JP2017507919A - Fcスペーサー領域に変異を有するキメラ抗原受容体(CAR)及びそれらの使用方法 - Google Patents
Fcスペーサー領域に変異を有するキメラ抗原受容体(CAR)及びそれらの使用方法 Download PDFInfo
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Abstract
Description
[0001] 本願は、図面を含めてその全体が本明細書に援用される、米国仮特許出願番号61/926,881(2014年1月13日出願)に対する優先権を主張する。
[0002] 本発明は、アメリカ国立衛生研究所(NIH)によって授与された認可番号P50 CA107399及びP01 CA030206の下での政府支援でなされたものである。米国政府は、本発明に一定の権利を有する。
[0019] 本明細書に記載される態様によれば、がん関連抗原を標的とする組換えキメラ抗原受容体(CAR)及びそれらの使用の方法が提供される。下記の態様によって記載されるように、CARには、限定されるものではないが、抗原結合性ドメイン、スペーサードメイン、膜貫通ドメイン、細胞内シグナル伝達ドメイン、及び細胞内共刺激ドメインのうち1以上を含めた、一連のタンパク質又はペプチドのドメインが含まれ得る。
[0025] CAR抗原結合性ドメインには、ペプチド又はポリペプチドとして発現される場合に、がん関連抗原のエピトープに結合するヌクレオチド配列が含まれ得る。いくつかの態様では、がん関連抗原は、がん細胞(例えば、腫瘍細胞、新生物細胞、悪性腫瘍細胞、又は他のあらゆるがん性細胞)によって発現又は過剰発現されるどの抗原であってもよく、タンパク質、ペプチド、炭水化物、糖タンパク質、ガングリオシド、プロテオグリカン、又はこれらのあらゆる組合せ又は複合体であり得る。いくつかの側面では、がん関連抗原は、がん又は腫瘍細胞上でのみ発現され得る腫瘍特異抗原(TSA)であって、一方他の側面では、がん関連抗原は、腫瘍細胞上でも正常細胞上でも発現され得る腫瘍関連抗原(TAA)である。他の側面では、がん関連抗原は、変異した発がん遺伝子又は腫瘍抑制遺伝子の産物、又は別の変異遺伝子の産物(例えば、過剰発現又は異常発現された細胞タンパク質、発がんウイルスによって産生された腫瘍抗原、腫瘍胎児抗原、改変された細胞表面糖脂質又は糖タンパク質、又は細胞種特異的な分化抗原)であり得る。
[0030] スペーサードメイン(「ヒンジ領域」又は「スペーサー/ヒンジ領域」とも呼ばれる)は、免疫グロブリンFc領域、例えば、IgG1 Fc領域、IgG2 Fc領域、IgG3 Fc領域、IgG4 Fc領域、IgE Fc領域、IgM Fc領域、又はIgA Fc領域の少なくとも一部に由来しても含まれてもよい。ある態様において、スペーサードメインには、そのCH2ドメインとCH3ドメインの内部に存する、IgG1、IgG2、IgG3、IgG4、IgE、IgM、又はIgAの免疫グロブリンFc領域の少なくとも一部が含まれる。いくつかの態様において、スペーサードメインには、対応する免疫グロブリンヒンジ領域の少なくとも一部も含まれ得る。いくつかの態様において、スペーサードメインは、改変免疫グロブリンFc領域、例えば、改変IgG1 Fc領域、改変IgG2 Fc領域、改変IgG3 Fc領域、改変IgG4 Fc領域、改変IgE Fc領域、改変IgM Fc領域、又は改変IgA Fc領域の少なくとも一部に由来するか又は含まれる。改変免疫グロブリンFc領域は、スペーサードメインのFc受容体(FcR)への結合性低下を引き起こす、1以上のアミノ酸置換、改変、又は欠失をもたらす1以上の変異(例えば点変異、挿入、欠失、重複)を有し得る。いくつかの側面において、改変免疫グロブリンFc領域は、スペーサードメインの1以上のFcR(限定されないが、FcγRI、FcγR2A、FcγR2B1、FcγR2B2、FcγR3A、FcγR3B、FcεRI、FcεR2、FcαRI、Fcα/μR、又はFcRnが含まれる)への結合性低下を引き起こす、1以上のアミノ酸置換、改変、又は欠失をもたらす1以上の変異を伴って設計され得る。
[0036] 非極性R基があるアミノ酸:アラニン、バリン、ロイシン、イソロイシン、プロリン、フェニルアラニン、トリプトファン、メチオニン。
[0038] 荷電・極性R基があるアミノ酸(pH6.0で負電荷):アスパラギン酸、グルタミン酸。
[0040] 別のグループは、フェニル基のあるアミノ酸:フェニルアラニン、トリプトファン、チロシンであり得る。
[0055] 細胞内シグナル伝達ドメインには、どの好適なT細胞受容体(TCR)複合シグナル伝達ドメイン又はその一部分も含まれ得る。いくつかの態様において、細胞内シグナル伝達ドメインは、CD3複合体に由来する。いくつかの態様において、細胞内シグナル伝達ドメインは、TCRζ鎖シグナル伝達ドメインである。ある態様では、ζ鎖シグナル伝達ドメインに、以下のようなアミノ酸配列をコードするヌクレオチド配列が含まれ得る:
[0058] いくつかの態様において、CAR遺伝子は、発現カセットの一部である。いくつかの態様において、発現カセットには、CAR遺伝子に加えて、アクセサリー遺伝子も含まれ得る。T細胞によって発現されるとき、アクセサリー遺伝子は、形質導入されたT細胞の選択マーカー、生体内追跡マーカー、又は形質導入されたT細胞の自殺遺伝子として役立つ場合がある。
[0070] いくつかの態様によれば、上記に記載したもののような、CAR遺伝子とCAR遺伝子で形質導入されるT細胞の集団を、被験者においてがんを治療する方法において使用し得る。そのような方法には、少なくとも1つのCAR遺伝子で形質導入されたT細胞の少なくとも1つの集団の治療有効量を該被験者へ投与する工程が含まれ得る。上記の態様において、CAR形質導入T細胞の集団は、上記に記載したもののような、1以上のCAR遺伝子を発現する。ある態様において、このT細胞は、本明細書に記載されるような、CD19R(L235E)又はCD19R(N297Q)構築体のような単一変異遺伝子構築体、本明細書に記載されるような、L235EとN297Qの両方の変異を有する二重変異遺伝子構築体(例、CD19R(EQ))、又は本明細書に記載されるような、欠失遺伝子構築体(例、CD19Rch2Δ)で形質導入されてそれを発現する。そのような細胞が養子免疫療法治療による投与されると、この形質導入されたT細胞は、がん関連抗原を発現する細胞(即ち、がん細胞)に生体内で(in vivo)特異的に標的指向してこれを溶解し、それによってがん細胞を消失させるその治療効果を送達する。
[0084] DNA構築体及びレンチウイルスベクター。CD19R28Z−T2A−EGFRt_epHIV7レンチウイルス構築体は、a)CD19特異的FMC63 mAbのVH及びVL遺伝子断片、IgG4ヒンジ−CH2−CH3、キメラ受容体の発現及び機能を高めるgg変異を含有する共刺激分子CD28の膜貫通ドメイン及び細胞質シグナル伝達ドメイン(Nguyenら、2003)、及びCD3ζ鎖の細胞質ドメイン(Kowolikら、2006)から成るキメラ抗原受容体(CAR)配列;b)リボソームスキップT2A配列(Szymczakら、2004)、並びにc)短鎖型EGFR配列(Wangら、2011a)を含有する。EGFRt−T2A−DHFRFS−T2A−IMPDH2IY_epHIV7レンチウイルスベクターは、既に報告されているようにして(Jonnalagaddaら、2013)作製した。CD19R(L235E)28Z−T2A−EGFRt_epHIV7ベクター、CD19R(N297Q)28Z−T2A−EGFRt_epHIV7ベクター、及びCD19R(EQ)28Z−T2A−EGFRt_epHIV7ベクターは、Geneartで合成してNheI/RsrIIで消化し、同様に消化したCD19R28Z−T2A−EGFRt_epHIV7と連結されている、コドンを最適化したCD19R28Z_pGプラスミドの、QuikChange II XLキット(Agilent Technologies、カリフォルニア州サンタクララ)を用いた部位特異的突然変異誘発により作製した。CD19Rch2Δ28Z−T2A−EGFRt_epHIV7ベクターは、Geneartで合成してNheI/RsrIIで消化し、同様に消化したCD19R28Z−T2A−EGFRt_epHIV7と連結されている、コドンを最適化したCD19R−HL−CH3(CO)_pMK−RQプラスミドより作製した。
[0088] SupB15及びK562白血病細胞株(ATCC)は、対応するATCC推奨培地において増殖させた。
[0092] CD19R+ T細胞は、NSGマウスに生着することができない。T細胞亜集団としてのセントラルメモリーT細胞(TCM)は、養子移入後に優れた生着可能性を有しており、したがって治療効果を有するものとして特徴付けられている(Wangら、2011b)。さらなる証拠は、NSGマウスを用いた生体内異種移植片モデルにおいて、TCM由来細胞上でのCAR発現が、生体内での存続減少と相関するように見えることを示している。本明細書に記載の試験が示すように、非形質導入TCM由来細胞の生着を、(i)CD19特異的CAR(CD19R)及び追跡マーカーとして短鎖型EGFR(EGFRt)の両方を発現するようにレンチウイルスで形質導入したTCM由来細胞、並びに(ii)EGFRt追跡マーカーのみを細胞表面上に発現するようにレンチウイルスで形質導入したTCM由来細胞の生着と比較する実験において、この存続減少を示した(図1)。細胞をマウスに静脈内投与した後7日目と14日目に採取した末梢血を見ると、抗ヒトCD45 mAでの染色は、非形質導入TCM由来細胞の検出を可能にした(図1c)。しかしながら、遺伝子改変細胞を検出するためにEGFRt追跡マーカーについて同時染色すると、入力した細胞の形質導入及び/又はEGFRt発現(図1b、78〜79%陽性)のレベルが同様であるにもかかわらず、CD19R/EGFRt+ TCMを受けたマウスの末梢血では、EGFRt+ TCMを受けたものと比較して、細胞の生着が有意に少ないことが明らかであった(図1c、p<0.0001、対応の無いスチューデントt検定を使用して、7日目又は14日目に各群のCD45/EGFRt+細胞の%を比較した場合)。CD19R/EGFRt+ TCM処理マウスについて検出されたT細胞は低レベルであったが、存続T細胞はすべて7日目及び14日目においてCAR陰性であった。この生体内での存続減少は、EGFRt導入遺伝子ではなくCAR導入遺伝子を発現するように形質導入した細胞に特異的であるため、T細胞のレンチウイルス形質導入に関連するものではない。さらに、これらNSGマウスにおけるCD19抗原の欠如、及び抗原特異性の異なるCARを発現するT細胞において同様の現象が見られている(データ示さず)という事実は、末梢血における生着/存続の欠如が抗原に異存しないことを示唆している。
[0098] 臨床的には、養子T細胞戦略の生体内治療効果は、養子移入時の生着及び存続と直接相関がある(Heslopら、2003;Brenner&Heslop、2010)。細胞移入前の宿主のリンパ球枯渇(Gattinoniら、2005)、細胞移入後のサイトカインサポート(ごく最近では、Overwijk&Schluns、2009に概説されている)、及び移入に最適なT細胞集団の使用(Bergerら、2008;Hinrichsら、2011;Yangら、2013;Gattinoniら、2011;Cieriら、2013)を含めた様々なアプローチが移入T細胞の存続を改善することが示唆されている。上記試験は、治療細胞の生着及び存続を管理する上でキメラ抗原受容体(CAR)のデザインが重要な役割果たすさらなる証拠を提供する。これまで、CARデザインは、第二及び第三世代のCARに共刺激シグナル伝達ドメインを含めることによって、治療細胞の生着及び存続に利するために活用されてきた(Cartellieriら、2010を参照のこと)。しかしながら、上記データがまた示唆するように、リガンド結合ドメインをCARのシグナル伝達ドメインに連結させるために使用される配列(スペーサー、ヒンジ、及び/又はリンカーとして知られる)は、マウス悪性疾患モデルにおける生体内治療結果にとって重要であることがこれまで正しく評価されていない。具体的には、Ig Fcスペーサーの使用により、NSGマウスモデルにおいてCAR発現細胞の生着及び/又は存続をFcγR結合性と相関するやり方で潜在的に阻害できることが見出された。したがって、CAR Fcドメイン内の関連配列の点変異又は欠失によりFcγR結合を妨げると、養子移入された細胞の生体内存続を、CARを発現しない細胞のそれまで回復させることができる。このように、スペーサーを最適化したCARによって介在される生体内存続の増加により、マウスモデルにおいて、有意に改善されたCAR指向性の抗腫瘍療法へ転換できる。
以下に列挙する参考文献、特許、及び公開特許出願、並びに上記明細書に引用したすべての参考文献は、本明細書に完全に記載されているかのように、その全体を本明細書に援用する。
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Claims (21)
- Fc受容体(FcR)への結合性が低下した組換えキメラ抗原受容体(CAR)であって:
抗原認識ドメイン;
FcRへの結合性低下をもたらす1以上の変異をそのCH2領域に有する改変免疫グロブリンFc領域に由来するスペーサードメイン;及び
細胞内シグナル伝達ドメイン、
を含んでなる、前記キメラ抗原受容体。 - 抗原認識ドメインがscFvである、請求項1の方法。
- 抗原認識ドメインが、5T4、8H9、αvβ6インテグリン、αフェトプロテイン(AFP)、B7−H6、CA−125炭酸脱水酵素9(CA9)、CD19、CD20、CD22、CD30、CD33、CD38、CD44、CD44v6、CD44v7/8、CD52、CD123、CD171、がん胎児性抗原(CEA)、EGFrvIII、上皮糖タンパク質−2(EGP−2)、上皮糖タンパク質−40(EGP−40)、ErbB1/EGFR、ErbB2/HER2/neu/EGFR2、ErbB3、ErbB4、上皮腫瘍抗原(ETA)、FBP、胎児型アセチルコリン受容体(AchR)、葉酸受容体−α、G250/CAIX、ガングリオシド2(GD2)、ガングリオシド3(GD3)、HLA−A1、HLA−A2、高分子量メラノーマ関連抗原(HMW−MAA)、IL−13受容体α2、KDR、κ−軽鎖、ルイスY(LeY)、L1細胞接着分子、メラノーマ関連抗原(MAGE−A1)、メソセリン、マウスCMV感染細胞、ムチン−1(MUC1)、ムチン−16(MUC16)、ナチュラルキラーグループ2メンバーD(NKG2D)リガンド、神経細胞接着分子(NCAM)、NY−ESO−1、腫瘍胎児抗原(h5T4)、前立腺幹細胞抗原(PSCA)、前立腺特異的膜抗原(PSMA)、受容体チロシンキナーゼ様オーファン受容体1(ROR1)、mAb IgEの標的となるTAA、腫瘍関連糖タンパク質−72(TAG−72)、チロシナーゼ、及び血管内皮増殖因子(VEGF)受容体から成る群より選択されるがん関連抗原を標的とする、請求項1の方法。
- 改変免疫グロブリンFc領域が、改変したIgG1、IgG2、IgG3、又はIgG4のFc領域である、請求項1の方法。
- 改変免疫グロブリンFc領域の1以上の変異が、S228Pアミノ酸置換、L235Eアミノ酸置換、N297Qアミノ酸置換、又はこれらの組合せより選択される1以上のアミノ酸置換を含む、請求項1の方法。
- 改変免疫グロブリンFc領域の1以上の変異が、1以上の欠失を含む、請求項1の方法。
- 膜貫通ドメインをさらに含む、請求項1の方法。
- 細胞内シグナル伝達ドメインが、T細胞受容体(TCR)ζ鎖シグナル伝達ドメインである、請求項1の方法。
- CD28、誘導性共刺激(ICOS)、OX40、CD27、DAP10、4−1BB、p56lck、又は2B4に由来する1以上の共刺激細胞内シグナル伝達ドメインをさらに含む、請求項8の方法。
- CARが、ウイルスベクターに挿入された核酸配列によってコードされる、請求項1の方法。
- CAR遺伝子が含まれる発現カセットを含んでなるウイルスベクターによって形質導入されたヒト免疫細胞の集団であって、CAR遺伝子を発現し、該遺伝子は:
抗原認識ドメイン;
FcRへの結合性低下をもたらす1以上の変異をそのCH2領域に有する改変免疫グロブリンFc領域に由来するスペーサードメイン;及び
細胞内シグナル伝達ドメイン、
をコードするヌクレオチド配列を含む、前記ヒト免疫細胞の集団。 - 抗原認識ドメインが、5T4、8H9、αvβ6インテグリン、αフェトプロテイン(AFP)、B7−H6、CA−125炭酸脱水酵素9(CA9)、CD19、CD20、CD22、CD30、CD33、CD38、CD44、CD44v6、CD44v7/8、CD52、CD123、CD171、がん胎児性抗原(CEA)、EGFrvIII、上皮糖タンパク質−2(EGP−2)、上皮糖タンパク質−40(EGP−40)、ErbB1/EGFR、ErbB2/HER2/neu/EGFR2、ErbB3、ErbB4、上皮腫瘍抗原(ETA)、FBP、胎児型アセチルコリン受容体(AchR)、葉酸受容体−α、G250/CAIX、ガングリオシド2(GD2)、ガングリオシド3(GD3)、HLA−A1、HLA−A2、高分子量メラノーマ関連抗原(HMW−MAA)、IL−13受容体α2、KDR、κ−軽鎖、ルイスY(LeY)、L1細胞接着分子、メラノーマ関連抗原(MAGE−A1)、メソセリン、マウスCMV感染細胞、ムチン−1(MUC1).ムチン−16(MUC16)、ナチュラルキラーグループ2メンバーD(NKG2D)リガンド、神経細胞接着分子(NCAM)、NY−ESO−1、腫瘍胎児抗原(h5T4)、前立腺幹細胞抗原(PSCA)、前立腺特異的膜抗原(PSMA)、受容体チロシンキナーゼ様オーファン受容体1(ROR1)、mAb IgEの標的となるTAA、腫瘍関連糖タンパク質−72(TAG−72)、チロシナーゼ、及び血管内皮増殖因子(VEGF)受容体から成る群より選択されるがん関連抗原を標的とする、請求項11の方法。
- 改変免疫グロブリンFc領域が、改変したIgG1、IgG2、IgG3、又はIgG4のFc領域である、請求項11の方法。
- 改変免疫グロブリンFc領域の1以上の変異が、S228Pアミノ酸置換、L235Eアミノ酸置換、N297Qアミノ酸置換、又はこれらの組合せより選択される1以上のアミノ酸置換を含む、請求項11の方法。
- 改変免疫グロブリンFc領域の1以上の変異が、1以上の欠失を含む、請求項11の方法。
- 細胞内シグナル伝達ドメインが、T細胞受容体(TCR)ζ鎖シグナル伝達ドメインである、請求項11の方法。
- CD28、誘導性共刺激(ICOS)、OX40、CD27、DAP10、4−1BB、p56lck、又は2B4に由来する1以上の共刺激細胞内シグナル伝達ドメインをさらに含む、請求項16の方法。
- 被験者においてがんを治療する方法であって、CAR遺伝子を形質導入されたヒト免疫細胞の集団を該被験者に投与することを含み、CAR遺伝子は:
がんに特異的ながん関連抗原を標的とする抗原認識ドメイン;
FcRへの結合性低下をもたらす1以上の変異をそのCH2領域に有する改変免疫グロブリンFc領域に由来するスペーサードメイン;及び
細胞内シグナル伝達ドメイン、
をコードするヌクレオチド配列を含む、前記方法。 - FcRへの結合性低下が、非改変免疫グロブリンFc領域に由来するスペーサードメインをコードするヌクレオチド配列を含んでなるCAR遺伝子で形質導入されたヒト免疫細胞と比べて、ヒト免疫細胞の改善された存続をもたらす、請求項18の方法。
- 幹細胞移植、放射線療法、外科的切除、化学療法剤、免疫療法剤、標的療法剤、又はこれらの組合せから選択される1以上の抗がん療法と組み合わせて、CAR遺伝子で形質導入されたヒト免疫細胞の集団を投与することをさらに含む、請求項18の方法。
- Fc受容体(FcR)への結合性が低下した組換えキメラ抗原受容体(CAR)であって:
scFvを含んでなる抗原認識ドメイン;
FcRへの結合性低下をもたらす1以上の変異をそのCH2領域に有する改変免疫グロブリンFc領域に由来するスペーサードメイン、ここで、1以上の変異は、S228Pアミノ酸置換、L235Eアミノ酸置換、N297Qアミノ酸置換、又はこれらの組合せから選択される;及び
細胞内シグナル伝達ドメイン、
を含んでなる、前記キメラ抗原受容体。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US11993652B2 (en) | 2013-12-20 | 2024-05-28 | Fred Hutchinson Cancer Center | Tagged chimeric effector molecules and receptors thereof |
US11827904B2 (en) | 2015-04-29 | 2023-11-28 | Fred Hutchinson Cancer Center | Modified stem cells and uses thereof |
JP2020535796A (ja) * | 2017-09-06 | 2020-12-10 | フレッド ハッチンソン キャンサー リサーチ センター | strepタグ特異的キメラ受容体およびその使用 |
JP7407701B2 (ja) | 2017-09-06 | 2024-01-04 | フレッド ハッチンソン キャンサー センター | strepタグ特異的キメラ受容体およびその使用 |
CN112055595A (zh) * | 2018-01-22 | 2020-12-08 | 恩多塞特公司 | Car t细胞的使用方法 |
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EP3626748A1 (en) | 2020-03-25 |
JP6560235B2 (ja) | 2019-08-14 |
CA2936501A1 (en) | 2015-07-16 |
ES2767423T3 (es) | 2020-06-17 |
WO2015105522A1 (en) | 2015-07-16 |
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AU2014376328A1 (en) | 2016-07-21 |
US20160333108A1 (en) | 2016-11-17 |
EP3094653B1 (en) | 2019-10-23 |
EP3094653A4 (en) | 2017-08-30 |
CN107074957B (zh) | 2021-05-07 |
AU2020204351A1 (en) | 2020-07-16 |
US20220372164A1 (en) | 2022-11-24 |
CN113307880A (zh) | 2021-08-27 |
AU2023203097A1 (en) | 2023-06-08 |
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