JP6980683B2 - 細胞分泌物の分析のための装置及び方法 - Google Patents
細胞分泌物の分析のための装置及び方法 Download PDFInfo
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Description
本出願は、2016年3月17日に出願された米国仮特許出願第62/309,663号明細書の優先権を主張するものであり、この開示は、参照によりその全内容が本明細書に組み入れられる。
個々のマイクロ流体チャンバーのアレイを含む2構成要素マイクロ流体装置を充填する効率を、複数種の微小粒子を装置の底部構成要素のオープンチャンバーに充填することによってアッセイした。マイクロ流体チャンバーの寸法は、80μm×120μm×160μm(幅、長さ、高さ)であった。
1型=0.53/チャンバー、SD=0.89;
2型=1.46/チャンバー、SD=1.4;
3型=2.45/チャンバー、SD=1.89;
4型=3.90/チャンバー、SD=2.33;
5型=2.89/チャンバー、SD=1.70。
接着読み出し細胞の充填を、本発明の2構成要素装置で評価し、MSLによって製造された組立済みのマイクロ流体装置への同じ細胞の充填と比較した。
チャンバーの培地の交換中の2構成要素マイクロ流体装置の性能に対するチャンバーのアスペクト比の影響を評価するために、一連の実験を行った。1つの実験では、アスペクト比(深さ/高さの最小の横寸法に対する比)が異なるチャンバーを有するマイクロ流体装置を試験して、細胞又はビーズを含むチャンバー上に溶液を供給することによる培地交換により、チャンバーからの細胞若しくはビーズの減少、又はチャンバー内での細胞若しくはビーズの変位が生じるか否かを決定した。
本明細書に記載の装置は、読み出し細胞型に特異的に結合する抗体を分泌する単一細胞を同定するための多段階アッセイを行うための手段を提供する。
本明細書に記載の装置は、個々の細胞によって分泌される抗体を同時にアッセイして、それらが1つ以上の抗原に結合するか否かを決定する手段を提供する。インフルエンザの場合、この手段は、複数の系統に結合することができる抗体を同定するのに有用である。
ビーズベースのアッセイは、腫瘍壊死因子(TNF)スーパーファミリーに属する2型膜貫通糖タンパク質である標的ヒト4−1BB(h4−1BB)に結合する抗体の検出を可能にするようにデザインされた。h4−1BB抗体も、マウス4−1BBに結合する能力について試験した。最後に、h4−1BB抗体を、4−1BBとその天然リガンドh4−1BBリガンドとの相互作用を遮断する能力について評価した。
本明細書で提示される2構成要素装置に上部構成要素を組み込むことにより、単一細胞から分泌される抗体の分析にいくつかの利点がもたらされる。例えば、2構成要素装置は、分泌された抗体を単一チャンバーの容積に閉じ込めることにより高い感度を提供し;多段階アッセイを行うために必要な流体のハンドリングステップを容易にし;バックグラウンド蛍光を減少させてS/N比を増大させ;かつ抗体の拡散によるチャンバー間の交差汚染を防止する。
多重免疫化及びスクリーニングを行って、5種類の抗原に対するウサギモノクローナル抗体を単離した。ウサギを、約6週間にわたって5種類の抗原の混合物で免疫化した。免疫化後、血液試料を5つの抗原全てに対して力価を示すウサギから得、この試料から末梢血単核細胞(PBMC)を単離した。次いで、形質細胞を含む単離されたPBMCを、5種類のビーズファミリー(Starfire(商標)ビーズ、Bangs Laboratories)の混合物が予め充填されたマイクロ流体装置の底層に充填した。各ビーズファミリーを、ウサギを免疫化するために使用される5つの抗原のうちの1つにコンジュゲートし、各ファミリーは、ビーズマトリックスに含まれる蛍光色素のレベルによって光学的に区別可能であった。細胞及びビーズの充填後、2構成要素装置を組み立て、チャンバーを約2時間インキュベートして、分泌された抗体の濃縮、及び対応する抗原を有するビーズ上での特異的抗体の効率的な捕捉を可能にした。次いで、ビーズマトリックスに使用されるフルオロフォアとは光学的に異なるフルオロフォアで標識された二次抗体を含む新鮮な培地でチャンバーを洗浄した。次いで、マイクロ流体装置を2つの蛍光チャネルでイメージングし、第1のチャネルの自動リアルタイム画像解析を用いて、各チャンバー内のビーズを自動的にセグメント化し、識別した。第2の蛍光チャネルで得た画像の画像解析を用いて、抗体が異なるビーズ型のそれぞれに結合したか否かを決定した。結果は、5つの抗原全てが検出可能であることを示した。
本明細書に記載の装置を、細菌病原体である肺炎桿菌(Klebsiella pneumonia)に対する完全ヒト抗体の発見のために使用した。抗体分泌細胞を、ヒト骨髄、扁桃腺、及びヒト血液から得た。これらの細胞のスクリーニングのために、肺炎桿菌(Klebsiella pneumonia)全体を、チャンバー当たり約100個の細菌濃度でマイクロ流体装置に充填した。次いで、抗体分泌細胞を装置のチャンバー内に充填し、上部構成要素を底層に整合させ、続いてインキュベートして分泌された抗体の蓄積を可能にした。ナノリットルの容積のチャンバーでの閉じ込めにより、抗体が細菌の表面に提示された抗原を認識し、続いてその細菌に結合することを可能にした。
以下の実験を行って、本明細書に記載の装置及び方法が、複数の他の細胞、例えば、他の抗体分泌細胞が同じチャンバー内に存在する場合に、単一細胞によって産生されるモノクローナル抗体を単一チャンバーで検出及び分析することができるアッセイでの使用に適していることを実証した。
以下の実施例は、本明細書に提示される2構成要素装置及び方法が、高い生存率での哺乳類細胞の長期培養を必要とする実験の実施を可能にすることを実証するために行った。マイクロ流体装置に、K562細胞の集団を充填した。装置の異なる区分には、チャンバー(チャンバーの寸法:幅200μm×長さ200μm×奥行き140μm)当たり1個の細胞から約20個の細胞までの範囲でチャンバーごとに異なる数の細胞を充填した。充填後、装置をイメージングして、各チャンバー内の細胞数を決定した。装置のチャンバーのサブセットを、明視野顕微鏡検査によって48時間監視して、各チャンバー内の細胞の増殖及び生存率を評価した。実験を通じて、チャンバーを6時間ごとに新鮮な培地で洗い流して、培地に十分な栄養素を確保し、細胞増殖を阻害し得る代謝産物を除去した。チャンバーが、強い増殖及び優れた生存率を示し、かつ細胞がコンフルエンスまで増殖したチャンバーでも強い細胞増殖が維持されたことが観察された(図40)。
以下の実施例を行って、個々の装置のチャンバーからの回収が、交差汚染することも、回収された細胞の完全性を損なうこともなく達成できることを実証した。
以下の実施例を行って、本明細書に提示される装置及び方法が、マイクロ流体装置の1つ以上のチャンバー内での培地交換に対する空間的及び時間的制御の実施を可能にすることを実証した。この制御は、機能的細胞外効果アッセイが高い時間分解能をイメージングに必要とする実験を行うときに特に有用であり得る。例えば、このようなアッセイは、因子、例えば抗体に曝露された細胞の溶解を監視すること、読み出し細胞内の蛍光タンパク質の転位を監視すること、刺激に応答した読み出し細胞内のイオンチャネルの流れを監視すること、刺激に応答した二次メッセージであるカルシウムの流れを監視することを含み得る。例えば、マイクロ流体単一細胞アッセイを行って、読み出し細胞に予め充填されたカルシウム感受性蛍光色素によって測定される、アゴニストの添加に応答して読み出し細胞での急速なカルシウムの流れを阻害する抗体を同定することができる。この場合、シグナルは一過性であるため、10,000個を超えるチャンバーを有する装置全体のイメージングが十分な時間分解能を提供しない可能性がある。この問題は、上部構成要素が、制御されたタイミングで装置の小区分にアゴニストを選択的に添加できるようにデザインされているため、チャンバーをアゴニスト添加後の既知の適切な時間にイメージングできる2構成要素マイクロ流体装置を使用することによって克服することができる。これは、選択されたチャンバーのサブセットのみの上を溶液が流れることを可能にする弁及びチャネル構造を上層が備える2構成要素マイクロ流体装置を用いて達成することができる。小区分の数及び小区分当たりのチャンバーの数は、アッセイの要件に依存し、流体ネットワークにデザインすることができる。あるいは、チャネルは有するが弁は有していない上部構成要素を使用して、規定数のチャンバーと連動する流体ネットワークの異なる区分のための別個の入口を有することによって同じ結果を得ることができる。あるいは、これは、アゴニストをチャンバー上に流すことができるオリフィスを備える最上層を使用することによって達成することができ、このオリフィスは、底層に対して位置が固定されるのではなく、異なる領域を露出させためにチャンバーアレイを横断することができる。あるいは、装置は、上層なしで使用することができ、ロボット制御毛細管を使用して、アレイの異なる領域にアゴニストを流すことができる。あるいは、装置は、上層なしで使用することができるが、それぞれがアッセイのための適切な数のチャンバーを有する装置の異なる小領域を分離するパーティションを含むようにデザインすることができ、異なるサブアレイのそれぞれへのアゴニストの添加は、サブアレイ上のピペット操作によって達成することができる。
Claims (22)
- 抗体分泌細胞(ASC)の分泌抗体による細胞外効果を示す、ASCを含む細胞集団を同定する方法であって、
それぞれ0.6以上の平均アスペクト比(チャンバーの高さ:最小横寸法)を有する複数のオープンチャンバー内に、それぞれ10〜100個の細胞を含む複数の細胞集団を保持するステップであって、前記異なる複数のオープンチャンバーが、マイクロ流体装置の第1の構成要素に存在し、前記第1の構成要素が、前記マイクロ流体装置の第2の構成要素と共に可逆的なシールを形成するように構成されており、
前記複数の細胞集団のうちの少なくとも1つの個々の細胞集団が、1つ以上のASCを含み、
前記複数のオープンチャンバーのうちの前記個々のオープンチャンバー又はそのサブセットが、1つ以上の読み出し粒子を含む読み出し粒子集団をさらに含む、ステップ、
チャンバーの内容物をインキュベートするステップ、
複数のチャンバー又はそのサブセットを細胞外効果の存在についてアッセイするステップであって、前記読み出し粒子集団又はその亜集団が、前記細胞外効果の直接的又は間接的な読み出しを提供する、ステップ、及び
前記アッセイするステップの結果に基づいて、少なくとも1つの個々の細胞集団内の1つ以上の前記ASCが前記細胞外効果を示すか否かを決定するステップを含む、方法。 - 前記ASCが、形質細胞、B細胞、形質芽球、記憶B細胞の増殖によって産生される細胞、ハイブリドーマ細胞、抗体を産生するようにエンジニアリングされた組換え細胞、又はこれらの組み合わせである、請求項1に記載の方法。
- 前記読み出し粒子集団のうちの1つ以上が、1つ以上の読み出しビーズ、1つ以上の読み出し細胞、又はこれらの組み合わせを含む、請求項1又は2に記載の方法。
- 前記複数の読み出し粒子集団又はそのサブセットが、その表面にGタンパク質共役受容体(GPCR)又は可溶化GPCRを発現する1つ以上の読み出し細胞を含み、かつ
前記細胞外効果が、GPCRのアンタゴニズム、GPCRのアゴニズム、又は前記1つ以上のASCによって分泌される抗体によるGPCRへの結合である、請求項1〜3のいずれか1項に記載の方法。 - 前記複数の読み出し粒子集団又はそのサブセットが、その表面にイオンチャネルを発現する1つ以上の読み出し細胞を含み、かつ
前記細胞外効果が、前記イオンチャネルのアンタゴニズム、前記イオンチャネルのアゴニズム、又は前記1つ以上のASCによって分泌される抗体による前記イオンチャネルへの結合である、請求項1〜4のいずれか1項に記載の方法。 - 前記読み出し粒子集団のうちの1つ以上が、抗原又はエピトープで官能化されている、請求項1に記載の方法。
- 前記読み出し粒子集団のうちの1つ以上が、抗体結合部分で官能化されている、請求項1に記載の方法。
- 前記抗体結合部分が、プロテインA、プロテインA/G、プロテインG、免疫グロブリンに結合するモノクローナル抗体、免疫グロブリンに結合するモノクローナル抗体断片、免疫グロブリンに結合するポリクローナル抗体、免疫グロブリンに結合するポリクローナル抗体断片、又はこれらの組み合わせである、請求項7に記載の方法。
- 前記複数の細胞集団が、液体カラムによって生成される静水圧によって、ディスペンサーによって、又は前記第2の構成要素若しくは前記第1の構成要素を上下に動かして流体をマイクロチャンバーに移動させることによって前記オープンチャンバーに充填される、請求項1に記載の方法。
- 前記複数の読み出し粒子集団又はそのサブセットが、液体カラムによって生成される静水圧によって、ディスペンサーによって、又は前記第2の構成要素若しくは前記第1の構成要素を上下に動かして流体をマイクロチャンバーに移動させることによって前記オープンチャンバーに充填される、請求項1〜9のいずれか1項に記載の方法。
- 前記細胞外効果が、前記1つ以上のASC又はそのサブセットによって分泌される抗体と前記読み出し粒子集団又はその亜集団との間の結合相互作用である、請求項1〜10のいずれか1項に記載の方法。
- 前記結合相互作用が、抗原−抗体結合特異性相互作用、抗原−抗体結合親和性相互作用、又は抗原−抗体結合動力学相互作用である、請求項11に記載の方法。
- 前記細胞外効果が、アポトーシスの調節、細胞増殖の調節、読み出し粒子の形態学的外観の変化、読み出し粒子内のタンパク質の局在の変化、読み出し粒子によるタンパク質の発現、前記ASCによって誘導される読み出し細胞の細胞溶解、前記ASCによって誘導される前記読み出し細胞の細胞アポトーシス、読み出し細胞の壊死、抗体の内在化、前記ASCによる酵素中和、可溶性シグナル伝達分子の中和、又はこれらの組み合わせである、請求項1〜12のいずれか1項に記載の方法。
- 前記細胞集団のうちの1つ以上を、前記複数のチャンバーのうちの1つ以上のチャンバーにおいて単一平面で維持するステップをさらに含む、請求項1〜13のいずれか1項に記載の方法。
- 前記読み出し粒子集団のうちの1つ以上を、前記1つ以上の細胞集団と同一平面で維持するステップをさらに含む、請求項14に記載の方法。
- 前記細胞外効果が検出されるチャンバーから細胞集団を回収して回収された細胞集団を得るステップをさらに含む、請求項1〜15のいずれか1項に記載の方法。
- 0.6以上の平均アスペクト比(チャンバーの高さ:最小横寸法)を有する複数の異なるオープンチャンバー内において、前記回収された細胞集団に由来する複数の細胞亜集団を保持するステップであって、前記複数の異なるオープンチャンバーが、マイクロ流体装置の第1の構成要素に存在し、前記第1の構成要素が、前記第2の構成要素と共に可逆的なシールを形成するように構成されており、
前記複数のオープンチャンバーは、前記第1の構成要素に存在し、
前記複数の細胞亜集団のうちの個々の細胞亜集団が、1つ以上の抗体分泌細胞(ASC)を含み、かつ前記複数のオープンチャンバーのうちの個々のオープンチャンバー内に保持され、
前記複数のオープンチャンバーのうちの個々のオープンチャンバー又はそのサブセットが、1つ以上の読み出し粒子を含む読み出し粒子集団をさらに含む、ステップ、
前記チャンバーの内容物をインキュベートするステップ、
前記複数のチャンバー又はそのサブセットを前記細胞外効果の存在についてアッセイするステップであって、前記読み出し粒子集団又はその亜集団が、前記細胞外効果の直接的又は間接的な読み出しを提供する、ステップ、並びに
前記アッセイするステップの結果に基づいて、前記細胞外効果を示す1つ以上のASCを含む複数の細胞亜集団の中から細胞亜集団を同定するステップをさらに含む、請求項16に記載の方法。 - 前記複数の細胞亜集団のうちの前記細胞亜集団が平均1〜25個の細胞を含む、請求項17に記載の方法。
- 前記第2の構成要素がエラストマーである、請求項1〜18のいずれか1項に記載の方法。
- 前記第2の構成要素が複数の層を含む、請求項19に記載の方法。
- 前記第2の構成要素がパターン化されていない、請求項19に記載の方法。
- 前記第2の構成要素が、1つ以上の流路及び1つ以上のプッシュダウン弁構造を備える、請求項19に記載の方法。
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