JP7492561B2 - ヒト化bcma抗体およびbcma-car-t細胞 - Google Patents
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Description
配列リストは、EFS-Webを介して明細書と共にASCII形式のテキストファイルとして、ファイル名Sequence Listing.txt、作成日2020年1月13日、サイズ4キロバイトで本明細書と同時に提出される。EFS-Webを介して出願された配列リストは本明細書の一部であり、参照によってその全体を本明細書に組み入れる。
B細胞成熟抗原(BCMA)は、CD269および腫瘍壊死因子受容体スーパーファミリーメンバー17(TNFRSF17)としても知られている細胞表面受容体であり、TNFRSF17遺伝子によってコードされている。この受容体は主に成熟Bリンパ球で発現し、ほとんどの場合、多発性骨髄腫(MM)で過剰発現される(4)。MMにおいてBCMAを標的とする現在の療法には、モノクローナル抗体、二重特異性抗体およびT細胞免疫療法、CAR-T療法が含まれる(4、5)。
B細胞の成熟および形質細胞への分化において主要な役割を担っている。それらのリガンドには、MM患者で発現が増加しているBAFFおよびAPRILが含まれる(4)。
本明細書で使用したように、「キメラ抗原受容体(CAR)」は、T細胞に特定のタンパク質を標的とする新しい能力を与えるように遺伝子操作された受容体タンパク質である。抗原結合機能およびT細胞活性化機能の両方を単一の受容体に組み合わせたので、受容体はキメラである。CARは、抗原、膜貫通ドメインおよび少なくとも1つの細胞内ドメインに結合することができる細胞外ドメインを含む融合タンパク質である。「キメラ抗原受容体(CAR)」は、「キメラ受容体」、「T体」または「キメラ免疫受容体(CIR)」と呼ばれることもある。「抗原に結合することができる細胞外ドメイン」とは、ある種の抗原に結合することができる任意のオリゴペプチドまたはポリペプチドを意味する。「細胞内ドメイン」とは、細胞内の生物学的プロセスの活性化または阻害を引き起こすシグナルを伝達するドメインとして機能することが知られている任意のオリゴペプチドまたはポリペプチドを意味する。
伝達され、その結果、細胞が活性化される。CARを発現する細胞の活性化は、宿主細胞の種類およびCARの細胞内ドメインに応じて変化し、指標として、例えば、サイトカインの放出、細胞増殖速度の改善、細胞表面分子の変化などに基づいて確認することができる。例えば、活性化された細胞からの細胞傷害性サイトカイン(腫瘍壊死因子、リンホトキシンなど)の放出は、抗原を発現する標的細胞の破壊を引き起こす。さらに、サイトカインの放出または細胞表面分子の変化は、その他の免疫細胞、例えば、B細胞、樹状細胞、NK細胞およびマクロファージを刺激する。
る。
BCMA scFvは、ハイブリドーマクローン4C8Aから得られた(国際公開第2019/195017号パンフレット)。マウスクローン4C8Aの重鎖および軽鎖可変領域の配列は決定され、ヒト化scFvを構築するために使用された。
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYVMHWVRQAPGQGLEWMGYIIPYNDATKYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARYNYDGYFDVWGQGTLVTVSS
GGGGSGGGGSGGGGS
EIVLTQSPATLSLSPGERATLSCRASQSISDYLHWYQQKPGQAPRLLIYYASQSITGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQNGHSFPPTFGGGTKVEIK
ヒト化(PMC306)BCMA-CAR構築物の設計図は図3に示されている。ヒト化scFv CAR配列のクローニングには、EF1aプロモーターを備えたレンチウイルスベクターを使用した。
ヌクレオチド
ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCG(配列番号7)
MALPVTALLLPLALLLHAARP(配列番号8)
gctagc
VH-リンカーVL、核酸配列およびアミノ酸配列については実施例1を参照すること。
CTCGAG
ヌクレオチド
AAGCCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGAGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCAGTGAT(配列番号9)
KPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASD(配列番号10)
ヌクレオチド
TTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTG(配列番号11)
FWVLVVVGGVLACYSLLVTVAFIIFWV(配列番号12)
ヌクレオチド
AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC(配列番号13)
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(配列番号14)
ヌクレオチド
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAAtag (配列番号15)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号16)
gaattc
M A L P V T A L L L P L A L L L H A A R P A S Q V Q L V Q S G A E V K K P G S S V K V S C K A S G Y T F T S Y V M H W V R Q A P G Q G L E W M G Y I I P Y N D A T K Y N E K F K G R V T I T A D K S T S T A Y M E L S S L R S E D T A V Y Y C A R Y N Y D G Y F D V W G Q G T L V T V S S G G G G S G G G G S G G G G S E I V L T Q S P A T L S L S P G E R A T L S C R A S Q S I S D Y L H W Y Q Q K P G Q A P R L L I Y Y A S Q S I T G I P A R F S G S G S G T D F T L T I S S L E P E D F A V Y Y C Q N G H S F P P T F G G G T K V E I K L E K P T T T P A P R P P T P A P T I A S Q P L S L R P E A S R P A A G G A V H T R G L D F A S D K P F W V L V V V G G V L A C Y S L L V T V A F I I F W V R S K R S R L L H S D Y MN M T P R R P
G P T R K H Y Q P Y A P P R D F A A Y R
S R V K F S R S A D A P A Y Q Q G Q N Q
L Y N E L N L G R R E E Y D V L D K R R
G R D P E M G G K P Q R R K N P Q E G L
Y N E L Q K D K M A E A Y S E I G M K G
E R R R G K G H D G L Y Q G L S T A T K
D T Y D A L H M Q A L P P R(配列番号17)
レンチウイルスは、[7]に記載されているように、293T細胞を使用した標準的手順によって作製された。本発明者らは、レンチウイルスベクター内に、レンチウイルスベクターのXbaIおよびEcoRI部位にクローニングされたヒト化BCMA-ScFv-CAR構築物を生成した。pCD510-FMC63-28zレンチウイルスCAR構築物は、XbaIとEcoRIのクローニング部位の間に、ヒト化BCMA ScFv-CD28-CD3ゼータ挿入物を含有していた。
全血(Stanford Hospital Blood Center、Stanford、CA)は、個体または混合ドナー(必要な血液量に応じて)から10mLのヘパリンバキュテナー(Becton Dickinson)中に収集した。全抗凝固血液約10mlを滅菌リン酸緩衝生理食塩水(PBS)緩衝液と混合し、50ml遠心管(PBS、pH7.4、Ca+2およびMg+2を含まない)中において総体積を20mlにし
た。血液/PBS(20ml)をコニカル遠心分離管中のFicoll-PaquePLUS(GE Healthcare)15mLの上部に静かに重層し、サンプルを室温で400×gで30~40分間遠心分離した。希釈血漿/フィコール界面の末梢血単核細胞(PBMC)を含有する細胞の層を取り出し、洗浄し、室温で200×gで10分間遠心分離した。細胞を血球計数器で計数した。PBMCを、5%AB血清およびアンホテリシンB(Gemini Bioproducts、CA)1.25μg/mL、ペニシリン100U/mLおよびストレプトマイシン100μg/mLを含むCAR-T培地(AIM V-AlbuMAX(BSA)(Life Technologies)で1回洗浄し、実験に使用するか、または-80℃で凍結した。
単離したPBMC細胞は、huIL2(1000×ストックから;Invitrogen)300U/mLを含むCAR-T培地に再懸濁し、CD3-CD28ビーズとビーズ対細胞比1:1で混合した。細胞は、ウイルス形質導入の前に、CO2の存在下で37℃で24時間インキュベートした。
PBMCの活性化後、細胞を37℃、5%CO2で24時間インキュベートした。1×106細胞の各ウェルに、レンチウイルス5×106およびTransplus培地(Alstem、Richmond、CA)(最終希釈率1:500)2μL/mLを添加した。ウイルスの添加を繰り返す前に、細胞をさらに24時間インキュベートした。次に、細胞を、IL-2を含むIL-2新鮮培地300U/MLの継続的な存在下で、12~14日間増殖させた(総インキュベーション時間は、必要なCAR-T細胞の最終数に応じた)。細胞濃度は2~3日ごとに分析し、その時点で培地を添加して細胞懸濁液を1×106細胞/mLに希釈した。
本発明者らは、実施例2に示したヒト化BCMA-CART構築物を用いて、ヒト化BCMA-CAR-T細胞を設計した。無関係のScFvと共にMock scFvを使用し、陰性対照としてMock-CAR-T細胞を生成した。レンチウイルスのヒト化BCMA-CARをT細胞に形質導入した後、ヒト化BCMA-CAR陽性細胞が検出された(図4)。
本発明者らは、ヒト化BCMA-CAR-T細胞を標的CHO-BCMA細胞およびCHO(BCMA陰性)対照細胞と共にインキュベートした。ヒト化BCMA-CAR-T細胞はCHO-BCMA細胞を特異的に致死させた(図5A)が、CHO細胞は致死させなかった(図5B)。結果は、BCMA抗原を標的とし、BCMA陽性細胞を致死させるためのヒト化BCMA-CAR-T細胞の高い特異性を示す。
本発明者らは、ヒト化BCMA-CAR-T細胞と標的CHO-BCMAおよび親CHO細胞の同時インキュベーション後に上清を収集し、IFN-ガンマアッセイを実施した
。BCMA-CAR-T細胞は、CHO-BCMA細胞ではIFN-ガンマを分泌したが、陰性対照CHO細胞では分泌しなかった(図6)。結果は、ヒト化BCMA-CAR-T細胞の特異性を立証した。
本発明者らは、BCMA-CAR-T細胞を多発性骨髄腫がん細胞RPMI8266およびBCMA陰性K562細胞(慢性骨髄性白血病細胞)と共にインキュベートし、IFN-ガンマについてFisherのキットを使用して製造元の手順に従ってELISAを実施した。ヒト化BCMA-CAR-T細胞は、BCMA陽性多発性骨髄腫がん細胞に対して高レベルのIFN-ガンマを分泌したが、BCMA陰性K562細胞に対しては分泌しなかった(図7)。死滅のレベルおよびIFN-ガンマの分泌は、T細胞およびMock CAR-T細胞よりもBCMA-CAR-T細胞の方が顕著に高かった。これは、造血BCMA陽性細胞に対するヒト化BCMA-CAR-T細胞の特異性を立証している。
多発性骨髄腫RPMI8226細胞をNSGマウス(1×10^7細胞/マウス)に皮下注射した後、ヒト化BCMA-CAR-T細胞をivによって(1×10^7CAR-T細胞/マウス)2回注射した。ヒト化BCMA-CAR-T細胞は、マウスにおけるRPMI8226腫瘍の増殖を顕著に減少させた(図8A)。ヒト化BCMA-CAR-T細胞で治療したマウスは、マウスの体重減少を引き起こさなかったので、CAR-T細胞はマウスに対して毒性がないことが示唆された(図8B)。研究中、行動や目に見える変化は観察されなかった。
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Claims (10)
- 配列番号3のアミノ酸配列を有する重鎖可変領域(VH);および
配列番号5のアミノ酸配列を有する軽鎖鎖可変領域(VL)
を含む、抗BCMA1本鎖可変断片(scFv);
CD8の膜貫通ドメインを含む膜貫通ドメイン;
4-1BB共刺激性ドメインを含む共刺激性ドメイン;ならびに
CD3ゼータ活性化ドメインを含む活性化ドメイン
を含む抗BCMAキメラ抗原受容体(CAR)を含む、ナチュラルキラー(NK)細胞。 - CARが配列番号17のアミノ酸配列を含む、請求項1に記載のNK細胞。
- 配列番号17のCARをコードし、5’末端および3’末端を有する核酸を含む、請求項1に記載のNK細胞。
- BCMA陽性がん細胞を致死させる方法で使用するための、抗BCMAキメラ抗原受容体(CAR)を含む、ナチュラルキラー(NK)細胞であって、前記方法は:
BCMA陽性がん細胞とNK細胞を接触させることを含み、前記CARは:
配列番号3のアミノ酸配列を有する重鎖可変領域(VH);および
配列番号5のアミノ酸配列を有する軽鎖鎖可変領域(VL)
を含む、抗BCMA1本鎖可変断片(scFv);
CD8の膜貫通ドメインを含む膜貫通ドメイン;
4-1BB共刺激性ドメインを含む共刺激性ドメイン;ならびに
CD3ゼータ活性化ドメインを含む活性化ドメイン
を含む、
NK細胞。 - 接触はインビトロである、請求項4に記載のNK細胞。
- BCMA陽性がん細胞は、多発性骨髄腫がん細胞を含む、請求項4に記載のNK細胞。
- 接触は腫瘍内である、請求項4に記載のNK細胞。
- 抗BCMA NK細胞を製造する方法であって、
配列番号3のアミノ酸配列を有する重鎖可変領域(VH);および
配列番号5のアミノ酸配列を有する軽鎖鎖可変領域(VL)
を含む、抗BCMA1本鎖可変断片(scFv);
CD8の膜貫通ドメインを含む膜貫通ドメイン;
4-1BB共刺激性ドメインを含む共刺激性ドメイン;ならびに
CD3ゼータ活性化ドメインを含む活性化ドメイン
を含む抗BCMAキメラ抗原受容体(CAR)をコードする核酸を、インビトロでNK細胞内に導入することを含む、方法。 - 核酸は、ウイルスベクターによってNK細胞内に導入される、請求項8に記載の方法。
- ウイルスベクターは、レトロウイルスベクター、アデノウイルスベクター、アデノ随伴ウイルス(AAV)ベクター、サルウイルスベクター、ワクシニアウイルスベクター、センダイウイルスベクター、エプスタインバーウイルス(EBV)ベクター、およびHSVベクターから成る群から選択される、請求項9に記載の方法。
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