステル、フッ素化ポリエチレン、フェノール、ポリ−4−メチルペンテン、ポリアクリロニトリル、ポリアミド、ポリアミドイミド、ポリアクリレート、ポリベンゾオキサゾール、ポリカーボネート、ポリシアノアリールエーテル、ポリエステル、ポリエステルカーボネート、ポリエーテル、ポリエーテルエーテルケトン、ポリエーテルイミド、ポリエーテルケトン、ポリエーテルスルホン、ポリエチレン、ポリフルオロオレフィン、ポリイミド、ポリオレフィン、ポリオキサジアゾール、ポリフェニレンオキシド、ポリフェニレンスルフィド、ポリプロピレン、ポリスチレン、ポリスルフィド、ポリスルホン、ポリテトラフルオロエチレン、ポリチオエーテル、ポリトリアゾール、ポリウレタン、ポリビニル、ポリフッ化ビニリデン、再生セルロース、シリコーン、尿素−ホルムアルデヒド、コラーゲン、ラミニン、フィブロネクチン、シルク、エラスチン、アルギネート、ヒアルロン酸、アガロース、またはそれらのコポリマーもしくは物理的ブレンドを含むがこれらに限定されない、様々な合成または自然発生材料から形成され得る。骨格構成は、液体ヒドロゲル懸濁液から、柔軟性多孔質骨格、硬質形状保持多孔質骨格に至るまで、様々となり得る。
本発明の細胞は、代謝、毒性および効用を含む、試験薬剤のいくつかのパラメータを試験するのに有用である。本発明の方法は、毒性を評価するために必要な情報を含むそのような情報を得るための、代謝または薬物動態プロファイルが知られていない実験薬物または「試験薬剤」のスクリーニングに使用され得る。毒性は、多くの場合、薬物対薬物の相互作用の結果生じ得る。したがって、本発明の方法は、試験薬剤と、既知の薬物または他の試験薬剤との組み合わせを試験するために使用され得る。
機能アッセイが、試験化合物の存在下での本発明の細胞集団の細胞の健康および生存能力を決定するために使用され得る。ある特定の実施形態において、細胞の健康および生存能力の指標は、細胞複製、ミトコンドリア機能、エネルギーバランス、膜の完全性および細胞死の指標を含むが、これらに限定されない。他の実施形態において、細胞の健康および生存能力の指標は、さらに、酸化ストレス、代謝活性化、代謝安定性、酵素誘導、酵素阻害、および細胞膜輸送体との相互作用の指標を含む。
本発明の細胞集団を使用した細胞ベース増殖アッセイは、試験薬剤の細胞増殖活性に対する効果を決定するために使用され得る。一般に、細胞増殖および細胞生存能力アッセイは、細胞が代謝的に活性である場合に検出可能なシグナルを提供するように設計される。
細胞が化学的刺激に暴露された場合、その挙動は、特に治療候補およびその有効性を開発および評価する場合に重要な考慮点である。治療試験薬剤等の化学的刺激に対する細胞または細胞群の反応を文書化することにより、化学的刺激の有効性をより良く理解することができる。
尿細管細胞マーカーであるγ−グルタミルトランスペプチダーゼ(GGT1)は、グルタチオン(GSH)の合成および分解、ならびに薬物および生体異物解毒の経路である、ガンマ−グルタミルサイクルにおいて重要な役割を果たすことが示されている。Siest G,et al.,(1992) Biochem.Pharmacol.43 (12):2527−2533。典型的なGGTアッセイは、GGT1によるニトロアニリン産生を測定するものであり、試験化合物の存在下での本発明の細胞集団の機能的特性を決定するために有用である。GGT1を使用した機能的アッセイは、当該技術分野において、例えば、Kelley et al.,Am J Physiol Renal Physiol.2010 Nov;299(5):F1026−39において周知である。
アルブミン取り込みの測定は、試験化合物の存在下で本発明の細胞の機能的特性を決定するために使用され得る。アルブミン取り込みアッセイは、文献において、例えばKelley et al.,Am J Physiol Renal Physiol.2010 Nov;299(5):F1026−39において、および以下の実施例10において記載されている。
他の実施形態において、腎損傷の診断薬としてのバイオマーカーの検出は、ロイシンアミノペプチダーゼ(LAP)の検出を含む。尿細管酵素であるLAPは、損傷した近位および/または遠位尿細管細胞から放出される。
一実施形態において、本発明は、B2細胞集団であって、尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一腎細胞集団を、試験化合物と接触させることと、腎毒性の指標のレベルであって、腎毒性を示す指標のレベルを決定することとを含む、試験薬剤または化合物の腎毒性を決定する方法を提供する。
「薬物動態」は、薬物に対する身体の作用を指す。薬物動態学的プロセスは、薬物の吸収、分布、代謝、および排出を含むが、これらに限定されない。取り込み輸送体アッセイは、試験薬剤の薬物動態プロファイルの決定に有用である。例となる輸送体取り込みアッセイは、本発明の細胞集団を使用した以下の輸送体との試験薬剤相互作用の決定を含む。
上記方法は、本明細書に記載の細胞集団の使用を必要とする。哺乳動物の初代細胞培養および細胞株培養において使用される技術は、当業者に周知である。
本発明は、単独の、または混合された、不活性または望ましくない成分、例えば、B1およびB5が欠乏した、本明細書に記載の生物活性成分、例えば、B2、B4、およびB3を含む、および/またはそれから形成されたオルガノイドをさらに提供する。一態様において、本発明は、1つ以上の細胞型、例えば、血管、内分泌、または内皮細胞が欠乏または不足した特定の副分画B4を含む、および/またはそれから形成されたオルガノイドを提供し、すなわち、B4’は、単独で、または他の生物活性副分画、例えば、B2および/もしくはB3と混合された場合に、治療特性、例えば、腎機能の安定化および/または改善および/または再生を保持する。好ましい実施形態において、生物活性細胞集団は、B2である。ある特定の実施形態において、B2細胞集団は、B4またはB4’と混合される。他の実施形態において、B2細胞集団は、B3と混合される。他の実施形態において、B2細胞集団は、B3およびB4の両方、またはB3および/もしくはB4の特定の細胞成分と混合される。全ての実施形態において、本発明のオルガノイドは、ex vivoで形成および培養される。
本発明は、さらに、本発明のポリマーマトリックスおよび関連材料、ならびに/または細胞培養物、ならびに/または薬物スクリーニングアッセイ試薬、ならびに取扱説明書を備えるキットを含む。取扱説明書は、例えば、細胞の培養、および細胞を使用して試験薬剤をスクリーニングする方法の説明書を含有してもよい。取扱説明書は、さらに、例えば、細胞の培養、ならびに、本明細書に記載の生物活性細胞調製物および/または混合体のin vivoでの可能な再生生物活性(すなわち、有効性)を決定するためのin vitro法の説明書を含有してもよい。
成体雄ブタ(イノシシ)における貧血を伴う特発性進行性慢性腎臓疾患(CKD)の症例が、細胞組成物の評価および年齢適合正常ブタ腎臓組織との直接的な比較による特性決定のための、新鮮な疾患腎臓組織を提供した。採取時の腎臓組織の組織学的検査では、重度のびまん性慢性間質線維症および多発性線維症を伴う半月体形成性糸球体腎炎を特徴とする腎臓疾患が確認された。臨床化学では、高窒素血症(血中尿素窒素および血清クレアチニンの上昇)、および軽度の貧血(ヘマトクリットの軽度の低減およびヘモグロビンレベルの低下)が確認された。細胞を単離し、増殖させ、疾患および正常腎臓組織の両方から特性決定した。PresnellらのWO/2010/056328の図1に示されるように、ゴモリトリクローム染色は、正常腎臓組織と比較して、疾患腎臓組織における線維症を強調する(矢印で示される青色染色)。キュブリン:メガリンを発現し、受容体媒介アルブミン輸送ができる機能的尿細管細胞を、正常および疾患腎臓組織の両方から増殖させた。エリスロポエチン(EPO)発現細胞もまた培養物中に存在し、複数の継代および凍結/解凍サイクルを通して維持された。さらに、分子分析により、正常および疾患組織の両方からのEPO発現細胞が、EPO、およびvEGFを含む他の低酸素制御遺伝子標的のHIF1a誘発誘導により、in vitroで低酸素条件に反応することが確認された。コラゲナーゼ+ディスパーゼでの酵素分解により、ブタ腎臓組織から細胞を単離し、また、単純な機械的分解および移植片培養を行うことにより、別個の実験において単離した。2回目の継代において、epo発現細胞を含有する移植片から得られた細胞培養物を、大気(21%)および様々な低酸素(5%未満)培養条件の両方に暴露し、低酸素への暴露がEPO遺伝子発現の上方制御に至るかどうかを決定した。げっ歯類培養物に関して述べられるように(実施例3を参照されたい)、正常なブタは、EPO遺伝子の酸素依存的発現および制御を示した。驚くべきことに、CKDブタの尿毒症/貧血状態(34未満のヘマトクリット、9.0超のクレアチニン)にもかかわらず、EPO発現細胞は組織から容易に単離および増殖され、EPO遺伝子の発現は、PresnellらのWO/2010/056328の図2に示されるように、低酸素制御されたままであった。PresnellらのWO/2010/056328の図3に示されるように、増殖された培養物中の細胞は、尿細管状構造への自己組織化能力を示した。PresnellらのWO/2010/056328の図4に示されるように、培養物(3回目の継代)中の機能的尿細管細胞の存在は、培養細胞によるFITC複合化アルブミンの受容体媒介取り込みを観察することにより確認された。緑色の点(細い白矢印により指し示される)は、尿細管細胞特異的受容体であるメガリンおよびキュビリンにより媒介される、取り込まれたフルオレセイン複合化アルブミンを表し、機能的尿細管細胞によるタンパク質再吸収を示している。青色染色(太い白矢印により指し示される)は、Hoescht染色核である。総合すると、これらのデータは、機能的尿細管および内分泌細胞が、CKDにより重度に悪化した腎臓組織であってもブタ腎臓細胞から単離および増殖され得ることを示唆している。さらに、これらの所見は、CKDの治療のための自己細胞系治療生成物の発展を補助する。
腎細胞単離:簡潔に述べると、10個の2週齢雄Lewisラット腎臓のバッチを、販売供給業者(Hilltop Lab Animals Inc.)から入手し、約4℃の温度のViaspan保存培地中で一晩で搬送された。本明細書に記載の全てのステップは、無菌性を保持するために、生物学的安全キャビネット(BSC)内で行った。腎臓をハンク平衡塩溶液(HBSS)中で3回洗浄し、Viaspan保存培地を洗い流した。3回目の洗浄後、残留した腎臓被膜と共に、残留したいかなる間質組織も除去した。顕微解剖法を使用して、大腎杯もまた除去した。次いで、無菌メスを使用して、腎臓をスラリーとなるまで細かく刻んだ。次いで、スラリーを50mlの円錐遠心管に移し、秤量した。RNAのために微量試料を回収し、RNAse不含無菌1.5ml微小遠心管に入れ、液体窒素中で急速冷凍した。凍結したら、分析まで−80度の冷凍庫に移した。10個の幼若動物腎臓の組織重量を、約1グラムに統一した。バッチの重量に基づき、組織1グラム当たり20mlの分解培地を提供するように、分解培地を調節した。この手順のための分解緩衝液は、HBSS中の4単位のディスパーゼ1(Stem Cell Tech社)、5mM CaCl2 (Sigma)を含む300単位/mlのコラゲナーゼIV型(Worthington社)を含有した。
原型B2およびB4の分布および組成に対する酸素条件の効果を決定するために、異なる種からの新規腎細胞調製物を、勾配段階の前に異なる酸素条件に暴露した。げっ歯類新規腎臓増強(NKA)細胞調製物(RK069)を、上で説明されたようにラット細胞単離および培養開始の標準的手順を用いて確立した。全てのフラスコを21%(大気)酸素条件下で2〜3日間培養した。培地を交換し、次いでさらに24時間、フラスコの半分を2%酸素に設定された酸素制御インキュベータに再配置し、一方残りのフラスコは、21%酸素条件に維持した。次いで、上記で説明された標準的酵素採取手順を使用して、細胞を各組の条件から採取した。標準的手順に従い段階勾配を調製し、「通常酸素」(21%酸素)および「低酸素」(2%酸素)培養物を別個に採取し、同一の段階勾配に並べて適用した(図2)。4つの帯およびペレットが両方の条件において生成されたが、勾配全体にわたる細胞の分布は、21%および2%酸素培養バッチにおいて異なっていた(表1)。具体的には、B2の収量は、低酸素で増加したが、同時にB3においては低下した。さらに、B4特異的遺伝子(例えばエリスロポエチン)の発現は、低酸素培養細胞から生成された最終的勾配において向上した(PresnellらのWO/2010/056328の図73を参照されたい)。
全体を通して説明された酵素単離方法により、正常ヒト腎臓組織から尿細管および糸球体細胞を単離および増殖させた。上述の勾配法により、尿細管細胞分画をex vivoで、および培養後に濃縮した。PresnellらのWO/2010/056328の図68に示されるように、表現型属性は、単離および増殖において維持された。また、標識化アルブミンの取り込みにより評価される尿細管細胞機能は、繰り返された継代および低温保存の後でも維持された。PresnellらのWO/2010/056328の図69は、尿細管濃縮および尿細管欠乏集団が3D動的培養において培養された場合、尿細管マーカーであるカドヘリンの発現の顕著な増加が、尿細管濃縮集団において示されたことを示している。これは、細胞が3D動的環境において培養された場合、尿細管細胞の濃縮が、初期濃縮を超えて維持され得ることを裏付けている。
上で実施例2において記載した、同じ腎細胞の培養集団を、フローサイトメトリー分析に供し、前方散乱および側方散乱を検査した。より粒状でない小さいEPO産生細胞集団が認識可能であり(8.15%)、フローサイトメーターの選別能力を使用した、より粒状でない小細胞集団の正の選択により分離された(PresnellらのWO/2010/056328の図70を参照されたい)。
腎細胞の非分画混合物を、上述のように自己免疫性糸球体腎炎患者試料から単離した。腎臓組織から単離および増殖された腎細胞の特定の部分集団の公正な遺伝子型組成を決定するために、定量的リアルタイムPCR(qrtpcr)分析(Brunskill et al..,上記参照 2008)を使用して、細胞副分画間の、差次的な細胞型特異的および経路特異的遺伝子発現パターンを特定した。表6.1に示されるように、HK20は、自己免疫性糸球体腎炎患者試料である。表6.2は、HK20から生成された細胞が、qRTPCRにより決定して、糸球体細胞を欠落していることを示す。
腎臓組織から単離および増殖された腎細胞の特定の部分集団の公正な遺伝子型組成を決定するために、定量的リアルタイムPCR(qrtpcr)分析(Brunskill et al.,上記参照 2008)を使用して、細胞副分画間の、差次的な細胞型特異的および経路特異的遺伝子発現パターンを特定した。糸球体の大部分が破壊されている巣状分節状糸球体硬化症(FSGS)の症例から得られたヒト調製HK023を、採取時のB4分画中の糸球体細胞の存在について評価した。簡潔に述べると、非分画(UNFX)培養物を生成し(Aboushwareb et al.,上記参照 2008)、標準的生検手順を使用して腎臓から取り出された(4つの)コア生検のそれぞれから独立して維持した。ex vivoでのUNFXの(2回の)継代後、細胞を採取し、(実施例8のように)密度勾配法に供して副分画B4を含む副分画を生成したが、これは、げっ歯類、イヌ、および他のヒト検体において行われた研究に基づいて、内分泌、血管および糸球体細胞が濃縮されていることが知られている。
蛍光活性化細胞選別(FACS)を使用して、単離された1次腎組織から、1つ以上の単離腎細胞を濃縮することができ、および/または1つ以上の特定の腎細胞型を欠乏させることができる。
単離された1次腎組織から、1つ以上の単離腎細胞を濃縮することができ、および/または1つ以上の特定の腎細胞型を欠乏させることができる。
20μlのダイレクトMACSマイクロビーズ(例えば抗PEマイクロビーズ)を添加し、次いで4℃で15分間インキュベートする。
細胞選択または欠乏の後、試料を回収し、使用するまで氷上に置く。
欠乏または選択された試料の純度を、フローサイトメトリーにより検証する。
本試験の目的は、ハイコンテント分析(HCA)によりヒトNKA細胞の機能的特性を決定することであった。ハイコンテント画像化(HCI)は、複数の試料にわたり2つ以上の蛍光プローブ(多重化)を使用して、複数の細胞内事象の同時画像化を提供する。ハイコンテント分析(HCA)は、ハイコンテント画像において撮像された複数の細胞パラメータの同時定量測定を提供する。簡潔に述べると、非分画(UNFX)培養物を生成し(Aboushwareb et al.,上記参照 2008)、標準的生検手順を使用して、進行した慢性腎臓疾患(CKD)に罹患した5つのヒト腎臓、および3つの非CKDヒト腎臓から取り出されたコア生検から独立して維持した。ex vivoでのUNFXの(2回の)継代後、細胞を採取し、(実施例2のように)密度勾配法に供して副分画B2、B3、および/またはB4を含む副分画を生成した。
慢性腎臓疾患(CKD)のモデルにおける治療機能を示した腎臓上皮細胞の選択された集団(B2)の単離および機能における、酸素圧の役割を調査した。本試験は、処理中の低酸素暴露が選択されたヒト選択腎細胞(SRC)または生物活性腎細胞(BRC)の組成および機能を改変するかどうかを検査するものであった。2%酸素への暴露時、以下が観察された:密度勾配にわたる細胞分布の改変(PresnellらのWO10/056328を参照されたい)、全体的な勾配後の収量の改善、酸素制御遺伝子発現の調節(以前にKelley et al.上記参照(2010)において報告されている)、エリスロポエチン、VEGF、HIF1−アルファおよびKDR(VEGFR2)の発現の増加。プロセス中の低酸素への暴露は、選択された生物活性腎細胞が損傷した尿細管を修復/再生する能力を向上させる。
細胞生存能力を決定するために、本発明の細胞集団を、24ウェルまたは96ウェル形式で、24〜48時間培養する。培養物の確立後、細胞をNCEに24〜96時間の期間暴露する。Prestoブルー試薬原液をKGMに1:10の比で混合し(KGM 9部に対してPresto Blue 1部)、これを十分に混合することにより、生存能力を評価する。次いで、培地およびNCEを各培養ウェルから除去し、Prestoブルーを少量培養ウェルに添加し(300ul/ウェルl/24ウェルまたは100ul/ウェル/96ウェル)、37℃で2時間インキュベートする。次いで、培地を除去し、96ウェルプレートに移し、530/590で読み出す。
カスパーゼ活性の定量的in vitro測定のために、Homogeneous Caspases Assay(Roche社、Indianapolis、IN)に従って蛍光カスパーゼアッセイを行う。まず、50μlの二重濃縮アポトーシス誘導薬剤を、96ウェルプレートのウェルにピペットで注入する。次いで、本発明の細胞集団を、50μlの細胞培養培地中で、ウェル当たり4×104個の細胞で、事前に希釈されたアポトーシス誘導薬剤に2連で播種する。細胞は、ブランク、標準、または陽性対照用に指定されたウェルには播種しない。次いで、100μlの細胞培養培地のみをブランク用に指定されたウェルに2連でピペットで注入する。100μlの事前に希釈された陽性対照を、陽性対照用に指定されたウェルに2連でピペットで注入する。100μlの事前に希釈された標準溶液を、特定濃度の標準用に指定されたウェルに2連でピペットで注入する。次いで、100μlの新しく調製された基質希釈標準溶液を、各ウェルに滴下する。96ウェルプレートを蓋で覆い、37℃で1時間超インキュベートする。470〜500nmに設定された励起フィルタおよび500〜560nmに設定されたエミッションフィルタを有するプレートリーダーを使用して、カスパーゼ活性を蛍光測定により測定する。
GGT(L−グルタミン酸ガンマ−p−ニトロアナリド塩酸塩)酵素活性を、懸濁液中の細胞に対して、または播種細胞に対して行うことができる。
本試験において、SRCを増加容量範囲の周知の腎毒性薬物(例えば、アミノグリコシド、化学療法薬、免疫抑制薬、抗菌薬、および抗レトロウイルス薬)に暴露し、毒性および機能についてスクリーニングした。(表15.1)本明細書において示されるように、周知の腎毒性化合物は、ヒト組織生理機能をex vivoでシミュレートする二次元(2D)および三次元(3D)ヒト腎細胞コンストラクトを使用して、初代ヒトSRC機能活性を、用量反応的に再現性をもって確実に阻害した。
2D培養SRCへの形態学的、遺伝子型、表現型および機能的変化を、周知の腎毒素アムホテリシンB(Amp B)の増加用量に対する暴露後72時間まで監視した。TC50は、SRC/NKA ex vivo GGT活性のAmp Bノックダウンにより推定した。
治療用途に好適な試験薬剤の開発は、最終的にin vivoでの評価を必要とする。しかしながら、そのような試験は、時間および費用を要し得るため、多くの場合、評価される試験薬剤の最初のin vitroスクリーニングが行われる。効果的なin vitroスクリーニングは、ある特定の試験薬剤候補を除外し、最も有望な選択肢のみがin vivoで試験され得るようにするために、関連反応に対し十分感受性でなければならない。この手法は、in vivo資源のより効率的な使用をもたらし、製品を市場に導入するために必要な費用および時間を削減する可能性がある。
NKAのin vivoでの潜在的再生生物活性(すなわち、有効性)を決定するための、in vitroでのオルガノイド/管形成に基づくアッセイが開発されている。NKA部位特異的な生着およびデノボ再生、すなわち、オルガノイドの形成および/または管形成および/または糸球体形成は、これらのin vitro有効性アッセイの使用により決定され得る。腎臓オルガノイドおよび尿細管の形成は、NKA生成物有効性の指標であることが判明している。
NKAからのオルガノイドおよび尿細管の形成は、以下のように誘導され得る。
1)尿細管およびオルガノイドと呼ばれるスフェロイド構造は、NKAの2D培養から自発的に自己集合する。
2)尿細管および管形成能を有するオルガノイドは、NKAの3D培養から自発的に自己集合する。
3)そのような器官形成生物活性は、NKA等の腎細胞集団(および、例えば乳腺、肺等の発達中に分岐形態形成を示す関連細胞集団)に制限され、HFF等の非関連細胞からは観察されず、したがって、in vivoでの可能性のある再生生物活性(すなわち、有効性)のin vitro診断指標として使用され得る。
Claims (21)
- 試験薬剤の腎臓毒性のレベルを決定する方法であって、
a)複数の濃度の試験薬剤を、尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一腎細胞集団と共に培養することであって、前記不均一腎細胞集団は、B1細胞集団が欠乏している、培養することと、
b)前記試験薬剤の毒性のレベルを決定することであって、少なくとも1つの毒性指標の存在は、前記試験薬剤の腎臓毒性のレベルを示す、決定することと
を含む方法。 - 前記不均一腎細胞集団は、エリスロポエチン(EPO)産生細胞、糸球体細胞および血管細胞のうちの1つ以上を含むB4細胞集団をさらに含む、請求項1に記載の方法。
- 前記不均一腎細胞集団は、B3細胞集団をさらに含む、請求項2に記載の方法。
- 前記不均一腎細胞集団は、B5細胞集団をさらに含む、請求項3に記載の方法。
- 前記細胞集団は、スフェロイドとして培養される、請求項1に記載の方法。
- 前記不均一腎細胞集団は、マトリックス上で培養される、請求項1に記載の方法。
- 前記マトリックスは、三次元(3D)マトリックスである、請求項6に記載の方法。
- 前記毒性指標は、減少したGGT発現である、請求項1から7のいずれか一項に記載の方法。
- 前記毒性指標は、対照と比較したアクアポリン1発現の変化である、請求項1から8のいずれか一項に記載の方法。
- 前記毒性指標は、対照と比較したアクアポリン2発現の変化である、請求項1から9のいずれか一項に記載の方法。
- 前記毒性指標は、LDHである、請求項1から10のいずれか一項に記載の方法。
- 前記毒性指標は、対照と比較した細胞集団の表現型の変化である、請求項1から11のいずれか一項に記載の方法。
- 前記試験薬剤の腎臓毒性のレベルの決定は、前記試験薬剤のTC50を計算することを含む、請求項1に記載の方法。
- 試験薬剤の代謝を決定するための方法であって、
a)試験薬剤および酵素を、尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一腎細胞集団と共にインキュベートすることであって、前記不均一腎細胞集団は、B1細胞集団が欠乏している、インキュベートすることと、
b)前記試験薬剤の1つ以上の代謝物を検出することと
を含む方法。 - 腎臓障害を有するヒト対象における治療用途に好適な試験薬剤を特定するためのin vitro法であって、
a)試験薬剤を、増殖マーカーおよびM2表現型の発現からなる群から選択される表現型を特徴とするB2細胞集団を含む不均一腎細胞集団と接触させることであって、前記B2細胞集団は、尿細管細胞の濃縮集団を含む、接触させることと、
b)試験薬剤が、非接触対照細胞集団に比べて、不均一腎細胞集団の増殖マーカーおよび/またはM2表現型の発現を調節するかどうかを決定することと
を含む方法。 - 前記不均一腎細胞集団は、エリスロポエチン(EPO)産生細胞、糸球体細胞および血管細胞のうちの1つ以上を含むB4細胞集団をさらに含む、請求項15に記載の方法。
- 前記不均一腎細胞集団は、マトリックス上で培養される、請求項15または16に記載の方法。
- 前記マトリックスは、三次元(3D)マトリックスである、請求項17に記載の方法。
- 尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一腎細胞集団を含むオルガノイドであって、前記不均一腎細胞集団は、B1細胞集団が欠乏している、オルガノイド。
- 尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一腎細胞集団を含むオルガノイドを形成する方法であって、前記不均一腎細胞集団は、B1細胞集団が欠乏しており、前記方法は、前記不均一腎細胞集団を、i)2D培養;ii)3D培養:COL(I)ゲル;iii)3D培養:Matrigel;iv)3D培養:撹拌に続くCOL(I)/Matrigel;およびv)3D培養:COL(IV)ゲルからなる群から選択される培養系中で培養することを含む方法。
- 尿細管細胞の濃縮集団を含むB2細胞集団を含む不均一細胞集団の再生能を決定する方法であって、前記不均一腎細胞集団は、B1細胞集団が欠乏しており、前記方法は、
a)前記不均一腎細胞集団を培養することと、
b)前記不均一細胞集団の再生能を決定することであって、尿細管および/またはオルガノイドの形成は、再生能を示す、決定することと
を含む方法。
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