JPWO2020017479A1 - 抗gpc3一本鎖抗体を含むcar - Google Patents
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Abstract
Description
〔1〕配列番号11に示されるアミノ酸配列からなるヒトGPC3(Glypican-3)由来のポリペプチドに特異的に結合する一本鎖抗体と、該一本鎖抗体のカルボキシル末端に融合した細胞膜貫通領域と、該細胞膜貫通領域のカルボキシル末端に融合した免疫担当細胞活性化シグナル伝達領域とを含むキメラ抗原受容体(CAR)であって、
前記一本鎖抗体が、
配列番号1に示されるアミノ酸配列からなる重鎖相補性決定領域(CDR)1、配列番号2に示されるアミノ酸配列からなる重鎖CDR2、及び配列番号3に示されるアミノ酸配列からなる重鎖CDR3と、
配列番号4に示されるアミノ酸配列からなる軽鎖CDR1、配列番号5に示されるアミノ酸配列からなる軽鎖CDR2、及び配列番号6に示されるアミノ酸配列からなる軽鎖CDR3とを含む、
前記CAR(以下、「本件CAR」ということがある)。
〔2〕一本鎖抗体が、
配列番号7に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列からなる重鎖可変領域と、配列番号8に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列からなる軽鎖可変領域とを含む、
上記〔1〕に記載のCAR。
〔3〕一本鎖抗体が、
配列番号12に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含むか、あるいは
配列番号13に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含む、
上記〔1〕又は〔2〕に記載のCAR。
〔4〕細胞膜貫通領域と、該細胞膜貫通領域のカルボキシル末端に融合した免疫担当細胞活性化シグナル伝達領域とが、配列番号14〜16のいずれかに示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含む、上記〔1〕〜〔3〕のいずれかに記載のCAR。
〔5〕上記〔1〕〜〔4〕のいずれかに記載のCARを発現する免疫担当細胞(以下、「本件免疫担当細胞」ということがある)。
〔6〕さらに、インターロイキン7(IL―7)、及びケモカインリガンド19(CCL19)を発現する上記〔5〕に記載の免疫担当細胞。
〔7〕上記〔5〕又は〔6〕に記載の免疫担当細胞と、薬学的に許容される添加剤とを含有する抗がん剤(以下、「本件抗がん剤」ということがある)。
〔8〕上記〔1〕〜〔4〕のいずれかに記載のCARをコードするCAR遺伝子(以下、「本件CAR遺伝子」ということがある)。
〔9〕プロモーターと、該プロモーターの下流に作動可能に連結されている請求項8に記載のCARをコードするCAR遺伝子とを含むベクター(以下、「本件CAR発現ベクター」ということがある)。
[CAR、hIL−7、hCCL19、及びHSV−TK発現レトロウイルスベクターの作製]
国内製薬メーカーが開発した抗GPC3抗体(GC33抗体)のH鎖V領域(VH)及びL鎖V領域(VL)のアミノ酸配列に基づき、2種類の抗GPC3 ヒト型scFv(VH−リンカー−VL[配列番号12のアミノ酸配列からなるポリペプチド]、及びVL−リンカー−VH[配列番号13のアミノ酸配列からなるポリペプチド])をデザインした(表1参照)。かかるリンカーは、ポリペプチド「GGGGS」を3回繰り返した15アミノ酸残基からなるものを使用した。
作製した抗GPC3 scFv CAR等発現用レトロウイルスベクターを、リポフェクタミン3000(ライフテクノロジー社製)を用いてGP2−293パッケージング細胞株(タカラバイオ社製)へトランスフェクションした。トランスフェクション48時間後に、産生された組換えレトロウイルス(抗GPC3 scFv CAR等発現用レトロウイルス)を含む培養上清を回収した。
抗GPC3 scFv CAR発現T細胞を作製するために、組換えレトロウイルス(抗GPC3 scFv CAR等発現用レトロウイルス)を、T細胞へ感染させることで、上記T細胞に上記抗GPC3 scFv CAR等発現用レトロウイルスベクターを導入した。具体的には、末梢血単核球を、健常人末梢血から定法に従って単離した後、固層化した抗CD3モノクローナル抗体クローン(OKT3)(5μg/mL)及びレトロネクチン(登録商標;タカラバイオ社製、25μg/mL)、並びにIL−2存在下で48時間活性化培養した。ウイルス吸着プレートは、レトロネクチンでコートしたプレート上に、抗GPC3 scFv CAR等発現用組換えレトロウイルスを含む培養上清を添加後、4℃、2000gにて2時間遠心し、作製した。作製したウイルス吸着プレート上に、活性化培養したヒトT細胞を1×105cells/mLとなるように播種し、IL−2の存在下で一晩培養した。翌日にT細胞を回収し、新しいウイルス吸着プレートに播種して2回目のウイルス感染を行った。4時間培養後に細胞を回収し、3倍量の培養液を添加して細胞培養用プレートに播種した後、3日間培養した。
[フローサイトメトリー解析]
抗GPC3 scFv CAR等発現用レトロウイルスを感染させたヒトT細胞が、抗GPC3 scFv CARを発現していることを確認するために、フローサイトメトリー解析を行った。具体的には、抗GPC3 scFv CAR等発現用レトロウイルスを感染させたヒトT細胞群(抗GPC3 scFv CAR−T細胞を含むT細胞群)を、ビオチン化したリコンビナントGPC3タンパク質(R&D社製)の存在下で、氷上で30分インキュベートした。FACS Buffer(1%BSA/PBS溶液)を加えて遠心処理し、上清を除いた後、APC標識抗CD8抗体(Biolegend社製)と、BV421標識ストレプトアビジン(Biolegend社製)を添加し、氷上で30分インキュベートした。APC及びBV421の検出、並びにこれらの蛍光レベルの測定は、フローサイトメーター(BD LSR Fortessa)(BD Biosciences社製)を用いて行った。なお、ネガティブコントロールとして、抗GPC3 scFv CAR等発現用レトロウイルス未感染のヒトT細胞群(T細胞群)についても、同様にフローサイトメトリー解析を行った。
抗GPC3 scFv CAR−T細胞のがん細胞傷害活性を確認するために、GPC3発現がん細胞を、抗GPC3 scFv CAR−T細胞を含むT細胞群存在下で培養した。具体的には、抗GPC3 scFv CAR−T細胞を含むT細胞群と、肝細胞がん由来細胞株(Sk−HEP−1細胞)(ECACCより購入)、又はGPC3を発現させたSk−HEP−1細胞(Sk−HEP−1 GPC3細胞)とを、1:1(1×105個/ウェル)にて混合し、24ウェルプレートで培養した。48時間後に細胞を回収し、Phycoerythrin標識抗CD45抗体(Biolegend社製)存在下で、氷上で30分インキュベートした。FACS Buffer(1%BSA/PBS溶液)を加えて遠心処理し、上清を除いた後、Phycoerythrinの検出及び蛍光レベルの解析は、フローサイトメーター(BD LSR Fortessa)(BD Biosciences社製)を用いて行い、CD45陽性細胞(T細胞に相当)、及びCD45陰性細胞(残存するSk−HEP−1 GPC3細胞に相当)の数及び割合を測定した。
抗GPC3 scFv CAR−T細胞が、インターフェロンγ(IFN−γ)産生能を有するか否かを解析した。具体的には、抗GPC3 scFv CAR−T細胞を含むT細胞群(図3中の「CAR−T細胞」)、又は遺伝子非導入T細胞群(図3中の「T細胞」)を、Sk−HEP−1細胞、又はSk−HEP−1 GPC3細胞と、1:1(1×105/ウェルずつ)にて混合し、24ウェルプレートで48時間培養し、培養上清中に産生されるIFN−γの濃度をELISA(Biolegend社製)にて測定した。
抗GPC3 scFv CAR−T細胞が、IL−7及びCCL19産生能を有するか否かを解析した。具体的には、抗GPC3 scFv CAR−T細胞を含むT細胞群(図4中の「CAR−T細胞」)、又は遺伝子非導入T細胞群(図4中の「T細胞」)を、Sk−HEP−1細胞、又はSk−HEP−1 GPC3細胞と、1:1(1×105/ウェルずつ)にて混合し、24ウェルプレートで48時間培養し、培養上清中に産生されるIL−7及びCCL19の濃度をELISA(R&D社製)にて測定した。ネガティブコントロールとして、CAR遺伝子非導入T細胞群(T細胞)と、Sk−HEP−1細胞、又はSk−HEP−1 GPC3細胞を同条件にて培養した。
[フローサイトメトリー解析]
抗GPC3 scFv CAR等発現用レトロウイルスを感染させたヒトT細胞群のうち、48.1%の細胞が、BV421が検出されるCAR陽性であることが示された(図1B参照)。一方、当該レトロウイルス未感染のヒトT細胞群ではほとんどCAR陽性細胞は認められなかった(図1A参照)。この結果は、抗GPC3 scFv CAR等発現用レトロウイルスを感染させたヒトT細胞群のうち、約50%の細胞が抗GPC3 scFv CARを発現するT細胞(抗GPC3 scFv CAR−T細胞)であることを示している。
抗GPC3 scFv CAR−T細胞を含むT細胞群は、抗GPC3 scFv CAR等発現用レトロウイルス未感染のT細胞群を用いた場合と比べ、Sk−HEP−1 GPC3細胞(図2の「GPC3」)に対する傷害活性が非常に高く、Sk−HEP−1 GPC3細胞のほとんどを死滅させた(図2参照)。一方、抗GPC3 scFv CAR−T細胞を含むT細胞群は、Sk−HEP−1細胞(図2の「mock」)に対しては、T細胞群と同様に、傷害活性をほとんど示さなかった(図2参照)。この結果は、抗GPC3 scFv CAR−T細胞は、GPC3を発現するがん細胞特異的に細胞傷害活性を発揮することを示している。
抗GPC3 scFv CAR−T細胞を含むT細胞群は、Sk−HEP−1 GPC3細胞存在下では、抗GPC3 scFv CAR等発現用レトロウイルス未感染のT細胞群を用いた場合と比べ、IFN−γ産生能が非常に高かった(図3参照)。一方、抗GPC3 scFv CAR−T細胞を含むT細胞群は、Sk−HEP−1細胞存在下では、T細胞群と同様に、IFN−γ産生能はほとんど認められなかった(図3参照)。この結果は、抗GPC3 scFv CAR−T細胞における抗GPC3 scFvが、がん細胞におけるGPC3表面抗原に結合し、活性化した結果、IFN−γが産生されたことを示している。
抗GPC3 scFv CAR−T細胞を含むT細胞群は、Sk−HEP−1細胞存在下では低値のIL−7とCCL19を産生したが、Sk−HEP−1 GPC3細胞存在下では、さらに高いIL−7とCCL19を産生した(図4参照)。抗GPC3 scFv CAR等発現用レトロウイルス未感染のT細胞群では、Sk−HEP−1細胞存在下でもSk−HEP−1 GPC3細胞存在下でも、IL−7産生とCCL19産生はほとんど認められなかった。この結果は、抗GPC3 scFv CAR−T細胞はIL−7やCCL19を産生することを示している。
Claims (9)
- 配列番号11に示されるアミノ酸配列からなるヒトGPC3(Glypican-3)由来のポリペプチドに特異的に結合する一本鎖抗体と、該一本鎖抗体のカルボキシル末端に融合した細胞膜貫通領域と、該細胞膜貫通領域のカルボキシル末端に融合した免疫担当細胞活性化シグナル伝達領域とを含むキメラ抗原受容体(CAR)であって、
前記一本鎖抗体が、
配列番号1に示されるアミノ酸配列からなる重鎖相補性決定領域(CDR)1、配列番号2に示されるアミノ酸配列からなる重鎖CDR2、及び配列番号3に示されるアミノ酸配列からなる重鎖CDR3と、
配列番号4に示されるアミノ酸配列からなる軽鎖CDR1、配列番号5に示されるアミノ酸配列からなる軽鎖CDR2、及び配列番号6に示されるアミノ酸配列からなる軽鎖CDR3とを含む、
前記CAR。 - 一本鎖抗体が、
配列番号7に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列からなる重鎖可変領域と、配列番号8に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列からなる軽鎖可変領域とを含む、
請求項1に記載のCAR。 - 一本鎖抗体が、
配列番号12に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含むか、あるいは
配列番号13に示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含む、
請求項1又は2に記載のCAR。 - 細胞膜貫通領域と、該細胞膜貫通領域のカルボキシル末端に融合した免疫担当細胞活性化シグナル伝達領域とが、配列番号14〜16のいずれかに示されるアミノ酸配列と少なくとも80%以上の配列同一性を有するアミノ酸配列を含む、請求項1〜3のいずれかに記載のCAR。
- 請求項1〜4のいずれかに記載のCARを発現する免疫担当細胞。
- さらに、インターロイキン7(IL―7)、及びケモカインリガンド19(CCL19)を発現する請求項5に記載の免疫担当細胞。
- 請求項5又は6に記載の免疫担当細胞と、薬学的に許容される添加剤とを含有する抗がん剤。
- 請求項1〜4のいずれかに記載のCARをコードするCAR遺伝子。
- プロモーターと、該プロモーターの下流に作動可能に連結されている請求項8に記載のCARをコードするCAR遺伝子とを含むベクター。
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CN113072643B (zh) * | 2021-03-22 | 2021-10-15 | 南京医科大学 | 抗Glypican-3耐酸性全人源抗体、其免疫毒素、其嵌合抗原受体细胞及应用 |
WO2022268196A1 (zh) * | 2021-06-25 | 2022-12-29 | 天辰生物医药(苏州)有限公司 | 靶向gpc3的抗原结合蛋白 |
WO2023286841A1 (ja) * | 2021-07-16 | 2023-01-19 | ノイルイミューン・バイオテック株式会社 | キメラ抗原受容体、前記受容体を発現する細胞、前記細胞を含む医薬組成物、前記細胞の製造方法、及び、前記キメラ抗原受容体をコードする塩基配列を含むポリヌクレオチド又はベクター |
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WO2018131586A1 (ja) * | 2017-01-10 | 2018-07-19 | 国立大学法人山口大学 | 抗gpc3抗体 |
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CN112469829B (zh) | 2023-07-07 |
WO2020017479A1 (ja) | 2020-01-23 |
US20230071098A1 (en) | 2023-03-09 |
CN112469829A (zh) | 2021-03-09 |
EP3825404A1 (en) | 2021-05-26 |
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