JP6657317B2 - B細胞成熟抗原を標的指向するキメラ抗原受容体 - Google Patents
B細胞成熟抗原を標的指向するキメラ抗原受容体 Download PDFInfo
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Description
本特許出願は、米国仮出願61/622,600号(出願日:2012年4月11日)の利益を主張し、該出願全体を参照により本願に含む。
本願と同時に提出される下記のコンピュターによる読み込み可能な核酸/アミノ酸配列リスティングは、全体が本願に参照により盛り込まれる:
"712361#ST25.TXT,"と命名する42,589 バイトASCII (テキスト)ファイル(2013年3月14日作製)。
多発性骨髄腫(MM)は、クローナルな形質細胞(プラズマ細胞)の蓄積を特徴とする悪性腫瘍である(例えば、Palumbo ら, New England J. Med., 364(11): 1046-1060 (2011), 及び Lonialら, Clinical Cancer Res., 17(6): 1264-1277 (2011) 参照)。MMに対する現在の治療法は、しばしば寛解をもたらすが、ほとんどの患者が最終的には再発し、死に至る(例えば、Lonialら, 前出及びRajkumar, Nature Rev. Clinical Oncol., 8(8): 479-491 (2011)参照)。同種造血幹細胞移植は、免疫介在性骨髄腫細胞除去を誘発することが示されてきたが、このアプローチは毒性も高く、治癒される患者はほとんどいない(例えば、Lonialら, 前出, 及びSalitら, Clin. Lymphoma, Myeloma, 及び Leukemia, 11(3): 247-252 (2011)参照)。現在、臨床的に有効なFDAが認可したMMに対するモノクローナル抗体若しくは自家T細胞治療法はない(例えば、Richardsonら, British J. Haematology, 154(6): 745-754 (2011)及びYi, Cancer Journal, 15(6): 502-510 (2009)参照)。
本発明は、抗原認識部分及びT細胞活性化部分を含み、抗原認識部分がB細胞成熟抗原(BCMA)に対し指向されたキメラ抗原受容体(CAR)をコードする単離又は精製された核酸配列を提供する。
本発明は、キメラ抗原受容体(CAR)をコードする単離された又は精製された核酸配列を提供するものであり、該CARは、抗原認識部分及びT細胞活性化部分を含む。キメラ抗原受容体(CAR)は、T細胞シグナル伝達又はT細胞活性化ドメインに結合した抗体の抗原結合ドメイン(例えば、単鎖可変フラグメント(scFv))を含む人工的に構築されたハイブリットタンパク質又はポリペプチドである。CARsは、MHCに限定されない態様で、モノクローナル抗体の抗原結合特性を利用して、T細胞の特異性及び反応性を選択した標的に向かうように指向させる能力を有する。このMHCに限定されない抗原認識により、CARを発現するT細胞は、抗原のプロセシングとは独立して抗原を認識する能力を得、このようにして腫瘍回避の主要なメカニズムを飛び越えて進むことができる。更にCARsは、T細胞に発現する時、内因性T細胞受容体(TCR)アルファ及びベータ鎖とダイマーを形成しないという利点も有する。
本実施例はヒト細胞におけるBCMAの発現パターンを実証する。
本実施例は、本発明の抗BCMAキメラ抗原受容体(CARs)をコードする核酸配列の構築を記載する。
軽鎖可変領域−リンカー−重鎖可変領域。
GSTSGSGKPGSGEGSTKG (SEQ ID NO: 7) (例えば、Cooperら, Blood, 101(4): 1637-1644 (2003)参照)。
CD8αシグナル配列、上記抗-BCMA scFv、ヒトCD8α分子のヒンジ及び膜貫通領域、 CD28分子の細胞質部分及びCD3ζ分子の細胞質部分。
CARをコードする核酸配列の概略図を図3Aに示す。C12A3.2 とC11D5.3からの可変領域を含むCARsは、それぞれ 抗-bcma1及び抗-bcma2と命名した。
CD8αシグナル配列、scFv、ヒトCD8α分子のヒンジ及び膜貫通領域、CD28分子の細胞質部分及びCD3ζ分子の細胞質部分。
G-抗-bcma2 CAR は、以下の要素を5'から3'に含んでいた:
ヒトGM-CSF 受容体シグナル配列、scFv、 ヒトCD8α分子のヒンジ及び膜貫通領域、CD28分子の細胞質部分及びCD3ζ分子の細胞質部分。
抗-bcma2-BB CAR は、5'から3'に以下の要素を含んでいた:
CD8αシグナル配列、scFv、ヒトCD8α分子のヒンジ及び膜貫通領域、4-1BB 分子の細胞質部分及びCD3ζ分子の細胞質部分。
抗-bcma2-OX40 CARは、5'から3'に以下の要素を含んでいた:
CD8αシグナル配列、scFv、ヒトCD8α分子のヒンジ及び膜貫通領域、OX40 分子の細胞質部分(例えば、Latzaら, European Journal of Immunology, 24: 677-683 (1994)参照)及び、CD3ζ分子の細胞質部分。
抗-bcma2-BBOX40は、5'から3'に以下の要素を含んでいた:
CD8αシグナル配列、scFv、ヒトCD8α分子のヒンジ及び膜貫通領域、4-1BB 分子の細胞質部分、OX40 分子の細胞質部分及びCD3ζ分子の細胞質部分。
7つのCAR配列のそれぞれに存在する要素を表1に示す。
本実施例は、本発明CARのBCMAに対する特異性を決定するのに用いられる一連の実験を記載する。
NCI-H929、U266及びRPMI8226はすべて、ATCC(それぞれ、ATCC Nos. CRL-9068, TIB-196及びCCL-155)から得たBCMA+多発性骨髄腫セルラインである。A549 (ATCC No. CCL-185)は、BCMA-陰性肺癌セルラインである。TC71は、BCMA-陰性肉腫セルラインである。CCRF-CEMは、BCMA-陰性Tセルラインである(ATCC No. CCL-119)。BCMA-K562は、BCMA全長をコードする核酸配列を、形質導入したK562細胞(ATCC No. CCL-243) である。NGFR-K562は、低親和性の神経成長因子(例えば、Kochenderferら, J. Immunotherapy., 32(7):689-702 (2009)参照)をコードする遺伝子を形質導入されたK562 細胞である。多発性骨髄腫を患う3人の患者(すなわち、骨髄腫患者1から3)からの末梢血液リンパ球(PBL) を用いたが、それらPBLは、3人の他の対象者であるドナーA、ドナーB及びドナーC由来のPBLである。ドナーAからCは皆、黒色腫を有していた。CD34+プライマリー細胞は、3人の正常で健常なドナーからのものである。形質細胞腫の試料は、骨髄腫患者1から得、骨髄試料は、骨髄腫患者3から得た。上記のヒト試料はすべて、国立癌研究所(National Cancer Institute)におけるIRB承認臨床試験に登録した患者から得たものである。小気道上皮細胞、気管支上皮細胞及び腸上皮細胞のプライマリーヒト上皮細胞は、Lonza, Inc. (Basel, Switzerl及び)から得た。
BCMA-陽性又はBCMA-陰性細胞を、AIM VTM 培地(Life Technologies, Carlsbad, CA)+5%ヒト血清中で、96ウエル丸底プレート(Corning Life Sciences, Lowell, MA)二揃いのウエルに入れたCAR形質導入T細胞と合わせた。プレートは、37℃において、18-20 時間インキュベートした。インキュベーション後、IFNγ及びTNFに対するELISAを、標準的な方法 (Pierce, Rockford, IL)を用いて行った。
** 示した標的細胞は、エフェクター細胞と合わせて一晩インキュベートし、IFNγELISA を行った。
二つのT細胞集団を、2本の別の管に調製した。一方の管は、BCMA-K562細胞を、他方の管は、NGFR-K562細胞を入れた。更に、管両方に、抗-bcma2 CAR及び抗-bcma2 CAR変異体を形質導入したT細胞、1 mL のAIM VTM培地(Life Technologies, Carlsbad, CA) + 5% ヒト血清、所定濃度の抗-CD107a 抗体(eBioscience, Inc., San Diego, CA; クローン eBioH4A3) 及び1μL のGolgi Stop (ゴルジストップ)(BD Biosciences, Franklin Lakes, NJ)を入れた。管はすべて、37℃で4時間インキュベートし、その後CD3、CD4及びCD8の発現のため染色した。
BCMA-K562細胞の集団及びNGFR-K562細胞の集団を、上述のように2つの別の管に調製した。2つの管両方に、更に骨髄腫患者2からの抗-bcma2 CARを形質導入されたT細胞、1 mL のAIM V 培地(Life Technologies, Carlsbad, CA) + 5% ヒト血清及び1μL のGolgi Stop(BD Biosciences, Franklin Lakes, NJ)を加えた。管は全て、37℃で6時間インキュベートした。細胞は、抗-CD3、抗-CD4及び抗-CD8 抗体で、表面染色した。細胞は、透過処理し、IFNγ(BD Biosciences, Franklin Lakes, NJ, クローン B27)、 IL-2 (BD Biosciences, Franklin Lakes, NJ, クローン MQ1-17H12)及びTNF (BD Biosciences, Franklin Lakes, NJ, クローン MAb11) に対し、細胞内染色をサイトフィクス/サイトパームキット(Cytofix/Cytoperm kit)(BD Biosciences, Franklin Lakes, NJ)の指示に従い実施した。
抗-bcma2 CARを形質導入されたT細胞のBCMA発現標的細胞で刺激された時の増殖能力を分析した。具体的には、0.5x106の照射を受けたBCMA-K562細胞又は0.5x106の照射を受けたNGFR-K562細胞を、抗-bcma2 CAR又はSP6 CARいずれかを形質導入された全体で1x106 のT細胞と共培養した。該T細胞は、Manneringら, J. Immunological Methods, 283(1-2):173-183 (2003)に記載されているように、カルボキシフルオレセイン二酢酸 サクシンイミジルエステル (CFSE) (Life Technologies, Carlsbad, CA)で標識化した。共培養には、AIM VTM 培地(Life Technologies, Carlsbad, CA) + 5% ヒトAB 血清の培地を用いた。IL-2は、培地には添加しなかった。開始4日後、死んだ細胞を排除するためトリパン青を用いて、各共培養中の生きた細胞を数えた。続いて、ポリクローナルビオチン標識されたヤギ-抗-ヒトBCMA抗体(R&D Systems, Minneapolis, MN)で、その後ストレプタビディン(BD Biosciences, Franklin Lakes, NJ)、 抗-CD38 抗体(eBioscience, Inc., San Diego, CA)及び抗-CD56抗体(BD Biosciences, Franklin Lakes, NJ)でT細胞を染色することにより流動細胞分析を行った。流動細胞計測データの分析は、フロウジョソフトウエア(FlowJo software )(Tree Star, Inc., Ashland, OR))を用いて行った。.
本実施例では、本発明の抗-BCMA CAR発現T細胞は、多発性骨髄腫セルラインを破壊することができることを例証する。
全ての実験において、抗-bcma2 CARを形質導入したエフェクターT細胞の細胞毒性は、SP6CARを形質導入された、同一対象者から得たネガティブコントロールのエフェクターT細胞の細胞毒性と対比した。共培養は、滅菌5mL試験管(BD Biosciences, Franklin Lakes, NJ)で2回、T細胞:標的細胞比 20.0:1, 7:1, 2:1及び0.7:1で行った。培養液は、37℃で4時間インキュベートした。インキュベーション後ただちに、7-アミノ-アクチノマイシンD(7AAD; BD Biosciences, Franklin Lakes, NJ)を添加した。生存しているBCMA発現標的細胞と生存しているCCRF-CEMネガティブコントロール細胞は、それぞれT細胞/標的細胞共培養液で決定した。
BCMA発現標的細胞の百分率細胞毒性=100−BCMA発現標的細胞の補正生存百分率。
本実施例は、本発明の抗-BCMA CARを発現するT細胞が、プライマリー多発性骨髄腫細胞を破壊することができることを例証する。
本実施例は、本発明の抗-BCMA CARsを発現するT細胞が、マウスに株化した腫瘍を破壊することができることを例証する。
Claims (24)
- キメラ抗原受容体(CAR)であって、
(a)SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 6、SEQ ID NO: 8、SEQ ID NO: 9、SEQ ID NO: 10、SEQ ID NO: 11、及びSEQ ID NO: 12からなる群から選択されるアミノ酸配列の(i)重鎖相補性決定領域(CDR)1、(ii)重鎖CDR2、(iii)重鎖CDR3、(iv)軽鎖CDR1、(v)軽鎖CDR2、及び(vi)軽鎖CDR3を含む、B細胞成熟抗原(BCMA)に対して指向されている単鎖可変フラグメント(scFv)、
(b)膜貫通ドメイン、並びに
(c)1以上の細胞内T細胞シグナリングドメイン
を含む、CAR。 - 該膜貫通ドメインが、CD28膜貫通ドメイン、及びCD8α膜貫通ドメインからなる群から選択される、請求項1に記載のCAR。
- 該膜貫通ドメインがCD28膜貫通ドメインである、請求項1又は請求項2に記載のCAR。
- 該膜貫通ドメインがCD8α膜貫通ドメインである、請求項1又は請求項2に記載のCAR。
- 該1以上の細胞内T細胞シグナリングドメインが、CD28、CD3ζ、FcRγ、CD27、OX40、及び4-1BBからなる群から選択されるタンパク質から単離される、請求項1−4のいずれか1項に記載のCAR。
- CD28細胞内T細胞シグナリングドメイン、及びCD3ζ細胞内T細胞シグナリングドメインを含む、請求項1−5のいずれか1項に記載のCAR。
- OX40細胞内T細胞シグナリングドメイン、及びCD3ζ細胞内T細胞シグナリングドメインを含む、請求項1−5のいずれか1項に記載のCAR。
- 4-1BB細胞内T細胞シグナリングドメイン、及びCD3ζ細胞内T細胞シグナリングドメインを含む、請求項1−5のいずれか1項に記載のCAR。
- 該膜貫通ドメインがCD8α膜貫通ドメインであり、かつ、更に4-1BB細胞内T細胞シグナリングドメイン、及びCD3ζ細胞内T細胞シグナリングドメインを含む、請求項1に記載のCAR。
- 請求項1−9のいずれか1項に記載のCARをコードする、単離された核酸分子。
- 請求項10に記載の単離された核酸分子を含むベクター。
- レトロウイルスベクターである、請求項11に記載のベクター。
- レンチウイルスベクターである、請求項11に記載のベクター。
- 請求項10に記載の単離された核酸分子を含む、単離された宿主細胞。
- 請求項11−13のいずれか1項に記載のベクターを含む、単離された宿主細胞。
- T細胞である、請求項14又は請求項15に記載の単離された宿主細胞。
- ナチュラルキラー(NK)細胞である、請求項14又は請求項15に記載の単離された宿主細胞。
- 請求項14−17のいずれか1項に記載の単離された宿主細胞、及び医薬的に許容可能な担体又は希釈剤を含む、組成物。
- 癌細胞の破壊方法であって、
BCMAを発現する癌細胞を、請求項14−17のいずれか1項に記載の単離された宿主細胞1個以上と接触させることを含み、
それによりCARが産生されて、癌細胞上のBCMAに結合し、癌細胞が破壊される、
癌細胞がin vitroのものである、方法。 - 癌細胞を破壊するための剤であって、
請求項1−9のいずれか1項に記載のCAR、請求項10に記載の単離された核酸分子、請求項11−13のいずれか1項に記載のベクター、請求項14−17のいずれか1項に記載の単離された宿主細胞、又は請求項18に記載の組成物を含む、剤。 - 該癌細胞が多発性骨髄腫又はホジキンリンパ腫細胞である、請求項20に記載の剤。
- 癌細胞を破壊するための医薬品の製造における、請求項1−9のいずれか1項に記載のCAR、請求項10に記載の単離された核酸分子、請求項11−13のいずれか1項に記載のベクター、請求項14−17のいずれか1項に記載の単離された宿主細胞、又は請求項18に記載の組成物の使用。
- 該癌細胞が多発性骨髄腫又はホジキンリンパ腫細胞である、請求項22に記載の使用。
- 請求項1−9のいずれか1項に記載のCARを発現する宿主細胞の製造方法であって、
請求項10に記載の単離された核酸分子、又は請求項11−13のいずれか1項に記載のベクターを宿主細胞にin vitroで導入することを含み、
該宿主細胞がT細胞又はNK細胞である、方法。
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