JP2023515655A - 改変免疫細胞とその使用 - Google Patents
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Abstract
Description
本明細書において、「リガンドを特異的に認識する細胞表面分子」という用語は、標的分子(例えば、リガンド)に特異的に結合することができる細胞の表面上に発現される分子を指す。このような表面分子は、通常、リガンドを特異的に結合可能なリガンド結合ドメイン、表面分子を細胞表面に固定する膜貫通ドメイン、及びシグナル伝達に関与する細胞内ドメインを含む。このような表面分子の例には、例えば、T細胞受容体又はキメラ抗原受容体が含まれる。
インターロイキンは、白血球によって産生され、白血球間で機能するサイトカインの一種であり、情報の伝達と、免疫細胞の活性化および調節と、T細胞およびB細胞の活性化、増殖、分化の媒介と、炎症反応において重要な役割を果たす。インターロイキンの生物学的効果は、通常、対応する受容体への結合によって達成され、例えば、IL-7の生物学的特性は、IL-7の受容体IL-7Rへの結合によって達成される。
チロシンキナーゼ受容体3リガンド(Fms-like tyrosine kinase 3 ligand,Flt3L)は、サイトカインであり、Fms様チロシンキナーゼ受容体3(Fms-like tyrosine kinase 3 receptor,Flt3R)に特異的に結合でき、それにより、DC細胞、ナチュラルキラー細胞、細胞傷害性Tリンパ球などの増殖、分化、成熟を促進することができる。Flt3Lは、あらゆるマウスの組織や臓器に広く存在する。Flt3Lは、ヒト末梢血単球で最も高く発現し、次に心臓、胎盤、肺、脾臓、胸腺、卵巣、小腸、肝臓、腎臓、膵臓で発現し、脳組織で最も低く発現した。
リンパ系ケモカインとしても知られるC型ケモカインファミリーは、主にCD8+T細胞とナチュラルキラー細胞によって産生されるXCL1とXCL2の2つのメンバーを含む。XCL1は、独自の配列機能と2つの交換可能なタンパク質空間コンフォメーションを有し、これによって、他のケモカインと異ならせ、独自の機能を果たすことができる。XCL1特異的受容体XCR1は、Gタンパク質共役型受容体ファミリーのメンバーであり、2つの間の相互作用が、胸腺のネガティブセレクションと自己免疫寛容の確立に重要な役割を果たすだけでなく、交差抗原提示を開始し、細胞傷害性免疫応答を仲介することもできる。XCL1は、免疫系のバランスを調節し、腸の免疫恒常性を維持するだけでなく、自己免疫疾患、腎炎、結核、ヒト免疫不全ウイルス感染症などの様々な疾患にも関連している。XCL2とXCL1の核酸配列は97%同一であり、7位と8位で2つのアミノ酸残基が異なる。XCL1ではAspとLysであり、XCL2ではHisとArgである。研究により、XCL2は、XCL1と比べて、発現プロファイル、構造、及び機能が非常に似っていることが分かった。例えば、XCL1と同様に、XCL2も、単量体と二量体の2つの相互変換可能なタンパク質空間コンフォメーションを有する。そのうち、単量体のコンフォメーションは、XCR1に結合して活性化させ、二量体のコンフォメーションは、グリコサミノグリカン(Glycosaminoglycan、GAG)のヘアピン構造に対してより高い親和性を示す。XCL1及びXCL2の受容体であるXCR1は、抗原提示能力を持つDC(cDC1)細胞で選択的に発現しており、いくつかの研究により、XCL1の導入により、抗腫瘍免疫療法及び標的ワクチンの有効性を効果的に改善できることがわかった。
本発明の外因性遺伝子、例えば、インターロイキン、Flt3L、XCL2及び/又はXCL1の発現は、構成的発現又は条件付き発現であり得る。
本発明は、さらに、(i)リガンドを特異的に認識する細胞表面分子をコードする核酸配列、(ii)インターロイキンをコードする核酸配列、及び(iii)Flt3L、XCL2及び/又はXCL1をコードする核酸配列を含む核酸分子を提供する。
本発明は、さらに、本発明に記載の核酸を含むベクターを提供する。ここで、リガンドを特異的に認識する細胞表面分子をコードする核酸配列、IL-7をコードする核酸配列、XCL1をコードする核酸、XCL2をコードする核酸及び/又はFlt3Lをコードする核酸配列は、1つ以上のベクターにすることができる。
本発明は、さらに、本発明の核酸又はベクターを含む改変免疫細胞を提供する。つまり、本発明の改変免疫細胞は、リガンドを特異的に認識する細胞表面分子、外因性IL-7遺伝子、並びにXCL1、XCL2及び/又はFlt3L遺伝子を発現する。
本発明は、本発明の改変免疫細胞、核酸分子又はベクターを含むキットを提供する。
・ペプチド細胞毒素、例えば、リシン、ジフテリア毒素、シュードモナス細菌外毒素A、DNase、及びRNaseなど;
・放射性核種、例えば、ヨウ素131、レニウム186、インジウム111、イリジウム90、ビスマス210及び213、アクチニウム225、及びアスタチン213;
・プロドラッグ、例えば、抗体指向酵素プロドラッグなど;
・免疫刺激剤血、例えば、血小板第4因子、黒色腫成長刺激タンパク質など;
・抗体又はそのフラグメント、例えば、抗CD3抗体又はそのフラグメント;
・補体活性化物質;
・異種タンパク質ドメイン、同種タンパク質ドメイン、ウイルス性/細菌性タンパク質ドメイン、ウイルス性/細菌性ペプチド。
本発明は、癌、感染症又は自己免疫疾患に罹患している被験者を治療する方法をさらに提供し、本発明による有効量の免疫細胞又は医薬組成物を被験者に投与することを含む。したがって、本発明は、癌、感染症又は自己免疫疾患の治療のための薬剤の製造における改変免疫細胞の使用をさらに含む。
1.pLV-mCD19プラスミドの調製
マウス脾臓の全mRNAをテンプレートとして、逆転写PCRによりマウス脾臓の全cDNA配列を取得し、さらに、PCRにより、XbaI、及びSalI制限部位を含むマウスmCD19配列を取得した。そして、mCD19遺伝子をpLV-BHAmプラスミドに組換えて、pLV-BHAm-mCD19プラスミドを得た。
T175フラスコでは、293T細胞を、30×106細胞/フラスコの密度で10%ウシ胎児血清を含む30 mlのDMEM培地に播種し、37°C、5%CO2のインキュベーターで一晩培養した。
6ウェル細胞培養プレートの各ウェルに、10%ウシ胎児血清を含むRPMI-1640培地(Gibco、ロット番号C12430500BT)、1×106個のマウス膵臓がん細胞Panc02(中国薬科大学の研究室から贈与)、及び200μl pLV-BHAm-mCD19レンチウイルスを加え、37℃、5%CO2条件下で48時間インキュベートした。その後、細胞を0.25%のトリプシンで消化して単細胞懸濁液を形成し、細胞を希釈して96ウェルプレートに移し、モノクローナル細胞が現れるまで培養を続けた。また、モノクローナル細胞を採取し、0.25%のトリプシンで単一細胞に再度消化し、200μlのopti-MEM培地で再懸濁した。APC anti-mouse CD19抗体(Biolegend、ロット番号115512)を使用して、フローサイトメトリーによって感染効率を検出し、CD19陽性クローンをスクリーニングした。陽性クローンを3~4回継代した後、フローサイトメトリーでCD19の発現レベルを検出した。ウイルスに感染していないPanc02細胞を対照として使用した。
1.レトロウイルスプラスミドの構築
mCD19-scFv、mCD8aヒンジ領域、膜貫通領域、マウス41bb細胞内ドメイン及びマウスCD3ζ細胞内ドメインのコード配列フラグメントを人工的に合成し、XhoI/EcoRI制限部位を両端に付加した。フラグメントをMSCVベクターにクローン化して、MSCV-mCD19-CARプラスミドを得た。
T175フラスコで、293T細胞を、30×106個の細胞/フラスコの密度で10%ウシ胎児血清を含む30 mlのDMEM培地に播種し、37°C、5%CO2のインキュベーターで一晩培養し、ウイルスをパッケージングした。
Tリンパ球をマウス脾臓から分離し、DynaBeads CD3/CD28 CTSTM(Gibco,ロット番号40203D)でT細胞を活性化させた後、37℃、5%CO2で1日間培養した。
1.細胞表面CARの発現レベル
実施例2によって調製された2×105個のCAR-T細胞を取り出し、Goat Anti-Rat IgG(H&L)Biotin(BioVision,ロット番号6910-250)を一次抗体として用い、APC Streptavidin(BD Pharmingen、ロット番号554067)をニ次抗体として用い、フローサイトメトリーで、CAR T細胞でのCARの発現レベルを検出した。図4はその結果示す。
実施例2によって調製されたCAR-T細胞の上清を収集し、メーカーのおすすめに従って、Mouse XCL1 DuoSet ELISA kitキット(R&D Systems,ロット番号DY486)を使用して、細胞におけるのXCL1の分泌レベルを検出した。図5は結果を示す。
実施例2によって調製されたCAR-T細胞の上清を収集し、メーカーのおすすめに従って、Mouse IL-7 DuoSet ELISA kitキット(R&D Systems,ロット番号DY407)を使用して、細胞におけるIL-7の分泌レベルを検出した。図6は結果を示す。
実施例2によって調製されたCAR-T細胞の上清を収集し、メーカーのおすすめに従って、Mouse CCL19 DuoSet ELISA kitキット(R&D Systems,ロット番号DY440)を使用して、細胞におけるCCL19の分泌レベルを検出した。図7は結果を示す。
実施例2によって調製されたCAR-T細胞の上清を収集し、メーカーのおすすめに従って、Mouse Flt-3 Ligand DuoSet ELISA kitキット(R&D Systems,ロット番号DY427)を使用して、細胞におけるFlt3Lの分泌レベルを検出した。図8は結果を示す。
2×105個の細胞/100μlの濃度で、NT細胞、mCD19-CAR細胞、mCD19-CAR-XCL1細胞、mCD19-CAR-Flt3L細胞、mCD19-CAR-IL-7-CCL19細胞、mCD19-CAR-IL-7-Flt3L細胞及びmCD19-CAR-IL-7-XCL1細胞を、96ウェルの丸底プレートに加えた。その後、各ウェルに1×104個の細胞/100μlの濃度で標的Panc02-mCD19細胞又は非標的Panc02細胞に加えた。37℃で24時間のインキュベーション後、培養上清を回収した。メーカーのおすすめに従って、Mouse IFN-gamma DuoSet ELISAキット(R&D、ロット番号DY485)を使用して、培養上清におけるIFN-γの発現レベルを検出した。
実施例1で調製された5×105個のPanc02-mCD19膵臓がん細胞を、健康なC57BL/6マウスの左前肢の腋窩に皮下接種した。
配列番号2:CD19 scFv
配列番号3:CD8α膜貫通ドメイン
配列番号4:CD8α膜貫通ドメイン
配列番号5:4-1BB共刺激ドメイン
配列番号6:4-1BB共刺激ドメイン
配列番号7:CD3ζシグナル伝達ドメイン
配列番号8:CD3ζシグナル伝達ドメイン
配列番号9:CD8αシグナルペプチド
配列番号10:CD8αシグナルペプチド
配列番号11:CD8αヒンジ領域
配列番号12:CD8αヒンジ領域
配列番号13:mCD19 scFv
配列番号14:mCD19 scFv
配列番号15:mCD8α膜貫通ドメイン
配列番号16:mCD8α膜貫通ドメイン
配列番号17:m4-1BB共刺激ドメイン
配列番号18:m4-1BB共刺激ドメイン
配列番号19:mCD3ζ細胞内シグナル伝達ドメイン
配列番号20:mCD3ζ細胞内シグナル伝達ドメイン
配列番号21:mCD8αヒンジ領域
配列番号22:mCD8αヒンジ領域
配列番号23:hIL-7
配列番号24:hIL-7
配列番号25:hXCL-1
配列番号26:hXCL-1
配列番号27:mIL-7
配列番号28:mIL-7
配列番号29:mXCL-1
配列番号30:mXCL-1
配列番号31:T2A
配列番号32:T2A
配列番号33:mCD8αシグナルペプチド
配列番号34:mCD8αシグナルペプチド
配列番号35:hFlt3L
配列番号36:hFlt3L
配列番号37:mFlt3L
配列番号38:mFlt3L
配列番号39:hIL-12
配列番号40:hIL-12
配列番号41:mIL-12
配列番号42:mIL-12
配列番号43:hIL-2
配列番号44:hIL-2
配列番号45:mIL-2
配列番号46:mIL-2
配列番号47:hIL-15
配列番号48:hIL-15
配列番号49:mIL-15
配列番号50:mIL-15
配列番号51:hIL-21
配列番号52:hIL-21
配列番号53:mIL-21
配列番号54:mIL-21
配列番号55:hIL-17
配列番号56:hIL-17
配列番号57:mIL-17
配列番号58:mIL-17
配列番号59:hIL-18
配列番号60:hIL-18
配列番号61:mIL-18
配列番号62:mIL-18
配列番号63:hIL-23
配列番号64:hIL-23
配列番号65:mIL-23
配列番号66:mIL-23
配列番号67:hXCL2
配列番号68:hXCL2
Claims (32)
- (i)リガンドを特異的に認識する細胞表面分子、(ii)外因性のインターロイキン、及び(iii)外因性のFlt3L、XCL2及び/又はXCL1遺伝子を、発現する改変免疫細胞。
- 前記リガンドを特異的に認識する細胞表面分子は、キメラ抗原受容体又はT細胞受容体である、請求項1に記載の改変免疫細胞。
- 前記リガンドを特異的に認識する細胞表面分子は、リガンド結合ドメイン、膜貫通ドメイン、共刺激ドメイン、及び細胞内シグナル伝達ドメインを含むキメラ抗原受容体である、請求項2に記載の改変免疫細胞。
- 前記インターロイキンは、IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、そのサブユニット、その組み合わせ、又はそのサブユニットの組み合わせである、請求項1~3のいずれか一項に記載の改変免疫細胞。
- 前記Flt3L遺伝子は、配列番号35又は37に示される核酸配列と少なくとも90%の同一性を有し、
または、前記Flt3L遺伝子によってコードされるポリペプチドは、配列番号36又は38に示されるアミノ酸配列と少なくとも90%の同一性を有する、請求項1~4のいずれか一項に記載の改変免疫細胞。 - 前記インターロイキンのコード遺伝子は、配列番号23、27、39、41、43、45、47、49、51、53、55、57、59に示される核酸配列と少なくとも90%の同一性を有し、
または、前記インターロイキンは、配列番号24、28、40、42、44、46、48、50、52、54、56、58、60に示されるアミノ酸配列と少なくとも90%の同一性を有する、請求項4に記載の改変免疫細胞。 - 前記XCL1遺伝子は、配列番号25又は29に示される核酸配列と少なくとも90%の同一性を有し、
または、前記XCL1遺伝子によってコードされるポリペプチドは、配列番号26又は30に示されるアミノ酸配列と少なくとも90%の同一性を有する、請求項1~6のいずれか一項に記載の改変免疫細胞。 - 前記XCL2遺伝子は、配列番号67に示される核酸配列と少なくとも90%の同一性を有し、
または、前記XCL2遺伝子によってコードされるポリペプチドは、配列番号68に示されるアミノ酸配列と少なくとも90%の同一性を有する、請求項1~7のいずれか一項に記載の改変免疫細胞。 - 前記免疫細胞は、T細胞、マクロファージ、樹状細胞、単核細胞、NK細胞、又はNKT細胞から選択されるものである、請求項1~8のいずれか一項に記載の改変免疫細胞。
- 前記T細胞は、CD4+/CD8+T細胞、CD4+ヘルパーT細胞、CD8+T細胞、腫瘍浸潤細胞、メモリーT細胞、ナイーブT細胞、γδ-T細胞又はαβ-T細胞である、請求項9に記載の改変免疫細胞。
- 前記リガンド結合ドメインは、scFv、Fab、単一ドメイン抗体、ナノ抗体、抗原結合リガンド、組換えフィブロネクチンドメイン、anticalin、及びDARPINから選択するものである、請求項3~10のいずれか一項に記載の改変免疫細胞。
- 前記リガンド結合ドメインは、TSHR、CD19、CD123、CD22、BAFF-R、CD30、CD171、CS-1、CLL-1、CD33、EGFRvIII、GD2、GD3、BCMA、GPRC5D、Tn Ag、PSMA、ROR1、FLT3、FAP、TAG72、CD38、CD44v6、CEA、EPCAM、B7H3、KIT、IL-13Ra2、メソテリン、IL-l lRa、PSCA、PRSS21、VEGFR2、LewisY、CD24、PDGFR-β、SSEA-4、CD20、AFP、Folate受容体α、ERBB2(Her2/neu)、MUC1、EGFR、CS1、CD138、NCAM、Claudin18.2、Prostase、PAP、ELF2M、Ephrin B2、IGF-I受容体、CAIX、LMP2、gploo、bcr-abl、チロシナーゼ、EphA2、Fucosyl GMl、sLe、GM3、TGS5、HMWMAA、o-アセチル-GD2、Folate受容体β、TEM1/CD248、TEM7R、CLDN6、GPRC5D、CXORF61、CD97、CD 179a、ALK、ポリシアル酸、PLAC1、GloboH、NY-BR-1、UPK2、HAVCR1、ADRB3、PANX3、GPR20、LY6K、OR51E2、TARP、WT1、NY-ESO-1、LAGE-la、MAGE-A1、レグマイン、HPV E6、E7、MAGE Al、ETV6-AML、精子タンパク質17、XAGE1、Tie 2、MAD-CT-1、MAD-CT-2、Fos関連抗原1、p53、p53変異体、前立腺特異的タンパク質、サバイビン及びテロメラーゼ、PCTA-l/Galectin 8、MelanA/MARTl、Ras変異体、hTERT、肉腫転座ブレークポイント、ML-IAP、ERG(TMPRSS2 ETS融合遺伝子)、NA17、PAX3、アンドロゲン受容体、Cyclin Bl、MYCN、RhoC、TRP-2、CYP1B 1、BORIS、SART3、PAX5、OY-TES 1、LCK、AKAP-4、SSX2、RAGE-1、ヒトテロメラーゼ逆転写酵素、RU1、RU2、腸のカルボキシルエステラーゼ、mut hsp70-2、CD79a、CD79b、CD72、LAIR1、FCAR、LILRA2、CD300LF、CLEC12A、BST2、EMR2、LY75、GPC3、FCRL5、IGLL1、PD1、PDL1、PDL2、TGFβ、APRIL、NKG2D、及びそれらの任意の組み合わせから選択される標的に結合する、請求項3に記載の改変免疫細胞。
- 前記膜貫通ドメインは、TCRα鎖、TCRβ鎖、TCRγ鎖、TCRδ鎖、CD3ζサブユニット、CD3εサブユニット、CD3γサブユニット、CD3δサブユニット、CD45、CD4、CD5、CD8α、CD9、CD16、CD22、CD33、CD28、CD37、CD64、CD80、CD86、CD134、CD137及びCD154のタンパク質の膜貫通ドメインから選択されるものである、請求項3~12のいずれか一項に記載の改変免疫細胞。
- 前記細胞内シグナル伝達ドメインは、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b及びCD66dのタンパク質のシグナル伝達ドメインから選択されるものである、請求項3~13のいずれか一項に記載の改変免疫細胞。
- 前記共刺激ドメインは、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、CARD11、CD2、CD7、CD8、CD18(LFA-1)、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD270(HVEM)、CD272(BTLA)、CD276(B7-H3)、CD278(ICOS)、CD357(GITR)、DAP10、DAP12、LAT、NKG2C、SLP76、PD-1、LIGHT、TRIM、ZAP70、及びそれらの組み合わせのタンパク質の共刺激シグナルである伝達ドメインから選択される1つ又は複数である、請求項3~14のいずれか一項に記載の改変免疫細胞。
- 免疫細胞が、CD52、GR、TCRα、TCRβ、CD3γ、CD3δ、CD3ε、CD247ζ、HLA-I、HLA-II、B2M、PD1、CTLA-4、LAG3、及びTIM3から選択される少なくとも1つの不活性化遺伝子をさらに含む、請求項1~15のいずれか一項に記載の改変免疫細胞。
- 前記インターロイキン、Flt3L、XCL2及び/又はXCL1遺伝子の発現は、条件付き発現である、請求項1~16のいずれか一項に記載の改変免疫細胞。
- 前記インターロイキン、Flt3L、XCL2及び/又はXCL1遺伝子は、条件付きで発現するように、誘導性、阻害性、又は組織特異的プロモーターに作動可能に連結されている、請求項17に記載の改変免疫細胞。
- 前記インターロイキン、Flt3L、XCL2及び/又はXCL1遺伝子は、局在化ドメインに作動可能に連結されている、請求項1~18のいずれか一項に記載の改変免疫細胞。
- (i)リガンドを特異的に認識する細胞表面分子をコードする核酸配列、(ii)インターロイキンをコードする核酸配列、及び(iii)Flt3L、XCL2及び/又はXCL1をコードする核酸配列、を含む核酸分子。
- 前記リガンドを特異的に認識する細胞表面分子は、キメラ抗原受容体である、請求項20に記載の核酸分子。
- 前記インターロイキンは、IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、そのサブユニット、その組み合わせ、又はそのサブユニットの組み合わせである、請求項20に記載の核酸分子。
- 請求項20~22のいずれか一項に記載の核酸分子を含むベクター。
- 前記ベクターは、プラスミド、レトロウイルス、レンチウイルス、アデノウイルス、ワクシニアウイルス、ラウス肉腫ウイルス(RSV)、ポリオーマウイルス、及びアデノ随伴ウイルス(AAV)から選択されるものである、請求項23に記載のベクター。
- 請求項1~19のいずれか一項に記載の改変免疫細胞、請求項20~22のいずれか一項に記載の核酸分子又は請求項23~24のいずれか一項に記載のベクターを含む、キット。
- 請求項1~19のいずれか一項に記載の改変免疫細胞、請求項20~22のいずれか一項に記載の核酸分子又は請求項23~24のいずれか一項に記載のベクター、及び様々な製薬上許容される賦形剤を含む、医薬組成物。
- (a)リガンドを特異的に認識する細胞表面分子をコードする第1の核酸配列又はそれがコードするリガンドを特異的に認識する細胞表面分子、(b)インターロイキンをコードする第2の核酸配列又はそれがコードするインターロイキン、及び(c)Flt3L、XCL2及び/又はXCL1をコードする第3の核酸配列又はそれがコードするFlt3L、XCL2及び/又はXCL1タンパク質を、免疫細胞に導入することを含む改変免疫細胞を調製する方法。
- 前記リガンドを特異的に認識する細胞表面分子は、キメラ抗原受容体である、請求項27に記載の方法。
- 前記インターロイキンは、IL-2、IL-7、IL-12、IL-15、IL-21、IL-17、IL-18、IL-23、そのサブユニット、その組み合わせ、又はそのサブユニットの組み合わせである、請求項27に記載の方法。
- 前記(a)、(b)及び(c)は、任意の順で免疫細胞に連続的に導入される、請求項27に記載の方法。
- 前記(a)、(b)及び(c)は、同時に免疫細胞に導入される、請求項27に記載の方法。
- がん、感染症又は自己免疫疾患を治療するための医薬の調製における、請求項1~19のいずれか一項に記載の改変免疫細胞、請求項20~22のいずれか一項に記載の核酸分子、請求項23~24のいずれか一項に記載のベクター、請求項25に記載のキット又は請求項26に記載の医薬組成物の使用。
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EP4089174A1 (en) | 2022-11-16 |
KR20220159414A (ko) | 2022-12-02 |
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