JP2020537640A - 組織因子標的化car−nk及びcar−t細胞療法 - Google Patents
組織因子標的化car−nk及びcar−t細胞療法 Download PDFInfo
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Abstract
Description
本出願は、2017年9月27日に出願された米国特許仮出願第62/564,006号公報の利益を主張し、その全体が本明細書に参照により組み込まれる。
冠詞「a」及び「an」は本明細書において、1つ、又は2つ以上(すなわち少なくとも1つ)の、冠詞の文法上の目的物を意味するように用いられる。例えば、「構成要素(an element)」は、1つの構成要素、又は2つ以上の構成要素を意味する。
組織因子(TF)標的化CAR−NK及びCAR−T細胞を、本明細書にて開示する。TF標的化CARの設計及び開発において、TFの認識ドメインとして、TFに対する抗体又はscFvの代わりに、TFの天然リガンドである、因子VII完全長(野生型及び活性部位変異)、又は軽鎖(fVII若しくはfVIIL)が用いられる。まず、TFに対するfVIIの親和性は、TF抗原に対する抗体より、約100〜1000倍大きい。次に、fVIIは、モノクローナル抗体のヒト化、又はscFvライブラリーのスクリーニングをすることなく、組み換えDNA技術により合成することができる。更に、fVIIの軽鎖(最初の152個のアミノ酸残基)は、TFを発現するヒト及びマウス癌細胞に、完全長fVIIと同等に、又はこれより強力に結合することができる(Hu et al.Cancer Immunology Research.2018)。したがって、本明細書にて開示したTF標的化CARは、ヒトIgG1のヒンジ領域を有しない、又は有し、CD28膜貫通及び細胞質ドメインに結合し、4−1BB及びCD3ζの細胞質ドメインが続き(図1)、TF標的化CAR1モノマー及びダイマー(それぞれ、GenBankアクセッション番号MF806378及びMF806379)という名前の、TF標的化ドメインとしての、ヒト因子VII軽鎖からなる。
本明細書にて開示する主題は、上述のとおり、TF結合ドメインを含むCARを発現する免疫応答細胞を提供する。免疫応答細胞は、細胞がCARを発現するように、本明細書にて開示するCARを形質導入することができる。本明細書にて開示する主題は、トリプルネガティブ乳癌(TNBC)などの、癌治療のためにこのような細胞を用いる方法もまた提供する。本明細書にて開示する主題の免疫応答細胞は、リンパ系リネージの細胞であることができ、一次細胞、又は、健常なドナー、及び/若しくは患者からの、エクスビボで活性化され膨張した細胞であることができる。細胞は、当業者に既知のあらゆる供給元から入手可能である。B、T、及びナチュラルキラー(NK)細胞を含むリンパ系リネージは、抗体の産生、細胞免疫系の制御、血液中での外来作用物質の検出、宿主に対して外来の細胞の検出などをもたらすことができる。
免疫応答細胞(例えばT細胞、CTL細胞、NK細胞)の遺伝子組み換えは、実質的に均質な細胞組成に、組み換えDNA又はRNA構築物を形質導入することにより実施することができる。ベクターは、DNA又はRNA構築物を宿主細胞ゲノムに導入するために用いられる、レトロウイルス(Liu et al.,Leukemia 2018)又はレンチウイルス(Mehta and Rezvani,Front Immunol 2018;Nowakowska et al.,Cancer Immunol Immunother 2018)ベクター(例えばガンマレトロウイルス)であることができる。図1〜4に記載されているレンチウイルスベクター同様に、例えば、TF特異的CARをコードするポリヌクレオチドをレトロウイルスベクターにクローニングすることができ、発現を、その内因性プロモーター、レトロウイルス長末端反復、又は代替の内部プロモーターからもたらすことができる。
本明細書にて開示する主題は、配列内で変化を生み出すことにより、アミノ酸配列又は核酸配列を最適化する方法を提供する。このような変化は、特定の変異、欠失、挿入、又は翻訳後修飾を含むことができる。本明細書にて開示する主題は、本明細書にて開示する主題の、任意の自然発生するポリペプチドの類似体を更に含む。類似体は、本明細書にて開示する主題の自然発生するポリペプチドとは、アミノ酸配列の差、翻訳後修飾、又はその両方が異なっていることができる。本明細書にて開示する主題の類似体は、本明細書にて開示する主題の自然発生するアミノ酸配列の全て又は一部と、少なくとも約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%、又はそれ以上の同一性を一般に示すことができる。配列比較の長さは、少なくとも5、10、15、20、25、50、75、100又はそれ以上のアミノ酸残基である。再び、同一性の程度を測定する例示的なアプローチにおいて、密接に関係した配列を示す、e”3〜e”100の確率スコアと共に、BLASTプログラムを用いることができる。修飾とは、ポリペプチドの、インビボ及びインビトロでの化学誘導体化、例えばアセチル化、カルボキシル化、リン酸化、又はグリコシル化を含み、このような改変は、ポリペプチド合成若しくは処理の間に生じ得る、又は単離した改変酵素による処理の後で生じ得る。類似体はまた、本明細書にて開示する主題の自然発生するポリペプチドとは、一次配列の変更が異なることもできる。これらは、自然、及び(例えば、エタンメチルサルフェートへの照射若しくは曝露によるランダム突然変異誘発から、又は、Sambrook,Fritsch and Maniatis,Molecular Cloning:A Laboratory Manual(2d ed.),CSH Press,1989,若しくはAusubel et al.,supraに記載されている部位特異的突然変異誘発により得られる)誘導の両方である、遺伝多様体を含む。L−アミノ酸以外の残基、例えばD−アミノ酸、又は、自然に生じない、若しくは合成アミノ酸、例えばベータ(β)若しくはガンマ(γ)アミノ酸を含有する、環化ペプチド、分子、及び類似体もまた、含まれる。
CAR−T及びNK細胞治療法は、臨床試験、及び認可済み臨床用途における血液学的悪性腫瘍で評価されており(Luskin et al.Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice.Curr Hematol Malig Rep,2017)、固形癌でもまた転用されている(Morello et al.Mesothelin−Targeted CARs:Driving T Cells to Solid Tumors.Cancer Discov,2016.6(2):p.133−46)。この方法は、効果的な癌免疫治療法に必要な全身性免疫を付与する(Spitzer,M.H.,et al.,Systemic Immunity Is Required for Effective Cancer Immunotherapy.Cell,2017.168(3):p.487−502 e15)だけでなく、腫瘍微小環境におけるT及びNK細胞の、局所性湿潤もまた増加させることができる。この発想と共に、チェックポイント阻害剤、及びCAR−T細胞を、多発性骨髄腫で使用することができる(Gay,F.,et al.,Immuno−oncologic Approaches:CAR−T Cells and Checkpoint Inhibitors.Clin Lymphoma Myeloma Leuk,2017.17(8):p.471−478)。そのために、多発性骨髄腫を使用して、CAR−T治療法とのチェックポイント遮断の併用療法の発想を試験し、腫瘍微小環境内でのT細胞の湿潤を増加させ、耐性を克服することができ、故に、免疫チェックポイント遮断療法の有効性を最適化することができる。
本明細書にて開示する主題のTF特異的CAR、及びこれを発現する免疫応答細胞は、TFに関連する疾患を治療又は予防するために、対象に全身的に、又は直接提供することができる。特定の実施形態において、TF特異的CAR、及びこれを発現する免疫応答細胞は、対象の器官(例えば、癌の影響を受けている器官)に、直接注射される。あるいは、又は更に、TF特異的CAR、及びこれを発現する免疫応答細胞は、例えば、循環系(例えば腫瘍脈管系)への投与により、対象の器官に、間接的に提供される。膨張剤及び分化剤は、細胞及び組成物の投与前、投与中、又は投与後に提供して、インビトロ又はインビボでの、T細胞産生を増加させることができる。
本明細書にて開示する主題の、一般のTF特異的CARを発現する免疫応答細胞、及びこれを含む組成物は、滅菌液調製物、例えば、等張性水溶液、懸濁液、エマルション、分散液、又は粘稠組成物として、便利に提供することができ、これらは、選択されたpHまで緩衝化することができる。脂質調製物は、ゲル、他の粘稠組成物、及び固体組成物よりも、調製が通常容易である。更に、液体組成物は、特に注射により、幾分か投与が便利である。一方、粘稠組成物は、適切な粘度範囲内で製剤化し、特定の組織とより長い時間接触させることができる。脂質又は粘稠組成物は担体を含むことができ、担体は、例えば水、生理食塩水、リン酸緩衝生理食塩水、ポリオール(例えば、グリセロール、プロピレングリコール、液体ポリエチレングリコールなど)、及びこれらの好適な混合物を含有する溶媒又は分散媒であることができる。
本明細書にて開示する主題は、癌などの、TFを発現する疾患の治療又は予防のためのキットを提供する。特定の実施形態において、キットは、単位剤形にTF特異的CARを含む、有効量の免疫応答細胞を含有する治療用又は予防用組成物を含む。特定の実施形態では、細胞は、少なくとも1つの共刺激リガンドを更に発現する。特定の実施形態において、キットは、治療用又は予防用ワクチンを含有する滅菌容器を含み、このような容器は、箱、アンプル、ボトル、バイアル瓶、チューブ、バッグ、パウチ、ブリスターパック、又は、当該技術分野において公知の他の好適な容器形態であることができる。このような容器は、プラスチック、ガラス、ラミネート加工紙、金属箔、又は、薬剤を保持するのに好適な他の材料から製造することができる。
実施例1:TF標的化CAR構築物
CAR構築物をNK及びT細胞に効率良く形質導入するために、CAR1ダイマー及びモノマーcDNA(配列番号1及び2)を、pCDHレンチベクターのマルチクローン部位(MCS)にサブクローニングし、これは、ヒトNK株及びNK92Xの感染に成功した((X.Chenet al.,A combinational therapy of EGFR−CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.Oncotarget 7,27764−27777(2016))。CAR1モノマー及びダイマーのcDNA配列を、Sanger DNA塩基配列決定法により確認し、Genbankに寄託した(アクセッション番号MF806378及びMF806379、配列番号1及び2)。
導入
組織因子(TF)は、標的化免疫療法が欠如することによる、典型的な治癒不可能な悪性疾患である、トリプルネガティブ乳癌(TNBC)に対する、新規であり一般的でありながら、選択的表面腫瘍標的であることが測定された。満たされていない治療の必要性に取り組むために、TNBCのCAR−NK免疫療法のための、TF−CAR1ダイマー及びモノマーとしての、細胞外標的化ドメイン(因子VII軽鎖、fVIIL)と、膜貫通ドメイン(CD28)との間に、(潜在的ホモ二量体化のための)ヒトIgG1のヒンジ領域を有する、又は有しない、fVIIL−CD28−4−1BB−CD3zetaを発現する、TF標的化CAR−NK細胞を、本明細書にて開示する。TF−CAR1−NK細胞は、インビトロでTNBC細胞を殺傷することができ、細胞株由来、及び患者の腫瘍由来の、異種移植片マウスモデルにおけるTNBCの治療に対して効果的であり、かつ安全であることを、結果は表している。
TF標的化CARの設計及び開発において、TFの認識ドメインとして、TFに対する抗体又はscFvの代わりに、TFの天然リガンドである、因子VIIを使用した。まず、TFに対するfVIIの親和性(E.Waxman et al.,Tissue factor and its extracellular soluble domain:the relationship between intermolecular association with factor VIIa and enzymatic activity of the complex.Biochemistry 31,3998−4003(1992))は、TF抗原に対する抗体(L.Presta et al.,Generation of a humanized,high affinity anti−tissue factor antibody for use as a novel antithrombotic therapeutic.Thrombosis and haemostasis 85,379−389(2001))よりも、約100〜1000倍大きい。次に、fVIIは、モノクローナル抗体のヒト化、又はscFvライブラリーのスクリーニングをすることなく、組み換えDNA技術により合成することができる。更に、fVIIの軽鎖(最初の152個のアミノ酸残基)は、TFを発現するヒト及びマウス癌細胞に、完全長fVIIと同等に、又はこれより強力に結合することができることが示されている(Z.Hu et al.,Targeting Tissue Factor for Immunotherapy of Triple−Negative Breast Cancer Using a Second−Generation ICON.Cancer Immunol Res 6,671−684(2018))。したがって、TF標的化CARは、ヒトIgG1のヒンジ領域を有しない、又は有し、CD28膜貫通及び細胞質ドメインに結合し、そして4−1BB及びCD3ζの細胞質ドメインが続き(図1)、TF標的化CAR1モノマー及びダイマー(それぞれ、GenBankアクセッション番号MF806378及びMF806379、配列番号1及び2)という名前の、TF標的化ドメインとしての、ヒト因子VII軽鎖からなる。
細胞免疫療法に対してTFを標的化するために、TF標的化CARベースのレンチウイルスベクターを開発し、ヒトNK株(NK92MI)をTF−CAR1レンチウイルスベクターで感染させることにより、TF−CAR−NK細胞を産生した。各CAR構築物に2つ又は1つのいずれかのTF標的化ドメインを有するCAR1−NK細胞は、同所性CDX及びPDXマウスモデルにおいて、インビトロ及びインビボでTNBCを治療することに対して効果的かつ安全であることが示された。これらのTF−CAR1 NK細胞はCD16も発現するため、TNBCの治療に関して、L−ICON1及び他の治療用抗体との併用療法において、潜在的にL−ICON1−ADCCを媒介することができる。したがって、本研究では、TNBCのCAR−NK細胞免疫療法に対する、TFを標的化する着想の証拠が確立された。TFは、癌だけでなく、病的血管新生依存性及びマクロファージ随伴ヒト疾患においても、選択的に発現される(Z.W.Hu,Therapeutic Antibody−Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis−Dependent as Well as Macrophage−Associated Human Diseases.Antibodies 7,(2018))。新生血管の形成である病的血管新生は、多くの臨床的に重大なヒト疾患、特に癌、加齢関連黄斑変性症(AMD)、子宮内膜症、及び関節リウマチ(RA)に関与している。マクロファージは、様々なヒト疾患、例えばアテローム性動脈硬化症並びにウイルス感染症(ヒト免疫不全ウイルス・HIV及びエボラ)の進行に関与する。TFは、これらの病的血管新生依存性ヒト疾患における血管由来VEC、及び疾患随伴マクロファージにおいて選択的に発現されることが十分に実証されている。CAR−NK及び−T治療法は、これらの血管新生依存性、及びマクロファージ随伴ヒト疾患を治療する能力を持つ新規の治療的アプローチをもたらすため、これらの臨床的に重大なヒト疾患に対する治療レジメンに、幅広く影響を及ぼすことができる。
細胞株
チャイニーズハムスター卵巣細胞(CHO−K1)及びNK92MIを、アメリカ合衆国培養細胞系統保存機関(ATCC,Manassas,VA)から、それぞれ2004年と2007年に購入した。CHO−K1は、10%加熱不活性化ウシ胎児血清(HI−FBS)(Sigma)、並びに1×ペニシリン及びストレプトマイシン(Invitrogen)を補充した、F12K完全増殖培地(ATCC)で増殖させた。293TN(SBI)、293FT(Invitrogen)、及び293AD(Cell Biolabs)を商業供給元から購入し、レンチウイルスベクター産生のため、DMEM完全増殖培地で増殖させた。ヒトTNBC細胞株MDA−MB−231(BRCA1−wt、BRCA2−変異)を、ATCCから2009年に購入し、10%HI−FBS、並びに1×ペニシリン及びストレプトマイシン(Invitrogen)を補充したL−15完全増殖培地で増殖させた。培養物を年に一度、マイコプラズマ汚染について試験した。Mycoalert Mycoplasma Detection Kit(Lonza,カタログ番号LT07−118)を用いてこの汚染を試験した最近の日付は、2017年6月26日であった。フローサイトメトリー、ウェスタンブロット、及び/又は細胞ELISAによりTF発現を検証することにより、癌細胞株の真偽を測定した。
TF標的化CAR1ダイマー及びモノマー構築物を、ヒトIgG1ヒンジ領域(CAR1のホモ二量体を形成するため)を有する、又はヒンジ領域(モノマーCAR1として)を有しない、ヒト因子VII軽鎖を(TF認識ドメインとして)、その後、CD28膜貫通及び細胞質ドメイン、4−1BB及びCD3zetaをコードするように、設計した。cDNA構築物を個別対応で、System Biosciences(SBI)のレンチウイルスシャトルベクターpCDH(SBIカタログ番号CD713B)内に合成した。TF標的化CAR1モノマー及びダイマーのcDNA配列を、Sanger DNA塩基配列決定法により検証し、それぞれ、アクセッション番号MF806378及びMF806379で、Genbankに寄託した。CAR1ダイマー及びモノマーをコードするレンチウイルスを、メーカーの指示に従い、PurFectionトランスフェクション試薬を用いて、pCDH−CAR1及びpPACKH1(SBI)と共に293TN(System Biosciences)に同時トランスフェクションすることにより産生した。細胞培養上清中のレンチウイルスを48及び72時間で回収し、上清(SNT)中で、非濃縮ウイルス粒子として使用した、又は、PEG−it試薬(SBI)を使用して濃縮した。
メーカーの指示に従い、細胞に、TransDUX及びMAX Enhancer(SBI)の存在下において、レンチウイルスを感染させた。要約すると、付着細胞又は懸濁細胞のいずれかの、ウェルあたり50,000個の細胞を、細胞培養培地の24ウェルプレートに播種する。翌日、2.5μLのTransDux(SBI)、100μLのMAX Enhancer、及び400μLの培地を含有する、500μL感染培地で細胞培養培地を交換し、その後、各ウェルに150μLの293TNレンチウイルス含有上清(SNT)を添加し、撹拌混合した。形質導入の72時間後、ウイルスゲノムを宿主細胞ゲノムに組み込み、細胞を、5μg/mLのピューロマイシン及び100ng/mLのハイグロマイシンを補充した完全増殖培地に移して増殖させ、安定した細胞株を確立する、又は後の実験で用いる。
RT−PCR及びウェスタンブロットを実施し、レンチウイルス感染、又はプラスミドトランスフェクション済みの細胞にて、CAR1及びCD16の発現を検証した。TriZol Reagent(Invitrogen)を使用して、NK92MI/fCD16対照、CAR1ダイマー及びモノマー細胞から、全てのRNAを抽出した。One−Step RT−PCRキット(New England Biolabs,カタログNo.E5315)、及び対応するプライマーを使用して、CAR1、CD16、及びβアクチンのRT−PCRを行い、アガロースゲル電気泳動により分析した。
CytoTox均質アッセイキット(Promega)を使用して、細胞傷害アッセイを試験した。ヒトTNBC MDA−MB−231細胞(標的細胞)を、96ウェルU底組織培養物処理済みマイクロプレート内の、10%加熱不活性化FBSを補充した100μLのMEMα増殖培地内で、ウェルあたり10,000個の細胞で一晩播種した。翌朝、50μLの培地を各ウェルから取り出した。NK92MI/fCD16を発現するCAR1ダイマー、モノマー、又は非感染対照(エフェクター細胞として)を、ADCCエフェクターアッセイ培地(0.5%の超低IgG HIーFBSを含むDMEM)に再懸濁し、10:1及び5:1のE:T比で、ウェルに添加した。5% CO2及び37℃にて4時間インキュベーションした後、300×gで5分間、マイクロプレートを遠心分離し、新しい96ウェル平底マイクロプレートに、50μLの上清を移した。細胞傷害アッセイ溶液を添加し(ウェルあたり50μL)て37Cで30分間インキュベートした後、メーカーの指示に従い停止溶液を添加した。490nmでの吸光度を、マイクロプレート読み取り機(Molecular Devices,i3)で読み取った。
1.U.Sturm et al.,Immunohistological detection of tissue factor in normal and abnormal human mammary glands using monoclonal antibodies.Virchows Archiv 421,79−86(1992).
2.J.Contrino,G.Hair,D.L.Kreutzer,F.R.Rickles,In situ detection of tissue factor in vascular endothelial cells:correlation with the malignant phenotype of human breast disease.Nat Med 2,209−215(1996).
3.T.Ueno,M.Toi,M.Koike,S.Nakamura,T.Tominaga,Tissue factor expression in breast cancer tissues:its correlation with prognosis and plasma concentration.British journal of cancer 83,164−170(2000).
4.J.Duanmu,J.Cheng,J.Xu,C.J.Booth,Z.Hu,Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII−targeted photodynamic therapy.British journal of cancer 104,1401−1409(2011).
5.Z.Hu et al.,Targeting Tissue Factor for Immunotherapy of Triple−Negative Breast Cancer Using a Second−Generation ICON.Cancer Immunol Res,(2018).
6.T.Kageshita et al.,Tissue factor expression and serum level in patients with melanoma does not correlate with disease progression.Pigment Cell Res 14,195−200(2001).
7.Z.Hu,Y.Sun,A.Garen,Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model.Proceedings of the National Academy of Sciences of the United States of America 96,8161−8166(1999).
8.M.Shoji et al.,Activation of coagulation and angiogenesis in cancer:immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.The American journal of pathology 152,399−411(1998).
9.R.Koomagi,M.Volm,Tissue−factor expression in human non−small−cell lung carcinoma measured by immunohistochemistry:correlation between tissue factor and angiogenesis.International journal of cancer 79,19−22(1998).
10.M.Sawada et al.,Expression of tissue factor in non−small−cell lung cancers and its relationship to metastasis.British journal of cancer 79,472−477(1999).
11.B.Wang et al.,Radiotherapy of human xenograft NSCLC tumors in nude mice with a 90Y−labeled anti−tissue factor antibody.Cancer biotherapy&radiopharmaceuticals 20,300−309(2005).
12.P.Goldin−Lang et al.,Tissue factor expression pattern in human non−small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis.Oncol Rep 20,123−128(2008).
13.R.T.Poon et al.,Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma.Clin Cancer Res 9,5339−5345(2003).
14.T.Kaido et al.,Tissue factor is a useful prognostic factor of recurrence in hepatocellular carcinoma in 5−year survivors.Hepato−gastroenterology 52,1383−1387(2005).
15.A.K.Kakkar,N.R.Lemoine,M.F.Scully,S.Tebbutt,R.C.Williamson,Tissue factor expression correlates with histological grade in human pancreatic cancer.The British journal of surgery 82,1101−1104(1995).
16.N.Nitori et al.,Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma.Clin Cancer Res 11,2531−2539(2005).
17.A.A.Khorana et al.,Tissue factor expression,angiogenesis,and thrombosis in pancreatic cancer.Clin Cancer Res 13,2870−2875(2007).
18.C.Shigemori et al.,Tissue factor expression and metastatic potential of colorectal cancer.Thromb Haemost 80,894−898(1998).
19.T.Nakasaki et al.,Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer.Am J Hematol 69,247−254(2002).
20.D.F.Altomare et al.,Tissue factor and vascular endothelial growth factor expression in colorectal cancer:relation with cancer recurrence.Colorectal Dis 9,133−138(2007).
21.S.A.Abdulkadir et al.,Tissue factor expression and angiogenesis in human prostate carcinoma.Hum Pathol 31,443−447(2000).
22.T.Akashi,Y.Furuya,S.Ohta,H.Fuse,Tissue factor expression and prognosis in patients with metastatic prostate cancer.Urology 62,1078−1082(2003).
23.V.Kaushal et al.,Expression of tissue factor in prostate cancer correlates with malignant phenotype.Appl Immunohistochem Mol Morphol 16,1−6(2008).
24.Z.Hu,A.Garen,Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer.Proceedings of the National Academy of Sciences of the United States of America 98,12180−12185(2001).
25.K.Uno et al.,Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer.British journal of cancer 96,290−295(2007).
26.K.Hamada et al.,Expression of tissue factor correlates with grade of malignancy in human glioma.Cancer 77,1877−1883(1996).
27.S.Takano,K.Tsuboi,Y.Tomono,Y.Mitsui,T.Nose,Tissue factor,osteopontin,alphavbeta3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression.British journal of cancer 82,1967−1973(2000).
28.M.Guan,J.Jin,B.Su,W.W.Liu,Y.Lu,Tissue factor expression and angiogenesis in human glioma.Clin Biochem 35,321−325(2002).
29.J.Thaler et al.,Intratumoral tissue factor expression and risk of venous thromboembolism in brain tumor patients.Thromb Res 131,162−165(2013).
30.F.R.Rickles,G.A.Hair,R.A.Zeff,E.Lee,R.D.Bona,Tissue factor expression in human leukocytes and tumor cells.Thromb Haemost 74,391−395(1995).
31.K.Andoh et al.,Tissue factor activity in leukemia cells.Special reference to disseminated intravascular coagulation.Cancer 59,748−754(1987).
32.K.A.Bauer et al.,Tissue factor gene expression in acute myeloblastic leukemia.Thromb Res 56,425−430(1989).
33.H.Tanaka et al.,Studies on leukemic cell tissue factor.Thromb Res 53,535−549(1989).
34.M.Tanaka,T.Kishi,Induction of tissue factor by interleukin−2 in acute myelogenous leukemia(AML)cells.Growth Factors 4,1−8(1990).
35.M.Tanaka,H.Yamanishi,The expression of tissue factor antigen and activity on the surface of leukemic cells.Leuk Res 17,103−111(1993).
36.T.Nakasaki et al.,Elevated tissue factor levels in leukemic cell homogenate.Clin Appl Thromb Hemost 6,14−17(2000).
37.T.Kubota,K.Andoh,H.Sadakata,H.Tanaka,N.Kobayashi,Tissue factor released from leukemic cells.Thromb Haemost 65,59−63(1991).
38.T.Nakasaki et al.,Decreased tissue factor and tissue−plasminogen activator antigen in relapsed acute promyelocytic leukemia.Am J Hematol 64,145−150(2000).
39.Y.Zhang et al.,Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor−induced tissue factor expression and fibrin deposition in mouse meth−A sarcoma.J Clin Invest 97,2213−2224(1996).
40.J.G.Bledsoe,S.M.Slack,Tissue factor expression by rat osteosarcoma cells adherent to tissue culture polystyrene and selected orthopedic biomaterials.J Biomater Sci Polym Ed 9,1305−1312(1998).
41.Y.M.Zhang et al.,Vascular origin of Kaposi’s sarcoma.Expression of leukocyte adhesion molecule−1,thrombomodulin,and tissue factor.The American journal of pathology 144,51−59(1994).
42.G.Cesarman−Maus,E.Braggio,C.Lome−Maldonado,A.L.Morales−Leyte,R.Fonseca,Absence of tissue factor is characteristic of lymphoid malignancies of both T−and B−cell origin.Thromb Res 133,606−609(2014).
43.Gupta et al.’Tissue Factor Is Frequently Expressed in Multiple Myeloma Cells.Blood’2009’114:2132;Abstract 2132
配列番号1:TF標的化CAR1モノマー
GCTAGCGCCACCATGGTCTCCCAGGCCCTCAGGCTCCTCTGCCTTCTGCTTGGGCTTCAGGGCTGCCTGGCTGCAGTCTTCGTAACCCAGGAGGAAGCCCACGGCGTCCTGCACCGGCGCCGGCGCGCCAACGCGTTCCTGGAGGAGCTGCGGCCGGGCTCCCTGGAGAGGGAGTGCAAGGAGGAGCAGTGCTCCTTCGAGGAGGCCCGGGAGATCTTCAAGGACGCGGAGAGGACGAAGCTGTTCTGGATTTCTTACAGTGATGGTGACCAGTGTGCCTCAAGTCCATGCCAGAATGGGGGCTCCTGCAAGGACCAGCTCCAGTCCTATATCTGCTTCTGCCTCCCTGCCTTCGAGGGCCGGAACTGTGAGACGCACAAGGATGACCAGCTGATCTGTGTGAACGAGAACGGCGGCTGTGAGCAGTACTGCAGTGACCACACGGGCACCAAGCGCTCCTGTCGGTGCCACGAGGGGTACTCTCTGCTGGCAGACGGGGTGTCCTGCACACCCACAGTTGAATATCCATGTGGAAAAATACCTATTCTAGAAAAAAGAAATGCCAGCAAGCCCCAAGGGCGAGGATCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCTTCGAACGTTTCTCTGTTGTTAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGAATTCAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTGAGTTTAAACGCGGCCGC
CAR1モノマー(hfVIIL−CD28−4−1BB−CD3zeta)の図
NheI−Kozak−fVII軽鎖(開始コドン+シグナル+成熟fVII軽鎖)−BamHI−CD28(TM+CD)−BstBI−4−1BB−EcoRI−CD3zeta CD−Stopコドン−PmeI−<u>NotI
</u> 配列番号2:TF標的化CAR1ダイマー
GCTAGCGCCACCATGGTCTCCCAGGCCCTCAGGCTCCTCTGCCTTCTGCTTGGGCTTCAGGGCTGCCTGGCTGCAGTCTTCGTAACCCAGGAGGAAGCCCACGGCGTCCTGCACCGGCGCCGGCGCGCCAACGCGTTCCTGGAGGAGCTGCGGCCGGGCTCCCTGGAGAGGGAGTGCAAGGAGGAGCAGTGCTCCTTCGAGGAGGCCCGGGAGATCTTCAAGGACGCGGAGAGGACGAAGCTGTTCTGGATTTCTTACAGTGATGGTGACCAGTGTGCCTCAAGTCCATGCCAGAATGGGGGCTCCTGCAAGGACCAGCTCCAGTCCTATATCTGCTTCTGCCTCCCTGCCTTCGAGGGCCGGAACTGTGAGACGCACAAGGATGACCAGCTGATCTGTGTGAACGAGAACGGCGGCTGTGAGCAGTACTGCAGTGACCACACGGGCACCAAGCGCTCCTGTCGGTGCCACGAGGGGTACTCTCTGCTGGCAGACGGGGTGTCCTGCACACCCACAGTTGAATATCCATGTGGAAAAATACCTATTCTAGAAAAAAGAAATGCCAGCAAGCCCCAAGGGCGAGGATCCGCAGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGGATCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCTTCGAACGTTTCTCTGTTGTTAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGAATTCAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTGAGTTTAAACGCGGCCGC
hfVIIL−ヒンジ−CD28−4−1BB−CD3zetaの図
NheI−Kozak−fVII軽鎖(開始コドン+シグナル+成熟fVII軽鎖)−BamHI*−hIgG1ヒンジ−BamHI*−CD28(TM+CD)−BstBI−4−1BB−EcoRI−CD3zeta CD−Stopコドン−PmeI−<u>NotI
</u> TM:膜貫通ドメイン。CD:細胞質ドメイン。NheI、BamHI、BstBI、EcoRI、PmeI、及びNotI:制限酵素は、個々の認識及びシグナル伝達断片を、プラスミド構築物に分子サブクローニングするために使用し、CARシグナル伝達断片の改変、例えば、4−1BBのOX40(TF標的化CAR2)での置き換え、又は、第四世代のCAR(TF標的化CAR3)として、OX40をCAR1に付加することを可能にする。
配列番号3:ヒト凝固因子VII軽鎖のcDNA配列
ATGGTCTCCCAGGCCCTCAGGCTCCTCTGCCTTCTGCTTGGGCTTCAGGGCTGCCTGGCTGCAGTCTTCGTAACCCAGGAGGAAGCCCACGGCGTCCTGCACCGGCGCCGGCGCGCCAACGCGTTCCTGGAGGAGCTGCGGCCGGGCTCCCTGGAGAGGGAGTGCAAGGAGGAGCAGTGCTCCTTCGAGGAGGCCCGGGAGATCTTCAAGGACGCGGAGAGGACGAAGCTGTTCTGGATTTCTTACAGTGATGGTGACCAGTGTGCCTCAAGTCCATGCCAGAATGGGGGCTCCTGCAAGGACCAGCTCCAGTCCTATATCTGCTTCTGCCTCCCTGCCTTCGAGGGCCGGAACTGTGAGACGCACAAGGATGACCAGCTGATCTGTGTGAACGAGAACGGCGGCTGTGAGCAGTACTGCAGTGACCACACGGGCACCAAGCGCTCCTGTCGGTGCCACGAGGGGTACTCTCTGCTGGCAGACGGGGTGTCCTGCACACCCACAGTTGAATATCCATGTGGAAAAATACCTATTCTAGAAAAAAGAAATGCCAGCAAGCCCCAAGGGCGA
配列番号4:38個のアミノ酸シグナルペプチド(下線)に、152個の成熟fVII軽鎖ペプチドが続く
MVSQALRLLC LLLGLQGCLA AVFVTQEEAH GVLHRRRRAN AFLEELRPGS LERECKEEQC SFEEAREIFK DAERTKLFWI SYSDGDQCAS SPCQNGGSCK DQLQSYICFC LPAFEGRNCE THKDDQLICV NENGGCEQYC SDHTGTKRSC RCHEGYSLLA DGVSCTPTVE YPCGKIPILE KRNASKPQGR //
1. Hu,Y.,Tian,Z.G.,and Zhang,C.(2018).Chimeric antigen receptor(CAR)−transduced natural killer cells in tumor immunotherapy.Acta Pharmacol Sin 39,167−176.
2. Liu,E.,Tong,Y.,Dotti,G.,Shaim,H.,Savoldo,B.,Mukherjee,M.,Orange,J.,Wan,X.,Lu,X.,Reynolds,A.,et al.(2018).Cord blood NK cells engineered to express IL−15 and a CD19−targeted CAR show long−term persistence and potent antitumor activity.Leukemia 32,520−531.
3. Mehta,R.S.,and Rezvani,K.(2018).Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer.Front Immunol 9,283.
4. Nowakowska,P.,Romanski,A.,Miller,N.,Odendahl,M.,Bonig,H.,Zhang,C.,Seifried,E.,Wels,W.S.,and Tonn,T.(2018).Clinical grade manufacturing of genetically modified,CAR−expressing NK−92 cells for the treatment of ErbB2−positive malignancies.Cancer Immunol Immunother 67,25−38.
5. Adorno−Cruz et al.,Cancer stem cells:targeting the roots of cancer,seeds of metastasis,and sources of therapy resistance.Cancer research 75,924−929(2015).
6. Afuwape,et al.,The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis.Histology and histopathology,17(3):961−972(2002).
7. Anders,et al.,Biology,metastatic patterns,and treatment of patients with triple−negative breast cancer.Clinical breast cancer 9 Suppl 2,S73−81(2009).
8. Bayraktar,et al.,Molecularly targeted therapies for metastatic triple−negative breast cancer.Breast cancer research and treatment 138,21−35(2013).
9. Berrada,et al.,Treatment of triple−negative metastatic breast cancer:toward individualized targeted treatments or chemosensitization? Annals of oncology:official journal of the European Society for Medical Oncology / ESMO 21 Suppl 7,vii30−35(2010).
10. Bora et al.,Immunotherapy for choroidal neovascularization in a laser−induced mouse model simulating exudative(wet)macular degeneration.Proceedings of the National Academy of Sciences of the United States of America 100,2679−2684(2003).
11. Bromberg,et al.,Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation.Proceedings of the National Academy of Sciences of the United States of America 92,8205−8209(1995).
12. Caine,et al.,The hypercoagulable state of malignancy:pathogenesis and current debate.Neoplasia 4,465−473(2002).
13. Callander,et al.,Immunohistochemical identification of tissue factor in solid tumors.Cancer 70,1194−1201(1992).
14. Chen et al.,A combinational therapy of EGFR−CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.Oncotarget 7,27764−27777(2016).
15. Cheng et al.,Effective Treatment of Human Lung Cancer by Targeting Tissue Factor with a Factor VII−Targeted Photodynamic Therapy.Curr Cancer Drug Targets 11,1069−1081(2011).
16. Clarke et al.,Cancer stem cells−−perspectives on current status and future directions:AACR Workshop on cancer stem cells.Cancer research 66,9339−9344(2006).
17. Contrino,et al.,In situ detection of tissue factor in vascular endothelial cells:correlation with the malignant phenotype of human breast disease.Nature medicine 2(2):209−215(1996).
18. Contrino,et al.,In situ characterization of antigenic and functional tissue factor expression in human tumors utilizing monoclonal antibodies and recombinant factor VIIa as probes.Am J Pathol 145,1315−1322(1994).
19. Duanmu,et al.,Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII−targeted photodynamic therapy.British journal of cancer.104(9):1401−1409(2011).
20. El Guerrab et al.,Differential impact of EGFR−targeted therapies on hypoxia responses:implications for treatment sensitivity in triple−negative metastatic breast cancer.PloS one 6,e25080(2011).
21. Ferrandina,et al.,Targeting CD133 antigen in cancer.Expert Opin Ther Targets 13,823−837(2009).
22. Ferrara N.VEGF and the quest for tumour angiogenesis factors.Nature reviews Cancer.2(10):795−803(2002).
23. Folkman,Tumor angiogenesis and tissue factor.Nat Med 2,167−168(1996).
24. Fujimoto,et al.,Angiogenesis in endometriosis and angiogenic factors.Gynecologic and obstetric investigation 48 Suppl 1:14−20(1999).
25. Hu et al.,Tissue factor is an angiogenic−specific receptor for factor VII−targeted immunotherapy and photodynamic therapy.Angiogenesis(2016).
26. Hu,et al.,Factor VII−Targeted Photodynamic Therapy for Breast Cancer and Its Therapeutic Potential for Other Solid Cancers and Leukemia,Breast Cancer−Current and Alternative Therapeutic Modalities,Esra Gunduz and Mehmet Gunduz(Ed.),ISBN:978−953−307−776−5,InTech,E.Gunduz,GunduzM.Ed.Breast Cancer−Current and Alternative Therapeutic Modalities(InTech,2011),pp.175−196.
27. Hu,et al.,Intratumoral injection of adenoviral vectors encoding tumor−targeted immunoconjugates for cancer immunotherapy.Proceedings of the National Academy of Sciences of the United States of America 97,9221−9225(2000).
28. Hu,et al.,Natural killer cells are crucial for the efficacy of Icon(factor VII/human IgG1 Fc)immunotherapy in human tongue cancer.BMC immunology 11,49(2010).
29. Hu,et al.,Selective and effective killing of angiogenic vascular endothelial cells and cancer cells by targeting tissue factor using a factor VII−targeted photodynamic therapy for breast cancer.Breast cancer research and treatment 126(3):589−600(2011).
30. Hu,et al.,Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines,tumor xenografts and patients of breast,lung and ovarian cancer.Oncotarget,(2016).
31. Hu,et al.,Targeting Tissue Factor for Immunotherapy of Triple−Negative Breast Cancer Using a Second−Generation ICON.Cancer Immunol Res 6,671−684(2018).
32. Hu,et al.,Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer.Proc Natl Acad Sci U S A 98,12180−12185(2001).
33. Hu,et al.,Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII−targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice.BMC cancer 10:235(2010).
34. Hu,et al.,Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model.Proceedings of the National Academy of Sciences of the United States of America 96,8161−8166(1999).
35. Hu,et al.,Therapeutic Antibody−Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis−Dependent as Well as Macrophage−Associated Human Diseases.Antibodies 7,(2018).
36. Hu,et al.,Tissue factor is an angiogenic−specific receptor for factor VII−targeted immunotherapy and photodynamic therapy.Angiogenesis 20,85−96(2017).
37. Hudis,et al.,Triple−negative breast cancer:an unmet medical need.The oncologist 16 Suppl 1,1−11(2011).
38. Hufnagel et al.,Icon immunoconjugate treatment results in regression of red lesions in a non−human primate(Papio anubis)model of endometriosis.Reprod Biol 18109−114(2018).
39. Jemal et al.,Global cancer statistics.CA:a cancer journal for clinicians 61,69−90(2011).
40. Kassam et al.,Survival outcomes for patients with metastatic triple−negative breast cancer:implications for clinical practice and trial design.Clinical breast cancer 9,29−33(2009).
41. Kasthuri,M.B.Taubman,N.Mackman,Role of tissue factor in cancer.J Clin Oncol 27,4834−4838(2009).
42. Kim,et al.Mapping the site on human IgG for binding of the MHC class I−related receptor,FcRn.European journal of immunology 29,2819−2825,doi:10.1002/(SICI)1521−4141(199909)29:09&#60;2819::AID−IMMU2819&#62;3.0.CO;2−6(1999).
43. Klagsbrun,et al.,Purification of endothelial cell growth factors by heparin affinity chromatography.Methods in enzymology 147:95−105(1987).
44. Koch,et al.,Cancer stem cells at the crossroads of current cancer therapy failures−−radiation oncology perspective.Seminars in cancer biology 20(2):116−124(2010).
45. Konigsberg,et al.,Molecular cloning of the cDNA for human tissue factor.Cell 52(5):639−640(1988).
46. Krikun et al.,The immunoconjugate’icon’targets aberrantly expressed endothelial tissue factor causing regression of endometriosis.Am J Pathol 176,1050−1056(2010).
47. Liedtke,et al.,Current Issues of Targeted Therapy in Metastatic Triple−Negative Breast Cancer.Breast care 6,234−239(2011).
48. Lopez−Pedrera,et al.,Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies.Leukemia 20,1331−1340(2006).
49. Lykke,e al.,The role of tissue factor in colorectal cancer.Eur J Surg Oncol 29,417−422(2003).
50. Milsom et al.,Tissue factor and cancer stem cells:is there a linkage? Arterioscler Thromb Vasc Biol 29,2005−2014(2009).
51. Moncharmont,et al.,Targeting a cornerstone of radiation resistance:cancer stem cell.Cancer letters 322(2):139−147(2012).
52. Montero,et al.,Bevacizumab in the treatment of metastatic breast cancer:friend or foe? Current oncology reports 14,1−11(2012).
53. Morrissey,et al.,Molecular cloning of the cDNA for tissue factor,the cellular receptor for the initiation of the coagulation protease cascade.Cell 50,129−135(1987).
54. Mousa,Role of current and emerging antithrombotics in thrombosis and cancer.Timely topics in medicine.Cardiovascular diseases 10,E19(2006).
55. Nemerson,Tissue factor and the initiation of blood coagulation.Advances in experimental medicine and biology 214:83−94(1987).
56. Nemerson,Tissue factor and hemostasis.Blood 71,1−8(1988).
57. Osterud,Tissue factor:a complex biological role.Thrombosis and haemostasis 78,755−758(1997).
58. Paszkiewicz,et al.,Targeted antibody−mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia.J Clin Invest 126,4262−4272(2016).
59. Peitzsch,Aet al.,Cancer stem cells:The root of tumor recurrence and metastases.Semin Cancer Biol 44,10−24(2017).
60. Penka,[Activation of blood coagulation in oncology patients].Vnitrni lekarstvi 43,337−339(1997).
61. Phillips,et al.,The response of CD24(−/low)/CD44+breast cancer−initiating cells to radiation.Journal of the National Cancer Institute 98,1777−1785(2006).
62. Presta et al.,Generation of a humanized,high affinity anti−tissue factor antibody for use as a novel antithrombotic therapeutic.Thrombosis and haemostasis 85,379−389(2001).
63. Rak,et al.,Tissue factor in cancer and angiogenesis:the molecular link between genetic tumor progression,tumor neovascularization,and cancer coagulopathy.Seminars in thrombosis and hemostasis 32,54−70(2006).
64. Rakha,et al.,Metastatic triple−negative breast cancer.Clinical oncology 23,587−600(2011).
65. Rao,et al.,Tissue factor on cells.Blood Coagul Fibrinolysis 9 Suppl 1,S27−35(1998).
66. Rickles,et al.,The role of the hemostatic system in tumor growth,metastasis,and angiogenesis:tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer.Int J Hematol 73,145−150(2001).
67. Ruf,et al.,Tissue factor and cell signalling in cancer progression and thrombosis.J Thromb Haemost 9 Suppl 1,306−315(2011).
68. Semeraro,et al.,Tissue factor in health and disease.Thrombosis and haemostasis 78,759−764(1997).
69. Sheridan et al.,CD44+/CD24−breast cancer cells exhibit enhanced invasive properties:an early step necessary for metastasis.Breast Cancer Res 8,R59(2006).
70. Spicer,et al.,Isolation of cDNA clones coding for human tissue factor:primary structure of the protein and cDNA.Proceedings of the National Academy of Sciences of the United States of America 84(15)5148−5152(1987).
71. Stapleton,et al.Competition for FcRn−mediated transport gives rise to short half−life of human IgG3 and offers therapeutic potential.Nature communications 2,599,doi:101038/ncomms1608(2011).
72. Tam,et al.,Characterization of genetically altered,interleukin 2−independent natural killer cell lines suitable for adoptive cellular immunotherapy.Hum Gene Ther 10,1359−1373(1999).
73. Tang,et al.,Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells.Cancer Gene Ther 14,346−353(2007).
74. Tezel,et al.,Targeting tissue factor for immunotherapy of choroidal neovascularization by intravitreal delivery of factor VII−Fc chimeric antibody.Ocul Immunol Inflamm 15,3−10(2007).
75. Versteeg,et al.,Tissue factor and cancer metastasis:the role of intracellular and extracellular signaling pathways.Mol Med 10,6−11(2004).
76. Vidal,et al.,Targeting cancer stem cells to suppress acquired chemotherapy resistance.Oncogene 33(36),4451−4463(2014).
77. Waxman,et al.,Tissue factor and its extracellular soluble domain:the relationship between intermolecular association with factor VIIa and enzymatic activity of the complex.Biochemistry 31,3998−4003(1992).
78. Yoshida,How to eliminate MYCN−positive hepatic cancer stem cells to prevent the recurrence? Proceedings of the National Academy of Sciences of the United States of America 115,E6388−E6389(2018).
Claims (23)
- キメラ抗原受容体(CAR)を含む組成物であって、前記CARが組織因子(TF)結合ドメインを含む、組成物。
- 前記TF結合ドメインが因子VII(fVII)又はその断片を含み、前記断片が、TFを認識するのに十分な長さである、請求項1に記載の組成物。
- 前記TF結合ドメインが、重鎖(VH)、軽鎖(VL)、又は一本鎖可変断片(scFv)などの可変断片を含む、請求項1又は2に記載の組成物。
- 前記CARが膜貫通ドメインを更に含む、請求項1〜3のいずれか一項に記載の組成物。
- 前記膜貫通ドメインがCD28を含む、請求項4に記載の組成物。
- 前記CARが1つ以上の細胞質ドメインを更に含む、請求項1〜5のいずれか一項に記載の組成物。
- 前記細胞質ドメインが4−1BBを含む、請求項6に記載の組成物。
- 細胞質ドメインがCD3ζを含む、請求項6又は7に記載の組成物。
- 前記CARがヒンジ領域を更に含む、請求項1〜8のいずれか一項に記載の組成物。
- 前記ヒンジ領域がヒトIgG1に由来する、請求項6に記載の組成物。
- 前記組成物が組織因子(TF)を標的化する、請求項1に記載の組成物。
- 因子VIIが軽鎖因子VIIを含む、請求項1に記載の組成物。
- 軽鎖fVIIが配列番号4を含む、請求項12に記載の組成物。
- 前記CARタンパク質が、配列番号1を含む核酸によりコードされる、請求項1に記載の組成物。
- 前記CARタンパク質が、配列番号2を含む核酸によりコードされる、請求項1に記載の組成物。
- 前記CARが免疫エフェクター細胞内で発現する、請求項1に記載の組成物。
- 前記免疫エフェクター細胞がNK細胞、NK−T細胞、サイトカイン誘導キラー細胞、腫瘍浸潤リンパ球(TILS)、骨髄浸潤リンパ球、及び/又はγδ T細胞である、請求項16に記載の組成物。
- 前記fVII又はその断片が、ヒトに由来する、マウスに由来する、又はヒトfVIIとマウスfVIIとの組み合わせである、請求項2に記載の組成物。
- 疾患の治療を必要とする対象における、疾患の治療方法であって、前記対象に、有効量の請求項16に記載の細胞を投与することを含む、方法。
- 前記疾患が、組織因子(TF)発現と関連している、請求項19に記載の方法。
- 前記疾患が、血管化(若しくは充実性)腫瘍を伴う病理学的新生血管、関節リウマチ、子宮内膜症、リンパ腫、白血病、肉腫、若しくは黄斑変性症、又は、アテローム性動脈硬化症におけるマクロファージなどの、TFを発現する疾患細胞を含む、請求項19に記載の方法。
- 免疫エフェクター細胞が、治療を必要とする患者に由来する、請求項21に記載の方法。
- 治療を必要とする対象の治療方法であって、前記方法が、キメラ抗原受容体(CAR)改変免疫細胞であり、前記CARがfVII又はその断片を含む、免疫細胞を産生することと、対象から免疫細胞を誘導することと、前記免疫細胞を前記CARで改変することと、前記対象に、前記CAR改変免疫細胞を投与することにより、前記対象を治療することと、を含む、方法。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003504315A (ja) * | 1999-07-01 | 2003-02-04 | エール ユニバーシティ | 血管新生標的免疫複合体 |
WO2004006962A2 (en) * | 2002-07-12 | 2004-01-22 | Novo Nordisk A/S | A tissue factor binding immunoconjugate comprising factor viia |
CN102875685A (zh) * | 2012-09-29 | 2013-01-16 | 郑骏年 | 嵌合抗原受体hFⅦL-CD8-OX40-CD3ζ及其用途 |
JP2013534427A (ja) * | 2010-07-09 | 2013-09-05 | バイオジェン アイデック ヘモフィリア インコーポレイテッド | キメラの凝固因子 |
WO2016174461A1 (en) * | 2015-04-30 | 2016-11-03 | Ucl Business Plc | T cell which expresses a gamma-delta t cell receptor (tcr) and a chimeric antigen receptor (car) |
WO2016210447A1 (en) * | 2015-06-26 | 2016-12-29 | University Of Southern California | Masking chimeric antigen receptor t cells for tumor-specific activation |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6924359B1 (en) * | 1999-07-01 | 2005-08-02 | Yale University | Neovascular-targeted immunoconjugates |
US8759292B2 (en) * | 2006-02-03 | 2014-06-24 | Prolor Biotech, Llc | Long-acting coagulation factors and methods of producing same |
EP4032552B1 (en) * | 2008-08-26 | 2023-10-04 | City of Hope | Method and compositions for enhanced anti-tumor effector functioning of t cells |
US8716448B2 (en) * | 2009-02-03 | 2014-05-06 | Amunix Operating Inc. | Coagulation factor VII compositions and methods of making and using same |
MX2018000869A (es) * | 2015-07-22 | 2018-07-06 | Iconic Therapeutics Inc | Metodos para tratar trastornos asociados con la angiogenesis y la neovascularizacion. |
JP7155144B2 (ja) * | 2017-03-14 | 2022-10-18 | オハイオ・ステイト・イノベーション・ファウンデーション | 組織因子標的化IgG3免疫複合体に関連する方法及び組成物 |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003504315A (ja) * | 1999-07-01 | 2003-02-04 | エール ユニバーシティ | 血管新生標的免疫複合体 |
WO2004006962A2 (en) * | 2002-07-12 | 2004-01-22 | Novo Nordisk A/S | A tissue factor binding immunoconjugate comprising factor viia |
JP2013534427A (ja) * | 2010-07-09 | 2013-09-05 | バイオジェン アイデック ヘモフィリア インコーポレイテッド | キメラの凝固因子 |
CN102875685A (zh) * | 2012-09-29 | 2013-01-16 | 郑骏年 | 嵌合抗原受体hFⅦL-CD8-OX40-CD3ζ及其用途 |
WO2016174461A1 (en) * | 2015-04-30 | 2016-11-03 | Ucl Business Plc | T cell which expresses a gamma-delta t cell receptor (tcr) and a chimeric antigen receptor (car) |
WO2016210447A1 (en) * | 2015-06-26 | 2016-12-29 | University Of Southern California | Masking chimeric antigen receptor t cells for tumor-specific activation |
Non-Patent Citations (2)
Title |
---|
ONCOTARGET (2017) VOL.8, NO.35,PP.59086-59102, JPN6022034596, ISSN: 0004854399 * |
ONCOTARGET (2017) VOL.8, NO.6, PP.9488-9499 (PUBLISHED ONLINE 2016.12.30), JPN6022034595, ISSN: 0004995470 * |
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