JP6810685B2 - 癌免疫療法のための栄養膜糖タンパク質(5t4、tpbg)特異的キメラ抗原受容体 - Google Patents
癌免疫療法のための栄養膜糖タンパク質(5t4、tpbg)特異的キメラ抗原受容体 Download PDFInfo
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Description
本発明は、大部分の骨髄系細胞に見出され患者における、胃、結腸、および卵巣の腫瘍などの固形腫瘍、ならびに前駆B細胞急性リンパ性白血病(ALL)を診断するために使用される細胞表面糖タンパク質5T4へ免疫細胞の特異性および反応性を向け直すことができる組換えキメラタンパク質であるキメラ抗原受容体(CAR)に関する。本発明によるCARは、T細胞またはNK細胞において発現された時、5T4抗原を保持する悪性細胞を処置するために特に有用である。得られた操作された免疫細胞は、免疫療法のための安全性および効率を付与する、悪性細胞に対する高レベルの特異性を示す。
エクスビボで生成された自己の抗原特異的T細胞の移入を含む養子免疫療法は、ウイルス感染および癌を処置するための有望な戦略である。養子免疫療法のために使用されるT細胞は、抗原特異的T細胞の増大または遺伝子操作を通したT細胞の向け直しのいずれかによって生成され得る(Park, Rosenberg et al. 2011)。ウイルス抗原特異的T細胞の移入は、移植に関連したウイルス感染および稀なウイルス関連悪性疾患の処置のために使用されている、よく確立された手法である。同様に、腫瘍特異的T細胞の単離および移入は、黒色腫の処置において成功が示されている。
[本発明1001]
図2に図示されるV1〜V6より選択されるポリペプチド構造のうちの一つを有する5T4(NTRKR1)特異的キメラ抗原受容体(CAR)であって、該構造が、モノクローナル抗5T4抗体由来のVHおよびVLを含む細胞外リガンド結合ドメインと、ヒンジと、膜貫通ドメインと、CD3ζシグナリングドメインおよび4-1BB由来の共刺激ドメインを含む細胞質ドメインとを含む、5T4(NTRKR1)特異的キメラ抗原受容体(CAR)。
[本発明1002]
構造V3がCD8αヒンジおよびCD8α膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1003]
構造V5がIgG1ヒンジおよびCD8α膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1004]
構造V1がFcγRIIIαヒンジおよびCD8α膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1005]
構造V2がFcγRIIIαヒンジおよび4-1BB膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1006]
構造V4がCD8αヒンジおよび4-1BB膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1007]
構造V6がIgG1ヒンジおよび4-1BB膜貫通ドメインを含む、本発明1001の5T4特異的CAR。
[本発明1008]
VHおよびVLがSEQ ID NO:11〜18より選択されるポリペプチド配列と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1001〜1007のいずれかの5T4特異的CAR。
[本発明1009]
細胞外リガンド結合ドメインが、SEQ ID NO:54(CDR1)、SEQ ID NO:55(CDR2)、およびSEQ ID NO:56(CDR3)のマウスモノクローナル抗体A1由来のCDRを含むVH鎖、ならびにNO.57(CDR1)、SEQ ID NO:58(CDR2)、およびSEQ ID NO:59(CDR3)のマウスモノクローナル抗体A1由来のCDRを含むVL鎖を含む、本発明1001〜1008のいずれかの5T4特異的CAR。
[本発明1010]
VHおよびVLが、それぞれ、SEQ ID NO:13(A1-VH)およびSEQ ID NO:14(A1-VL)と少なくとも80%、好ましくは少なくとも90%、より好ましくは少なくとも95%、さらに好ましくは少なくとも99%の配列同一性を有する、本発明1001〜1009のいずれかの5T4特異的CAR。
[本発明1011]
細胞外リガンド結合ドメインが、SEQ ID NO:61(CDR1)、SEQ ID NO:61(CDR2)、およびSEQ ID NO:63(CDR3)のマウスモノクローナル抗体A2由来のCDRを含むVH鎖、ならびにSEQ ID NO:64(CD1)、SEQ ID NO:65(CD2)、およびSEQ ID NO:65(CDR3)のマウスモノクローナル抗体A2由来のCDRを含むVL鎖を含む、本発明1001〜1008のいずれかの5T4特異的CAR。
[本発明1012]
VHおよびVLが、それぞれ、SEQ ID NO:15(A2-VH)およびSEQ ID NO:16(A2-VL)と少なくとも80%、好ましくは少なくとも90%、より好ましくは少なくとも95%、さらに好ましくは少なくとも99%の配列同一性を有する、本発明1001〜1008および1011のいずれかの5T4特異的CAR。
[本発明1013]
細胞外リガンド結合ドメインが、SEQ ID NO:66(CDR1)、SEQ ID NO:67(CDR2)、およびSEQ ID NO:68(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVH鎖、ならびにSEQ ID NO:69(CDR1)、SEQ ID NO:70(CDR2)、およびSEQ ID NO:71(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVL鎖を含む、本発明1001〜1008のいずれかの5T4特異的CAR。
[本発明1014]
VHおよびVLが、それぞれ、SEQ ID NO:17(A3-VH)およびSEQ ID NO:18(A3-VL)と少なくとも80%、好ましくは少なくとも90%、より好ましくは少なくとも95%、さらに好ましくは少なくとも99%の配列同一性を有する、本発明1001〜1008および1013のいずれかの5T4特異的CAR。
[本発明1015]
細胞外リガンド結合ドメインが、SEQ ID NO:48(CDR1)、SEQ ID NO:49(CDR2)、およびSEQ ID NO:50(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVH鎖、ならびにNO.51(CDR1)、SEQ ID NO:52(CDR2)、およびSEQ ID NO:53(CDR3)のマウスモノクローナル抗体H18由来のCDRを含むVL鎖を含む、本発明1001〜1008のいずれかの5T4特異的CAR。
[本発明1016]
VHおよびVLが、それぞれ、SEQ ID NO:11(H18-VH)およびSEQ ID NO:12(H18-VL)と少なくとも80%、好ましくは少なくとも90%、より好ましくは少なくとも95%、さらに好ましくは少なくとも99%の配列同一性を有する、本発明1001〜1008および1015のいずれかの5T4特異的CAR。
[本発明1017]
4-1BB由来の共刺激ドメインが、SEQ ID NO:8と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1001〜1016のいずれかの5T4特異的CAR。
[本発明1018]
CD3ζシグナリングドメインが、SEQ ID NO:9と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1001〜1017のいずれかの5T4特異的CAR。
[本発明1019]
FcγRIIIαヒンジが、SEQ ID NO:3と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1004、1005、または1008〜1018のいずれかの5T4特異的CAR。
[本発明1020]
CD8αヒンジが、SEQ ID NO:4と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1002、1006、または1008〜1018のいずれかの5T4特異的CAR。
[本発明1021]
IgG1ヒンジが、SEQ ID NO:5と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1003、1007、または1008〜1018のいずれかの5T4特異的CAR。
[本発明1022]
CD8α膜貫通ドメインが、SEQ ID NO:6と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1002〜1004または1008〜1021のいずれかの5T4特異的CAR。
[本発明1023]
4-1BB膜貫通ドメインが、SEQ ID NO:7と少なくとも80%、好ましくは90%、より好ましくは95%、さらに好ましくは99%の同一性を有する、本発明1005〜1007または1008〜1021のいずれかの5T4特異的CAR。
[本発明1024]
5T4に特異的でない別の細胞外リガンド結合ドメインをさらに含む、本発明1001〜1023のいずれかの5T4特異的CAR。
[本発明1025]
SEQ ID NO:21、SEQ ID NO:27、SEQ ID NO:33、およびSEQ ID NO:39と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1002の構造V3の5T4特異的CAR。
[本発明1026]
SEQ ID NO:23、SEQ ID NO:29、SEQ ID NO:34、およびSEQ ID NO:41と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1003の構造V5の5T4特異的CAR。
[本発明1027]
SEQ ID NO:19、SEQ ID NO:25、SEQ ID NO:31、およびSEQ ID NO:37と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1004の構造V1の5T4特異的CAR。
[本発明1028]
SEQ ID NO:20、SEQ ID NO:26、SEQ ID NO:32、およびSEQ ID NO:38と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1005の構造V2の5T4特異的CAR。
[本発明1029]
SEQ ID NO:22、SEQ ID NO:28、SEQ ID NO:34、およびSEQ ID NO:40と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1006の構造V4の5T4特異的CAR。
[本発明1030]
SEQ ID NO:24、SEQ ID NO:30、SEQ ID NO:36、およびSEQ ID NO:42と少なくとも80%の同一性を有するポリペプチド配列を含む、本発明1007の構造V6の5T4特異的CAR。
[本発明1031]
シグナルペプチドをさらに含む、本発明1001〜1030のいずれかの5T4特異的CAR。
[本発明1032]
シグナルペプチドがSEQ ID NO:1またはSEQ ID NO:2と少なくとも80%の配列同一性を有する、本発明1031の5T4特異的CAR。
[本発明1033]
本発明1001〜1032のいずれかのキメラ抗原受容体をコードするポリヌクレオチド。
[本発明1034]
本発明1033の核酸を含む発現ベクター。
[本発明1035]
本発明1001〜1032のいずれかの5T4特異的キメラ抗原受容体を細胞表面膜に発現する、操作された免疫細胞。
[本発明1036]
炎症性Tリンパ球、細胞傷害性Tリンパ球、制御性Tリンパ球、またはヘルパーTリンパ球に由来する、本発明1035の操作された免疫細胞。
[本発明1037]
NK細胞に由来する、本発明1035の操作された免疫細胞。
[本発明1038]
治療において使用するための、本発明1035〜1037のいずれかの操作された細胞。
[本発明1039]
ヒトの治療において使用するための、本発明1035〜1038のいずれかの操作された細胞。
[本発明1040]
状態が5T4発現細胞を特徴とする前悪性または悪性の癌状態である、治療において使用するための本発明1035〜1039のいずれかの操作された細胞。
[本発明1041]
状態が、過剰量の5T4発現細胞を特徴とする状態である、治療において使用するための本発明1035〜1040のいずれかの操作された細胞。
[本発明1042]
状態が血液癌状態である、治療において使用するための本発明1035〜1041のいずれかの操作された細胞。
[本発明1043]
血液癌状態が白血病である、治療において使用するための本発明1035〜1042のいずれかの操作された細胞。
[本発明1044]
血液癌状態が小児前駆B細胞急性リンパ芽球性白血病である、治療において使用するための本発明1035〜1043のいずれかの操作された細胞。
[本発明1045]
状態が固形腫瘍である、治療において使用するための本発明1035〜1041のいずれかの操作された細胞。
[本発明1046]
腫瘍が、胃、結腸直腸、前立腺、乳房、肺、腎臓、または卵巣の腫瘍である、治療において使用するための本発明1045の操作された細胞。
[本発明1047]
前記免疫細胞においてTCRの発現が抑制されている、本発明1035〜1046のいずれかの操作された細胞。
[本発明1048]
前記免疫細胞において少なくとも1種のMHCタンパク質、好ましくはβ2mまたはHLAの発現が抑制されている、本発明1035〜1047のいずれかの操作された細胞。
[本発明1049]
少なくとも1種の免疫抑制薬または化学療法薬に対する耐性を付与するために変異させた、本発明1035〜1048のいずれかの操作された細胞。
[本発明1050]
癌細胞の傷害を引き起こすために有効な量の本発明1035〜1049のいずれかの操作された細胞と血液癌細胞を接触させる工程を含む、血液癌細胞に傷害を与える方法。
[本発明1051]
(a)免疫細胞を準備する工程、
(b)本発明1001〜1032のいずれかの少なくとも1種の5T4特異的キメラ抗原受容体を該細胞の表面に発現させる工程
を含む、免疫細胞を操作する方法。
[本発明1052]
(a)免疫細胞を準備する工程、
(b)5T4特異的キメラ抗原受容体をコードする少なくとも1種のポリヌクレオチドを該細胞へ導入する工程、
(c)該細胞においてポリヌクレオチドを発現させる工程
を含む、本発明1051の免疫細胞を操作する方法。
[本発明1053]
(a)免疫細胞を準備する工程、
(b)5T4特異的キメラ抗原受容体をコードする少なくとも1種のポリヌクレオチドを該細胞へ導入する工程、
(c)5T4に特異的でない少なくとも1種の他のキメラ抗原受容体を導入する工程
を含む、本発明1051の免疫細胞を操作する方法。
[本発明1054]
(a)本発明1001〜1032のいずれかの5T4特異的キメラ抗原受容体を表面に発現している免疫細胞を準備する工程、
(b)該免疫細胞を患者へ投与する工程
を含む、その必要のある対象を処置する方法。
[本発明1055]
免疫細胞がドナーから提供される、本発明1051〜1054のいずれかの方法。
[本発明1056]
免疫細胞が患者自身から提供される、本発明1051〜1054のいずれかの方法。
本明細書において特に定義されない限り、使用される技術用語および科学用語は、全て、遺伝子治療、生化学、遺伝学、および分子生物学の領域の当業者によって一般的に理解されるのと同一の意味を有する。
本発明は、細胞外リガンド結合ドメイン、膜貫通ドメイン、およびシグナリング伝達ドメインを含む、抗5T4キメラ抗原受容体(CAR)の新しい設計に関する。
−SEQ ID NO:48(CDR1)、SEQ ID NO:49(CDR2)、およびSEQ ID NO:50(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVH鎖、ならびにNO.51(CDR1)、SEQ ID NO:52(CDR2)、およびSEQ ID NO:53(CDR3)のマウスモノクローナル抗体H18由来のCDRを含むVL鎖;または
−SEQ ID NO:54(CDR1)、SEQ ID NO:55(CDR2)、およびSEQ ID NO:56(CDR3)のマウスモノクローナル抗体A1由来のCDRを含むVH鎖、ならびにNO.57(CDR1)、SEQ ID NO:58(CDR2)、およびSEQ ID NO:59(CDR3)のマウスモノクローナル抗体A1由来のCDRを含むVL鎖;または
−SEQ ID NO:60(CDR1)、SEQ ID NO:61(CDR2)、およびSEQ ID NO:62(CDR3)のマウスモノクローナル抗体A2由来のCDRを含むVH鎖、ならびにSEQ ID NO:63(CDR1)、SEQ ID NO:64(CDR2)、およびSEQ ID NO:65(CDR3)のマウスモノクローナル抗体A2由来のCDRを含むVL鎖;または
−SEQ ID NO:66(CDR1)、SEQ ID NO:67(CDR2)、およびSEQ ID NO:68(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVH鎖、ならびにNO.69(CDR1)、SEQ ID NO:70(CDR2)、およびSEQ ID NO:71(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVL鎖
を含む。
本発明は、本発明による前記のCARをコードするポリヌクレオチド、ベクターにも関する。
本発明は、以前に記載されたように、5T4 CARの一つをコードするポリヌクレオチドまたはベクターを免疫細胞へエクスビボで導入する工程を含む、免疫療法のための免疫細胞を調製する方法を包含する。
上記の様々な方法は、CARを細胞へ導入する工程を含む。非限定的な例として、CARは、1種のプラスミドベクターによってコードされたトランスジーンとして導入され得る。プラスミドベクターは、ベクターを受容した細胞の同定および/または選択を提供する選択マーカーも含有し得る。
本発明は、細胞を操作する方法によって入手可能な単離された細胞または細胞株にも関する。具体的には、単離された細胞は、少なくとも1種の上記のCARを含む。別の態様において、単離された細胞は、各々異なる細胞外リガンド結合ドメインを含むCARの集団を含む。具体的には、単離された細胞は、CARをコードする外因性のポリヌクレオチド配列を含む。本発明の遺伝子改変免疫細胞は、活性化されており、抗原結合機序と無関係に増殖する。
本発明の遺伝子改変免疫細胞は、活性化されており、抗原結合機序と無関係に増殖するが、本発明の免疫細胞、具体的には、T細胞は、T細胞の遺伝子改変の前であっても後であっても、例えば、米国特許第6,352,694号;第6,534,055号;第6,905,680号;第6,692,964号;第5,858,358号;第6,887,466号;第6,905,681号;第7,144,575号;第7,067,318号;第7,172,869号;第7,232,566号;第7,175,843号;第5,883,223号;第6,905,874号;第6,797,514号;第6,867,041号;および米国特許出願公開第20060121005号に記載されるような方法を一般に使用して、さらに活性化させ増大させることができる。T細胞は、インビトロまたはインビボで増大させることができる。
別の態様において、既に記載されたような異なる方法によって入手された単離された細胞または単離された細胞に由来する細胞株は、医薬として使用され得る。別の態様において、医薬は、その必要のある患者において、癌を処置するため、具体的には、癌腫および白血病の処置のため、使用され得る。別の態様において、本発明による単離された細胞または単離された細胞に由来する細胞株は、その必要のある患者における癌の処置のための医薬の製造において使用され得る。
(a)既に記載された方法のいずれか一つによって入手可能な免疫細胞を準備する工程、
(b)形質転換された免疫細胞を患者へ投与する工程
のうちの少なくとも一つを含む、その必要のある患者を処置する方法に依る。
ポリペプチド配列内のアミノ酸残基は、1文字コードによって本明細書において表記され、例えば、QはGln、すなわちグルタミン残基を意味し、RはArg、すなわちアルギニン残基を意味し、DはAsp、すなわちアスパラギン酸残基を意味する。
初代細胞
健常ボランティアドナー(Etablissement Francais du Sang)由来のバフィーコートから、密度勾配遠心分離によって、末梢血単核細胞を単離した。次いで、EasySepヒトT細胞濃縮キット(Stemcell Technologies)を使用して、Tリンパ球を精製し、20ng/ml IL-2(Miltenyi)および5%ヒトAB血清(Seralab)が補足されたX-vivo 15培地(Lonza)においてDynabeads Human T-Activator CD3/CD28(Life Technologies)によって活性化した。
HCT116細胞株、MCF-7細胞株、SK-MEL-28細胞株、およびDaudi細胞株は、American Type Culture Collectionから入手された。HCT116細胞は、10%熱不活化FCS、2mmol/L L-グルタミン、および100単位/mlペニシリン、および100μg/mLストレプトマイシンが補足されたマッコイにおいて培養された。MCF-7細胞は、10%熱不活化FCS、2mmol/L L-グルタミン、および100単位/mlペニシリン、および100μg/mLストレプトマイシン、および0.01mg/mlヒトインスリンが補足されたDMEMにおいて培養された。SK-MEL-28細胞は、10%熱不活化FCS、2mmol/L L-グルタミン、および100単位/mlペニシリン、および100μg/mLストレプトマイシンが補足されたMEMにおいて培養された。Daudi細胞は、10%熱不活化FCS、2mmol/L L-グルタミン、および100単位/mlペニシリン、および100μg/mLストレプトマイシンが補足されたRPMI 1640において培養された。
scCARをコードするDNA配列は、GenScriptによって合成され、CAR mRNAのインビトロ合成のため、T7プロモーターを含有しているプラスミドにクローニングされた。
CARをコードする配列がT7プロモーターの調節下にある直鎖化されたプラスミドを鋳型として使用して、scCARをコードするmRNAを合成した。インビトロの転写およびポリアデニル化を、製造業者の説明書に従い、mMessage mMachine T7 Ultraキット(Life technologies)を使用して行った。RNAをRNeasyカラム(Qiagen)によって精製し、cytoporation medium T(Harvard Apparatus)で溶出させ、Nanodrop ND-1000分光光度計を使用して、260nmで吸光度を測定することによって定量化した。RNAの品質を、変性ホルムアルデヒド/MOPSアガロースゲルで確認した。
11〜12日間の活性化の後、AgilePulse MAX系(Harvard Apparatus)を使用して、メッセンジャーRNAの電気導入によって、Tリンパ球をトランスフェクトした。活性化ビーズの除去の後、細胞をペレット化し、25×106細胞/mlでcytoporation medium Tに再懸濁させた。5×106個の細胞を、0.4cmキュベットで、15μgのscCARをコードするmRNAと混合した。電気穿孔は、1200Vでの2回の0.1msパルスの後の130Vでの4回の0.2msパルスからなっていた。電気穿孔の後、細胞を培養培地で希釈し、37℃/5%CO2でインキュベートした。
96穴プレートにおいて、1ウェル当たり0.1mlで、5×104個のT細胞のバッチを、5×104個の5T4陽性細胞(MCF7もしくはHCT116)または5T4陰性細胞(Daudi)と共培養した。1μg/mlの抗CD49d(BD Biosciences)、1μg/mlの抗CD28(Miltenyi)、および1×モネンシン溶液(eBioscience)に加えて、APCによって標識された抗CD107a(BD Biosciences)を、共培養の開始時に添加した。6時間のインキュベーションの後、細胞を、固定可能な生死細胞判定色素(eBioscience)およびvioblueによって標識された抗CD8(Miltenyi)によって染色し、MACSQuantフローサイトメーター(Miltenyi)を使用して分析した。脱顆粒する細胞傷害性T細胞は、CD8+CD107a+細胞に相当する。
5T4陽性細胞および5T4陰性細胞を、それぞれ、CellTrace CFSEおよびCellTrace Violetによって標識した。96穴プレートにおいて、1ウェル当たり0.1mlで、2×104個の5T4陽性細胞(MCF7またはHCT116)を、4×105個のT細胞と共に、2×104個の5T4陰性細胞(SKMEL28)と共培養した。4時間のインキュベーションの後、細胞を採集し、固定可能な生死細胞判定色素(eBiosciences)によって染色し、MACSQuantフローサイトメーター(Miltenyi)を使用して分析した。
T細胞受容体α定常鎖領域(TRAC)遺伝子内の15bpスペーサーによって分離された2個の17bp長配列(半標的と呼ばれる)を標的とする異種二量体TALEヌクレアーゼを設計し作製した。各半標的は、表10にリストされた半TALEヌクレアーゼのリピートによって認識される。
8種のヒト細胞株を、ウエスタンブロットおよびフローサイトメトリーによって、5T4発現についてスクリーニングした(下記の表11を参照すること)。
図2に表されるように、4種の異なるscFvの配列を、3種の異なるスペーサー、2種の異なる膜貫通ドメイン、1種の共刺激ドメイン、および1種の刺激ドメインの配列と組み合わせることによって、(図3〜6および表3〜表6に模式的に示される)5T4に特異的な第二世代単鎖CARを作出した。
- scFvについては、H8抗体、A1抗体、A2抗体、またはA3抗体;
- スペーサードメインについては、IgG1分子、FcεRIIIγ分子、またはCD8α分子;
- 膜貫通ドメインについては、CD8α分子または4-1BB分子;
- 共刺激ドメインについては、4-1BB分子;
- 刺激ドメインについては、CD3ζ分子
に由来する。
5T4特異的単鎖CARの活性を評価するため、健常ボランティア由来のヒトT細胞を、CD3/CD28ビーズによって活性化し、活性化の11日後に、CARをコードするmRNAによって電気穿孔した。トランスフェクションの1〜2日後に、T細胞脱顆粒ならびに5T4陽性標的細胞および5T4陰性標的細胞に対するT細胞細胞傷害を測定することによって、CARの活性および特異性を分析した。
Claims (18)
- モノクローナル抗5T4抗体由来のVHおよびVLを含む細胞外リガンド結合ドメインと、CD8αヒンジと、CD8α膜貫通ドメインと、CD3ζシグナリングドメインおよび4-1BB由来の共刺激ドメインを含む細胞質ドメインとを含むポリペプチド構造を有する、5T4特異的キメラ抗原受容体(CAR)であって、
細胞外リガンド結合ドメインが、SEQ ID NO:66(CDR1)、SEQ ID NO:67(CDR2)、およびSEQ ID NO:68(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVH鎖、ならびにSEQ ID NO:69(CDR1)、SEQ ID NO:70(CDR2)、およびSEQ ID NO:71(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVL鎖を含むか、または
細胞外リガンド結合ドメインが、SEQ ID NO:48(CDR1)、SEQ ID NO:49(CDR2)、およびSEQ ID NO:50(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVH鎖、ならびにSEQ ID NO:51(CDR1)、SEQ ID NO:52(CDR2)、およびSEQ ID NO:53(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVL鎖を含む、
5T4特異的キメラ抗原受容体(CAR)。 - 細胞外リガンド結合ドメインが、SEQ ID NO:66(CDR1)、SEQ ID NO:67(CDR2)、およびSEQ ID NO:68(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVH鎖、ならびにSEQ ID NO:69(CDR1)、SEQ ID NO:70(CDR2)、およびSEQ ID NO:71(CDR3)のマウスモノクローナル抗体A3由来のCDRを含むVL鎖を含む、請求項1記載の5T4特異的CAR。
- VHおよびVLが、それぞれ、SEQ ID NO:17(A3-VH)およびSEQ ID NO:18(A3-VL)と少なくとも90%、好ましくは少なくとも95%、より好ましくは少なくとも99%の配列同一性を有する、請求項2記載の5T4特異的CAR。
- 細胞外リガンド結合ドメインが、SEQ ID NO:48(CDR1)、SEQ ID NO:49(CDR2)、およびSEQ ID NO:50(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVH鎖、ならびにSEQ ID NO:51(CDR1)、SEQ ID NO:52(CDR2)、およびSEQ ID NO:53(CDR3)のマウスモノクローナル抗体H8由来のCDRを含むVL鎖を含む、請求項1記載の5T4特異的CAR。
- VHおよびVLが、それぞれ、SEQ ID NO:11(H8-VH)およびSEQ ID NO:12(H8-VL)と少なくとも90%、好ましくは少なくとも95%、より好ましくは少なくとも99%の配列同一性を有する、請求項4記載の5T4特異的CAR。
- 4-1BB由来の共刺激ドメインが、SEQ ID NO:8のアミノ酸配列を有する、請求項1〜5のいずれか一項記載の5T4特異的CAR。
- CD3ζシグナリングドメインが、SEQ ID NO:9のアミノ酸配列を有する、請求項1〜6のいずれか一項記載の5T4特異的CAR。
- CD8αヒンジが、SEQ ID NO:4のアミノ酸配列を有する、請求項1〜7のいずれか一項記載の5T4特異的CAR。
- CD8α膜貫通ドメインが、SEQ ID NO:6のアミノ酸配列を有する、請求項1〜8のいずれか一項記載の5T4特異的CAR。
- SEQ ID NO:21またはSEQ ID NO:39のポリペプチド配列を含む、請求項1記載の5T4特異的CAR。
- シグナルペプチドをさらに含む、請求項1〜10のいずれか一項記載の5T4特異的CAR。
- 請求項1〜11のいずれか一項記載のキメラ抗原受容体をコードするポリヌクレオチド。
- 請求項1〜11のいずれか一項記載の5T4特異的キメラ抗原受容体を細胞表面膜に発現する、操作された免疫細胞。
- 炎症性Tリンパ球、細胞傷害性Tリンパ球、制御性Tリンパ球、またはヘルパーTリンパ球に由来する、請求項13記載の操作された免疫細胞。
- 前記免疫細胞においてTCRの発現が抑制されている、請求項13または14記載の操作された免疫細胞。
- 少なくとも1種の免疫抑制薬または化学療法薬に対する耐性を付与するために変異させた、請求項13〜15のいずれか一項記載の操作された免疫細胞。
- 血液癌状態の治療において使用するための医薬の調製における、請求項13〜16のいずれか一項記載の操作された免疫細胞の使用。
- 小児前駆B細胞急性リンパ芽球性白血病の治療において使用するための医薬の調製における、請求項13〜16のいずれか一項記載の操作された免疫細胞の使用。
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