JP6845236B2 - Pd−l1遮断薬を持つキメラ抗原受容体修飾免疫エフェクター細胞 - Google Patents
Pd−l1遮断薬を持つキメラ抗原受容体修飾免疫エフェクター細胞 Download PDFInfo
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Description
可溶性PD-1 (sPD-1)、
可溶性PD-1とhIgG4e1-FcのCH3ドメインの融合ペプチド、
可溶性PD-1とhIgG4e1-Fcの融合ペプチド、又は
特異的抗PD-L1抗体、を含む(但しこれらに限らない)。
前記hIgG4e1-Fcの配列において288番目のアミノ酸がSerからProに突然変異した。
前記PD-L1遮断薬をコードする配列と細胞外抗原結合領域をコードする配列との間に、更にリボソームスキップ配列(F2A)が含まれる。
可溶性PD-1、
可溶性PD-1とhIgG4e1-FcのCH3ドメインの融合ペプチド、
可溶性PD-1とhIgG4e1-Fcの融合ペプチド、又は
特異的抗PD-L1抗体、を含む(但しこれらに限らない)。
細胞外抗原結合領域-CD8膜貫通領域-4-1BB-CD3ζ、
細胞外抗原結合領域-CD28a-CD28b-CD3ζ、
細胞外抗原結合領域-CD28a-CD28b-4-1BB-CD3ζ、
及びその組み合わせの群から選ばれるものであってもよい。但し関連するキメラ抗原受容体蛋白質中のCD28aはCD28分子の膜貫通領域を示し、CD28bはCD28分子の細胞内シグナル領域を示す。
し、かつ腫瘍組織において有效生存することが証明された。よって、本発明のキメラ抗原受容体をコードする核酸、当該核酸を含むプラスミド、当該プラスミドを含むウイルス、前記核酸、プラスミド又はウイルスが形質導入された遺伝子組み換え免疫エフェクター細胞は、腫瘍の免疫治療に有効適用できる。
(1) ヒト由来sPD-1等配列デザイン
図1に示されるように、ヒト由来sPD-1蛋白質はPD-1のシグナルペプチド及び細胞外ドメインを含む。ヒト由来sPD-1-CH3蛋白質はPD-1のシグナルペプチド、細胞外ドメインを含むとともに、リンカー(linker)を介してhIgG4e1-FcのCH3ドメインを結合する。ヒト由来sPD-1-Fc融合蛋白質はPD-1のシグナルペプチド及び細胞外ドメインを保留するとともに、リンカーを介してhIgG4e1-Fcドメインを融合することで、その安定性を増大させる。hIgG4e1-FcはS288P突然変異を有するため、hIgG4e1-Fcが人体内で引き起こす補体依存の細胞毒性(CDC)及び抗体依存性細胞仲介の細胞毒性(ADCC)を低減させることができる。hIgG4e1-Fc配列はInvivogen社のpFUSE-hIgG4e1-Fc1プラスミド(http://www.invivogen.com/pfuse-higg4e1-fc)を参照できる。
sPD-1はリンカーを介してhIgG4e1-Fc中のCH3ドメインと連結し、リンカー配列はTATGGTである。CH3ドメイン配列はpFUSE-hIgG4e1-Fc1プラスミドを参照できる。
sPD-1はリンカーを介してhIgG4e1-Fcドメインと連結し、リンカー配列はTATGGTである。hIgG4e1-Fcドメイン配列はpFUSE-hIgG4e1-Fc1 v01プラスミドを参照できる。
sPD-1、sPD-1-CH3又はsPD-1-FcをM27-CARと連結する。具体的には以下のとおり:
(1) sPD-1-Fc配列を含むプラスミドT-sPD-1-Fcプラスミド (上海捷鋭生物工程有限公司から購入) を鋳型とし、
sPD-1-CH3/sPD-1-Fc-F2A-M27 CAR T細胞の陽性率の結果は図3を参照できる。sPD-1-CH3-M27-28Zを発現するCAR T(T-CH3-28Z)細胞陽性率は66.8%、sPD-1-CH3-M27-BBZ(T-CH3-BBZ)は66.3%、sPD-1-CH3-M27-28BBZ (T-CH3-28BBZ)は64.1%、sPD-1-Fc-M27-28Z(T-Fc-28Z)は71.7%、sPD-1-Fc-M27-BBZ(T-Fc-BBZ)は70.6%、sPD-1-Fc-M27-28BBZは81.9%、対照Mockを発現したT細胞(T-Mock)陽性率は88.4%であった。
但し各実験群及び各対照群は以下のとおりである:
各実験群:各標的細胞+異なるキメラ抗原受容体を発現するCTL、
対照群1:標的細胞最大放出LDH;
対照群2:標的細胞自発放出LDH;
対照群3:エフェクター細胞自発放出LDH;
Claims (22)
- キメラ抗原受容体(CAR)に加えて、分泌発現されるPD-L1遮断薬を持つキメラ抗原受容体修飾免疫エフェクター細胞であって、前記PD-L1遮断薬は、
可溶性PD-1、
可溶性PD-1とhIgG4e1-FcのCH3ドメインの融合ペプチド、又は
可溶性PD-1とhIgG4e1-Fcの融合ペプチド、
から選択されることを特徴とする、細胞。 - 前記可溶性PD-1は、シグナルペプチドとPD-1の細胞外領域を含む、請求項1に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記シグナルペプチドは配列番号1に示されるヌクレオチド配列でコードされ、前記PD-1の細胞外領域は配列番号2に示されるヌクレオチド配列でコードされることを特徴とする、請求項2に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記hIgG4e1-FcのCH3ドメインは配列番号3に示されるヌクレオチド配列でコードされること、及び/又は前記hIgG4e1-Fcの配列は、位置288におけるSerからProへの変異を含むことを特徴とする、請求項1に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- キメラ抗原受容体は細胞外抗原結合領域、膜貫通領域及び細胞内シグナル領域を含み、前記細胞外抗原結合領域は腫瘍に高発現する抗原に特異的に結合する抗体であることを特徴とする、請求項1に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記細胞内シグナル領域はCD3ζ、FcεRIγ、CD27、CD28、4-1BB、CD134、CD40の細胞内シグナル領域配列又はMyd88、若しくはその組み合わせを含むことを特徴とする、請求項5に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記膜貫通領域はCD8膜貫通領域、CD28膜貫通領域を含むことを特徴とする、請求項6に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記腫瘍に高発現する抗原はEGFR、GPC3、HER2、EphA2、クローディン18.1、クローディン18.2、クローディン6、GD2、EpCAM、メソテリン、CD19、CD20、ASGPR1、EGFRvIII、de4 EGFR、CD19、CD33、IL13R、LMP1、PLAC1、NY-ESO-1、MAGE4、MUC1、MUC16、LeY、CEA、CAIX、CD123を含むことを特徴とする、請求項5に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 前記免疫エフェクター細胞はTリンパ球、NK細胞又はNKT細胞、Treg細胞を含むことを特徴とする、請求項1に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 腫瘍が、PD-L1を発現している腫瘍である、請求項5に記載のキメラ抗原受容体修飾免疫エフェクター細胞。
- 免疫エフェクター細胞を修飾するための融合ポリペプチドをコードする核酸構築物であって、前記核酸構築物は、順に連結している、請求項1に定義された、分泌発現されるPD-L1遮断薬をコードする配列、細胞外抗原結合領域をコードする配列、膜貫通領域及び細胞内シグナル領域をコードする配列を含み、前記細胞外抗原結合領域は腫瘍に高発現する抗原に特異的に結合する抗体である、核酸構築物。
- 前記PD-L1遮断薬をコードする配列と細胞外抗原結合領域をコードする配列との間はリンカーペプチドをコードする配列で連結されること、及び/又は、
前記PD-L1遮断薬をコードする配列と細胞外抗原結合領域をコードする配列との間に、リボソームスキップ配列が含まれることを特徴とする、請求項11に記載の核酸構築物。 - 腫瘍が、PD-L1を発現している腫瘍である、請求項11に記載の核酸構築物。
- 請求項11から13のいずれか一項に記載の核酸構築物を含む発現ベクター。
- 請求項14に記載の発現ベクターを含むことを特徴とするウイルス。
- 腫瘍にターゲッティングするキメラ抗原受容体修飾免疫エフェクター細胞を製造するための、請求項11の核酸構築物、又は当該核酸構築物を含む発現ベクター若しくはウイルスの使用。
- 腫瘍が、PD-L1を発現している腫瘍である、請求項16に記載の使用。
- 腫瘍抑制医薬組成物を製造するための、請求項1〜10のいずれかに記載のキメラ抗原受容体修飾免疫エフェクター細胞の使用。
- 請求項1〜10のいずれかに記載のキメラ抗原受容体修飾免疫エフェクター細胞を含むことを特徴とする、腫瘍抑制用医薬組成物。
- 免疫エフェクター細胞の抗腫瘍作用を増大させるための、キメラ抗原受容体修飾免疫エフェクター細胞の製造のための分泌発現されるPD-L1遮断薬の使用であって、
前記PD-L1遮断薬は、
可溶性PD-1、
可溶性PD-1とhIgG4e1-FcのCH3ドメインの融合ペプチド、又は
可溶性PD-1とhIgG4e1-Fcの融合ペプチド、
から選択されることを特徴とする、使用。 - 腫瘍が、PD-L1を発現している腫瘍である、請求項20に記載の使用。
- 請求項11に記載の核酸構築物を免疫エフェクター細胞に導入することを含むことを特徴とする、キメラ抗原受容体修飾免疫エフェクター細胞の製造方法。
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