JP2021517450A - Ssea4に結合するキメラ抗原受容体及びその使用 - Google Patents
Ssea4に結合するキメラ抗原受容体及びその使用 Download PDFInfo
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- JP2021517450A JP2021517450A JP2020520005A JP2020520005A JP2021517450A JP 2021517450 A JP2021517450 A JP 2021517450A JP 2020520005 A JP2020520005 A JP 2020520005A JP 2020520005 A JP2020520005 A JP 2020520005A JP 2021517450 A JP2021517450 A JP 2021517450A
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Abstract
Description
抗SSEA4 CARをコードするレンチウイルスベクターの構築
レンチウイルスコンストラクトを、大腸菌において標準的な組み換えDNA技術を使用して調製し、DNAシーケンシングにより検証した。より具体的には、配列番号3の配列を有するscFvをコードする核酸を、レンチウイルスプラスミドベクター中にEF−1αプロモーター及びシグナルペプチドをコードする配列の下流でCD8ヒンジをコードする配列の上流にクローニングして、CARカセットを作製した。そのCARカセットはまた、CD8膜貫通ドメインと、CD137細胞内シグナル伝達ドメインと、CD3ζエンドドメインと、トセア・アシグナ(Thosea asigna)の自己開裂性ペプチドT2Aと、EGFRtドメインIII−IVとをコードする。このCARカセットは、配列番号1の核酸配列を有する。レンチウイルスプラスミドベクターは、レンチウイルス粒子の産生を促す追加の配列を含む。
レンチウイルスのパッケージング及び産生は、確立された技術を使用して実施した。パッケージング用細胞、すなわち293T細胞を、10cm培養皿中で10mLの完全培養培地において5×106個の細胞で播種した。それらの細胞を5%のCO2中、37℃で一晩インキュベートした。PBS中でトランスフェクション試薬と、上記レンチウイルスベクターと、パッケージングベクターと、エンベロープベクターとを混ぜ合わせることにより、トランスフェクション複合体を調製した。そのトランスフェクション複合体を、パッケージング用細胞を含む培養皿に加え、細胞を5%のCO2中、37℃で6時間〜8時間インキュベートした。培地を取り替え、細胞を24時間インキュベートした。培養培地を収集し、新鮮な培地と置き換えた。この24時間のインキュベート及び培地収集を2回繰り返した。全ての収集された培地を一緒にして、0.45μmフィルターに通した。濾液を50000×gで2時間遠心分離することで、レンチウイルス粒子をペレット化した。レンチウイルスストックをPBS中で懸濁し、−80℃で貯蔵した。
感染された細胞のゲノム中に組み込まれたレンチウイルスDNAの量を測定することにより、レンチウイルス力価を決定した。293T細胞を24ウェルプレートにおいて1ウェル当たり50000個の細胞の密度で播種し、一晩インキュベートした。高濃度のレンチウイルスストックをポリブレンと一緒に各ウェルに加えて6μg/mLの濃度にした。そのプレートを軽く遠心分離した後に、5%のCO2を有する37℃のインキュベーター中に72時間置いた。レンチウイルスで形質導入された細胞からゲノムDNAを市販のキットで抽出した。
レンチウイルス力価=播種された細胞数×1細胞当たりのレンチウイルスのコピー数/加えられたレンチウイルスストックの容量
を使用して計算した。
確立された技術を使用して抗SSEA4 CARを発現するT細胞を作製した。まず、全血から標準的な血液分離管を用いて末梢血単核細胞(PBMC)を分離し、それらの細胞を完全培養培地中に再懸濁した。PBMCから標準的な磁気ビーズ分離技術を使用してT細胞を分離した。
抗SSEA4 CAR T細胞が標的細胞を溶解する能力を共培養アッセイにより評価した。SSEA−4を発現するMCF−7乳癌細胞を標的細胞として使用した。1mL当たり5×105個の細胞の100μLのMCF−7標的細胞を96ウェルプレートの各ウェルへと移し、5%のCO2中、37℃で一晩培養した。エフェクター細胞、すなわち抗SSEA4 CAR T細胞、形質導入されていないT細胞及びネガティブコントロールレンチウイルスで形質導入されたT細胞をそれぞれ無血清RPMI1640培地中で懸濁した。96ウェルプレートから培養培地を取り出し、標的細胞をPBSで1回洗浄した。T細胞を1:1、2:1、5:1及び10:1のエフェクター対標的(E/T)の比率で別個のウェルへと加えた。各ウェル中の培地の最終容量を、RPMI1640を使用して100μL/ウェルに調節した。共培養物を5%のCO2中、37℃で6時間インキュベートした。
上記のCAR−T細胞を、96ウェルプレートにおいて種々のE/T比率で、10%のFBSを補充したRPMI1640培地中で5%のCO2、37℃で標的細胞系統MCF7と一緒に24時間共培養した。培養培地を採取して、CAR−T細胞によるサイトカイン放出を測定した。簡潔には、96ウェルプレートを室温で1200×gで5分間遠心分離し、その後に各ウェルからの50μLの上清を新たな96ウェルプレートへと移した。市販のELISAキットを使用して製造業者の使用説明書に従って、サイトカインIL−2及びIFN−γの濃度を決定した。それらの結果は、図2A及び図2Bに示されている。データは、SSEA4特異的CAR−T細胞が、標的腫瘍細胞に結合した後にIL−2及びIFN−γの両方を頑健に分泌し、この分泌レベルが、形質導入されていないT細胞又はCARコンストラクトを有しないレンチウイルスで形質導入されたT細胞のどちらよりも有意に大きかったことを示している。
本明細書に開示されるあらゆる特徴は、任意の組み合わせで組み合わせることができる。本明細書に開示されるそれぞれの特徴は、同じ目的、同等の目的又は同様の目的を担う代替的な特徴により置き換えることができる。特段の定めがない限り、開示されるそれぞれの特徴は、包括的な一連の同等の特徴又は同様の特徴の1つの例であるにすぎない。
Claims (20)
- 配列番号3のポリペプチドをコードするヌクレオチド配列を含む、単離された核酸。
- 前記ヌクレオチド配列は、配列番号1である、請求項1に記載の単離された核酸。
- 配列番号2のポリペプチドを発現する、請求項2に記載の単離された核酸を含む組み換え細胞。
- 前記細胞はT細胞である、請求項3に記載の組み換え細胞。
- ウイルスベクターは、レンチウイルスベクター、ガンマレトロウイルスベクター又はアデノ随伴ウイルスベクターである、請求項1に記載の単離された核酸を含むウイルスベクター。
- 前記ヌクレオチド配列は配列番号1である、請求項5に記載のウイルスベクター。
- ステージ特異的胎児性抗原4に特異的に結合する、配列番号3の配列を含む単離されたポリペプチド。
- ステージ特異的胎児性抗原4に特異的に結合する一本鎖Fv(scFv)と、CD3ζ又はFcεRIγ由来の第1のエンドドメインとを含み、前記scFvが配列番号3の配列を有する、キメラ抗原受容体。
- CD28、CD137、CD4、OX40又はICOS由来の第2のエンドドメインを更に含み、前記scFvは、前記第2のエンドドメインに融合され、前記第2のエンドドメインは、前記第1のエンドドメインに融合される、請求項8に記載のキメラ抗原受容体。
- 前記キメラ抗原受容体は、配列番号4の配列を有する、請求項9に記載のキメラ抗原受容体。
- 被験体における腫瘍を治療する方法であって、
腫瘍を有する被験体からT細胞を取得することと、
ステージ特異的胎児性抗原4(SSEA4)を特異的に認識するscFvを含むキメラ抗原受容体(CAR)をコードする核酸を含むベクターで前記T細胞をin vitroで形質導入し、それにより、形質導入されたT細胞が前記CARを発現することと、
前記形質導入されたT細胞をin vitroで増殖させることと、
前記腫瘍を有する被験体へと前記増殖された形質導入されたT細胞を注入し、それにより、抗腫瘍T細胞応答が惹起されることと、
を含み、前記scFvは、配列番号3のアミノ酸配列を有し、前記腫瘍内の細胞は、SSEA4を発現する、方法。 - 前記CARは、配列番号4のアミノ酸配列を有する、請求項11に記載の方法。
- 前記ベクターは、レンチウイルス、ガンマレトロウイルス又はアデノ随伴ウイルスである、請求項12に記載の方法。
- 前記腫瘍は、***腫瘍、結腸腫瘍、胃腸腫瘍、腎臓腫瘍、肺腫瘍、肝臓腫瘍、卵巣腫瘍、膵臓腫瘍、直腸腫瘍、胃腫瘍、精巣腫瘍、胸腺腫瘍、子宮頸部腫瘍、前立腺腫瘍、膀胱腫瘍、皮膚腫瘍、鼻咽頭腫瘍、食道腫瘍、口腔腫瘍、頭頸部腫瘍、骨腫瘍、軟骨腫瘍、筋肉腫瘍、リンパ節腫瘍、骨髄腫瘍又は脳腫瘍である、請求項13に記載の方法。
- 前記形質導入されたT細胞は、配列番号5のポリペプチドを更に発現し、それにより、前記注入された増殖されたT細胞は、抗上皮成長因子受容体抗体によりin vivoで消失され得る、請求項11に記載の方法。
- 前記CARは、配列番号4のアミノ酸配列を有する、請求項15に記載の方法。
- 前記核酸は、配列番号1の配列を有する、請求項16に記載の方法。
- 前記腫瘍は、***腫瘍、結腸腫瘍、胃腸腫瘍、腎臓腫瘍、肺腫瘍、肝臓腫瘍、卵巣腫瘍、膵臓腫瘍、直腸腫瘍、胃腫瘍、精巣腫瘍、胸腺腫瘍、子宮頸部腫瘍、前立腺腫瘍、膀胱腫瘍、皮膚腫瘍、鼻咽頭腫瘍、食道腫瘍、口腔腫瘍、頭頸部腫瘍、骨腫瘍、軟骨腫瘍、筋肉腫瘍、リンパ節腫瘍、骨髄腫瘍又は脳腫瘍である、請求項15に記載の方法。
- 前記腫瘍は、***腫瘍、結腸腫瘍、胃腸腫瘍、腎臓腫瘍、肺腫瘍、肝臓腫瘍、卵巣腫瘍、膵臓腫瘍、直腸腫瘍、胃腫瘍、精巣腫瘍、胸腺腫瘍、子宮頸部腫瘍、前立腺腫瘍、膀胱腫瘍、皮膚腫瘍、鼻咽頭腫瘍、食道腫瘍、口腔腫瘍、頭頸部腫瘍、骨腫瘍、軟骨腫瘍、筋肉腫瘍、リンパ節腫瘍、骨髄腫瘍又は脳腫瘍である、請求項16に記載の方法。
- 前記腫瘍は、***腫瘍、結腸腫瘍、胃腸腫瘍、腎臓腫瘍、肺腫瘍、肝臓腫瘍、卵巣腫瘍、膵臓腫瘍、直腸腫瘍、胃腫瘍、精巣腫瘍、胸腺腫瘍、子宮頸部腫瘍、前立腺腫瘍、膀胱腫瘍、皮膚腫瘍、鼻咽頭腫瘍、食道腫瘍、口腔腫瘍、頭頸部腫瘍、骨腫瘍、軟骨腫瘍、筋肉腫瘍、リンパ節腫瘍、骨髄腫瘍又は脳腫瘍である、請求項17に記載の方法。
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JP2017525361A (ja) * | 2014-08-19 | 2017-09-07 | ミルテニイ バイオテック ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ssea4抗原に特異的なキメラ抗原受容体 |
WO2017172990A1 (en) * | 2016-03-29 | 2017-10-05 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
WO2018023121A1 (en) * | 2016-07-29 | 2018-02-01 | Obi Pharma, Inc. | Human antibodies, pharmaceutical compositions and methods |
WO2018039274A1 (en) * | 2016-08-22 | 2018-03-01 | CHO Pharma Inc. | Antibodies, binding fragments, and methods of use |
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US20200338177A1 (en) | 2020-10-29 |
US20190290744A1 (en) | 2019-09-26 |
TW202003049A (zh) | 2020-01-16 |
CN111629762A (zh) | 2020-09-04 |
AU2019239730A1 (en) | 2020-04-23 |
EP3678711A1 (en) | 2020-07-15 |
KR20200135760A (ko) | 2020-12-03 |
IL274258A (en) | 2020-06-30 |
US10751399B2 (en) | 2020-08-25 |
SG11202002994SA (en) | 2020-04-29 |
TWI817997B (zh) | 2023-10-11 |
EP3678711A4 (en) | 2021-06-02 |
BR112020015723A2 (pt) | 2020-12-08 |
WO2019183025A1 (en) | 2019-09-26 |
IL274258B (en) | 2022-04-01 |
JP7378152B2 (ja) | 2023-11-13 |
US11628210B2 (en) | 2023-04-18 |
CA3078304A1 (en) | 2019-09-26 |
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