JP2019534246A - Duocarを用いてがんを処置するための組成物および方法 - Google Patents
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、その全内容が参照により本明細書に組み込まれる、2016年9月2日出願の米国仮特許出願第62/382,791号に対する優先権の利益を主張する。
本出願は、がんの分野、特に、機能的キメラ抗原受容体をコードする少なくとも2つのベクターを含む組成物および患者特異的免疫療法におけるその使用方法に関する。
がんは、ヒトの健康に対する重大な脅威の1つである。米国だけで、がんは毎年ほぼ130万人の新たな患者が罹患し、心血管疾患に次いで2番目に多い死因であり、死亡数の約4分の1を占めている。固形腫瘍が、これらの死亡のほとんどの原因である。ある特定のがんの医学的処置においては顕著な進歩があったものの、全てのがんについての5年全生存率は過去20年間で約10%しか改善しなかった。がんまたは悪性腫瘍は、制御されずに迅速に転移および成長し、処置を非常に困難にする。現代のがん処置における困難の1つは、患者の生検およびがんの診断ならびに有効な処置の間に経過する時間である。この時間の間に、患者の腫瘍は妨げなしに成長する可能性があり、その結果、疾患は、処置が適用される前にさらに進行してしまう。これは、がんの予後および転帰に負の影響を与える。
2つ以上のベクターが形質導入されたリンパ球を含む新規養子免疫療法組成物、ならびにがんならびに他の疾患および状態を処置するために使用され得る患者特異的併用免疫療法におけるその使用の方法が、本明細書で提供される。
定義
本明細書で使用する場合、単数形「1つの(a)」、「1つの(an)」および「この(the)」とは、文脈が明らかに他を示さない限り、単数形および複数形の両方を指す。例えば、用語「1つの抗原」は、単数または複数の抗原を含み、語句「少なくとも1つの抗原」と等価とみなされ得る。本明細書で使用する場合、用語「含む(comprises)」とは、「含む(includes)」を意味する。したがって、「1つの抗原を含む(comprising)」とは、他の要素を排除することなく、「1つの抗原を含む(including)」を意味する。語句「および/または」とは、「および」または「または」を意味する。核酸またはポリペプチドについて与えられた任意のおよび全ての塩基サイズまたはアミノ酸サイズ、ならびに全ての分子量または分子質量値は、特記しない限り、おおよそであり、便宜的に提供されていることをさらに理解すべきである。本明細書に記載されるものと類似または等価な多くの方法および材料が使用され得るが、特に適切な方法および材料が以下に記載される。矛盾する場合、用語の説明を含む本明細書が支配する。さらに、材料、方法および実施例は、例示にすぎず、限定を意図しない。種々の実施形態の再検討を容易にするために、以下の用語の説明が提供される。
本明細書で開示されるDuoCARは、各ベクターが機能的CARをコードする少なくとも2つのベクターを含み、それにより、ベクターの組合せは2つ以上の同一でない結合ドメインの発現を生じ、各ベクターによりコードされた結合ドメイン(複数可)は膜貫通ドメインおよび1または複数の同一でない細胞内シグナル伝達モチーフ、抗原に結合できる少なくとも1つの細胞外ドメイン、少なくとも1つの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共有結合で連結される。
一実施形態では、本明細書に開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるCARは、さもなければ抗原結合性ドメインまたは部分と呼ばれる標的特異的結合エレメントを含む。ドメインの選択は、標的細胞の表面を規定するリガンドの型および数に依存する。例えば、抗原結合性ドメインは、特定の疾患状態と関連する標的細胞上の細胞表面マーカーとして作用するリガンドを認識するように選択され得る。したがって、CAR中の抗原結合性ドメインに対するリガンドとして作用し得る細胞表面マーカーの例には、ウイルス、細菌および寄生生物感染、自己免疫疾患ならびにがん細胞と関連するものが含まれる。
本明細書に開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるDuoCARでは、CARは、CARの細胞外ドメインに融合された1または複数の膜貫通ドメインを含む。
本明細書に開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるDuoCARでは、スペーサードメインは、細胞外ドメインとTNFRSF膜貫通ドメインとの間、または細胞内ドメインとTNFRSF膜貫通ドメインとの間に配置され得る。スペーサードメインは、TNFRSF膜貫通ドメインを細胞外ドメインと連結させるように、および/またはTNFRSF膜貫通ドメインを細胞内ドメインと連結させるように機能する、任意のオリゴペプチドまたはポリペプチドを意味する。スペーサードメインは、最大で300アミノ酸、好ましくは10〜100アミノ酸、最も好ましくは25〜50アミノ酸を含む。
CARの細胞質ドメインまたはさもなければ細胞内シグナル伝達ドメインは、CARが中に置かれた免疫細胞の正常なエフェクター機能のうち少なくとも1つの活性化を担う。用語「エフェクター機能」とは、細胞の特殊化した機能を指す。例えば、T細胞のエフェクター機能は、サイトカインの分泌を含む細胞溶解活性またはヘルパー活性であり得る。したがって、用語「細胞内シグナル伝達ドメイン」とは、エフェクター機能シグナルを伝達し、特殊化した機能を実行するように細胞を指示する、タンパク質の部分を指す。通常は細胞内シグナル伝達ドメイン全体が使用され得るが、多くの場合、鎖全体を使用する必要はない。細胞内シグナル伝達ドメインの短縮された部分が使用される限りにおいて、かかる短縮された部分は、それがエフェクター機能シグナルを伝達する限り、インタクトな鎖の代わりに使用され得る。したがって、用語、細胞内シグナル伝達ドメインとは、エフェクター機能シグナルを伝達するのに十分な、細胞内シグナル伝達ドメインの任意の短縮された部分を含むことを意味する。
本明細書で開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるDuoCARの機能的部分もまた、本発明の範囲内に明示的に含まれる。用語「機能的部分」とは、CARに関して使用する場合、本明細書に開示されるDuoCARの1または複数の任意の一部または断片を指し、この一部または断片は、それがその一部であるCAR(親CAR)の生物学的活性を保持する。機能的部分は、例えば、親CARと類似の程度、同じ程度、またはより高い程度まで、標的細胞を認識する能力、または疾患を検出、処置もしくは予防する能力を保持する、CRAの一部を包含する。親CARに関して、機能的部分は、例えば、親CARの約10%、25%、30%、50%、68%、80%、90%、95%以上を含み得る。
一実施形態は、本明細書に開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるCAR、CARを発現するT細胞、本明細書で開示された抗原のうち1または複数に特異的に結合する抗体またはその抗原結合性ドメインもしくは部分をさらに提供する。本明細書で使用する場合、「CARを発現するT細胞」または「CAR T細胞」とは、CARを発現するT細胞を意味し、例えば、CARの抗体由来の標的化ドメインによって決定される抗原特異性を有する。
本明細書に開示される患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるDuoCAR、CARを発現するT細胞、または本明細書に開示された抗原のうち1もしくは複数に対して特異的なモノクローナル抗体もしくはその抗原結合性断片は、当業者に公知のいくつもの手段を使用して、エフェクター分子または検出可能なマーカーなどの薬剤にコンジュゲートされ得る。共有結合および非共有結合の両方の手段が使用され得る。コンジュゲートには、本明細書に開示された抗原のうち1または複数に特異的に結合する抗体または抗原結合性断片へのエフェクター分子または検出可能なマーカーの共有結合的連結が存在する分子を含むがこれらに限定されない。当業者は、化学療法剤、抗血管新生剤、毒素、放射活性剤、例えば、125I、32P、14C、3Hおよび35S、ならびに他の標識、標的部分およびリガンドなどを含む(がこれらに限定されない)種々のエフェクター分子および検出可能なマーカーが使用され得ることを理解する。
本明細書に記載されるDuoCAR、抗体またはその抗原結合性部分(その機能的部分および機能的バリアントを含む)のいずれかをコードするヌクレオチド配列を含む核酸が、本発明の一実施形態によってさらに提供される。本発明の核酸は、本明細書に記載されるリーダー配列、抗原結合性ドメイン、膜貫通ドメインおよび/または細胞内T細胞シグナル伝達ドメインのいずれかをコードするヌクレオチド配列を含み得る。
患者特異的自家抗腫瘍リンパ球細胞集団(複数可)において使用されるDuoCARは、哺乳動物において疾患を処置または予防する方法において使用され得ることが企図される。これに関して、一実施形態は、DuoCAR、核酸、組換え発現ベクター、宿主細胞、細胞の集団、抗体および/もしくはその抗原結合性部分、ならびに/または医薬組成物を、哺乳動物においてがんを処置または予防するのに有効な量で哺乳動物に投与するステップを含む、哺乳動物においてがんを処置または予防する方法を提供する。上述のDuoCARのさらなる使用方法は、上に開示されている。
担体(例えば、医薬的に許容される担体)中に、開示されたDuoCAR、またはCARを発現するT細胞、抗体、抗原結合性断片、コンジュゲート、DuoCAR、または本明細書に開示された1もしくは複数の抗原に特異的に結合するCARを発現するT細胞のうち1または複数を含む、遺伝子治療、免疫療法、養子免疫療法および/または細胞療法における使用のためのバイオ医薬組成物または生物製剤組成物(本明細書で以下「組成物」)が、本明細書で提供される。これらの組成物は、対象への投与のために単位投薬形態で調製され得る。所望の転帰を達成するための投与の量およびタイミングは、処置を行う臨床医の裁量である。これらの組成物は、全身(例えば、静脈内)または局所(例えば、腫瘍内)投与のために製剤化され得る。一例では、開示されたDuoCAR、またはCARを発現するT細胞、抗体、抗原結合性断片、コンジュゲートは、静脈内投与などの非経口投与のために製剤化される。本明細書に開示されるCAR、またはCARを発現するT細胞、コンジュゲート、抗体もしくは抗原結合性断片を含む組成物は、腫瘍、例えば、限定としてではなく、神経芽細胞腫の、例えば、処置および検出などのために使用される。一部の例では、これらの組成物は、癌の処置または検出に有用である。本明細書に開示されるCAR、またはCARを発現するT細胞、コンジュゲート、抗体もしくは抗原結合性断片を含む組成物は、例えば、病理学的血管新生の検出にも使用される。
一態様では、本明細書に開示されるDuoCARを使用するキットもまた提供される。例えば、対象における腫瘍を処置するためのキットまたは本明細書に開示されるDuoCARのうち1もしくは複数を発現するCAR T細胞を作製するためのキット。キットは、典型的には、本明細書に開示される、開示された抗体、抗原結合性断片、コンジュゲート、核酸分子、DuoCARまたはCARを発現するT細胞を含む。開示された抗体、抗原結合性断片、コンジュゲート、核酸分子、CARまたはCARを発現するT細胞のうち1よりも多くが、キット中に含まれ得る。
細胞株(PBMCおよび標的)
特記しない限り、全ての細胞株および試薬は、American Tissue Culture Collection(ATCC、Manassas、VA)から購入した。バーキットリンパ腫細胞株Raji、急性リンパ性白血病細胞株REH、および慢性骨髄性白血病細胞株K562を、10%熱不活性化ウシ胎児血清(FBS、Hyclone、Logan、UT)および2mM L−Glutamax(Thermo Fisher Scientific、Grand Island、NY)を補充したRPMI−1640培地において培養した。ヒト胎児由来腎臓細胞株293Tは、10%熱不活性化FBSを補充したダルベッコ変法イーグル培地中で増殖させた。
CAR抗原結合ドメイン、scFv、配列は、CD19についてのマウス融合細胞FMC−63(FMC−63:AA 1−267、GenBank ID:HM852952.1)ならびにCD20についてのLeu−16[1]、VLおよびVHの全体配列に由来した。CD22 scFv結合は、公表されている配列から創出した。タンデムCAR19_20またはCAR20_19を、各抗体のscFvをインフレームでCD8ヒンジおよび膜貫通ドメイン(AA 123−191、参照配列ID NP_001759.3)、4−1BB(CD137、AA 214−255、UniProt配列ID Q07011)トランス活性化ドメインおよびCD3ゼータシグナル伝達ドメイン(CD247、AA 52−163、参照配列ID:NP_000725.1.)に連結することによって生成した。19Aおよび20AのscFv領域を可撓性鎖間リンカー(GGGGS)5、に続いてCD8、4−1BBおよびCD3ゼータドメインによって配列中に連結した。ヒト顆粒球マクロファージコロニー刺激因子受容体アルファサブユニット由来リーダー配列は、[2]に記載のとおり、全ての構築物に含まれた。CAR構築物配列をコドン最適化し(DNA2.0、Newark、CA)、ヒトEF−1αプロモーターの調節下で第3世代レンチウイルスプラスミド骨格(Lentigen Technology Inc.、Gaithersburg、MD)にクローニングした。レンチウイルスベクター(LV)含有上清を、[3]に既に記載のとおり、HEK 293T細胞の一過性トランスフェクションによって生成した。回収した沈殿レンチウイルス上清を−80℃で保存した。
正常ドナーから選択されたCD4+およびCD8+ヒト初代T細胞を40IU/ml IL−2を補充したTexMACS培地(無血清)中で細胞0.3から2x106個/mlの密度で培養し、CD3/CD28 MACS(登録商標)GMP TransAct reagent(Miltenyi Biotec)を用いて活性化し、3日目にCAR構築物をコードするレンチウイルスベクターを用いて10ug/ml硫酸プロタミン(Sigma−Aldrich、St.Louis、MO)の存在下で一晩形質導入し、4日目に培地を交換した。5日目に培養物を、200IU/ml IL−2を補充したTexMACS培地に移し、10〜13日目の回収まで増殖させた。
細胞媒介性細胞傷害を決定するために(CTLアッセイ)、ホタルルシフェラーゼを用いて安定に形質導入された5,000個の標的細胞を様々なエフェクター対標的比でCAR T細胞と組み合わせ、一晩インキュベートした。SteadyGlo reagent(Promega、Madison WI)を各ウエルに加え、生じた発光をEnSpire plate reader(Perkin Elmer、Shelton、Connecticut)上で分析し、1秒当たりのカウントとして記録した(試料CPS)。標的のみのウエル(最大CPS)および1%Tween−20を加えた標的のみのウエル(最少CPS)をアッセイ範囲を決定するために使用した。特異的溶解のパーセントを:(1−(試料CPS−最少CPS)/(最大CPS−最少CPS))として算出した。
特記しない限り、フローサイトメトリーのための全ての細胞染色試薬は、Miltenyi Biotecからのものであった。100万個のCAR T形質導入細胞を培養物から回収し、冷却染色緩衝液(0.5%ウシ血清アルブミンを含むAutoMACS溶液)中で2回洗浄し、350xg、5分間、4℃で沈殿させた。形質導入されたT細胞上のCAR表面発現を、タンパク質L−ビオチンコンジュゲート(ストック1mg/ml、1:1000希釈、GenScript、Piscataway、NJ)を用いて30分間、4℃で染色し、続く2回の洗浄およびストレプトアビジン−PEコンジュゲートを用いる30分間、4℃での染色(ストック:1.0ml、1:200希釈、Jackson ImmunoResearch Laboratories、West Grove、PA)によって最初に検出した。非形質導入細胞およびストレプトアビジン−PEのみを用いて染色した形質導入細胞を陰性対照として使用した。抗CD4抗体をCAR T陽性集団のCD4対CD8比を決定するために使用し、2回目のインキュベーションステップの際に加えた。死細胞を7AAD染色(BD Biosciences、San Jose、CA)によって排除した。フローサイトメトリーによる定量的分析の前に細胞を2回洗浄し、200ul染色緩衝液に再懸濁した。特異的DuoSet CAR T染色を、CD3−CD28ナノマトリックス(TransAct、Miltenyi Biotec)を用いて活性化し、DuoSetベクターを用いてIL−2の存在下で形質転換したヒトT細胞上で実行し、CD19−、CD20−またはCD22−scFvドメインの発現について、抗体に関する染色のために組換えCD19、CD20またはCD22を使用するフローサイトメトリーによって分析した。
初代ヒトT細胞上のDuoCAR(2+1 DuoSet)の発現
原理の証明として、2つのCAR−Tベクターから構成されるDuoSetを創出した。セットのメンバーの1つは、CD8膜貫通ならびにCD28およびCD3−ゼータシグナル伝達ドメイン(LTG2228)、配列番51および配列番号52に連結されたタンデムCD20_CD19結合ドメインを発現した。DuoSetの第2のメンバーは、CD8膜貫通ならびに4−1BBおよびCD3ゼータシグナル伝達ドメイン(LTG2200)、配列番号9および配列番号10に連結されたCD22バインダーを含むCAR構築物であった。図7では、対になった列は、CD20およびCD19 scFvs、左列ならびにCD22およびCD19 scFvs、右列についての二重染色を示している。列1は、形質導入されておらず、それにより結合を示さないT細胞を示している(UTD)。列2は、CD8膜貫通ならびに細胞内CD28およびD3ゼータシグナル伝達ドメインを含む、CD20_CD19 CARベクターをコードするLVを用いて形質導入されたT細胞を示している(20−19−28z)。二重染色がCD20およびCD19結合(左パネル)について見られる一方で、CD19結合だけが右パネルにおいては見られる。列3は、CD8膜貫通ならびに細胞内4−1BBおよびCD3−ゼータシグナル伝達ドメインを含むCD22 CARベクターを用いて形質導入されたT細胞を示している(22−BBz)。CD19またはCD20(左パネル)では二重染色は見られず、細胞の単一の集団だけがCD22に結合できることが見られる(右パネル)。列4では、T細胞は、列2および列3における両方のベクターから構成されるDuoSetを用いて形質導入される。DuoSetだけが3つ全ての、CARによりコードされる結合ドメインを発現している(42%の細胞はCD20_19を発現し(左パネル)、38%はCD22およびCD19結合ドメインを発現する(右パネル)。CD22およびCD19 scFvが、DuoSetを含む2つの別々の膜貫通タンパク質上にそれぞれあることから、38%がこの実施例における真のDuoSet発現集団を表している。
DuoCARを発現しているヒトT細胞調製物の抗白血病活性
DuoCARを発現しているヒトT細胞調製物の抗白血病活性は、3つの白血病抗原を同時に標的化する(DuoCAR発現特徴について図7を参照されたい)。CD20_19タンデムCARおよびCD22特異的単一CAR(実施例1において調製されたとおり)から構成されるDuoSetは、白血病細胞株および標的としてのモデル細胞株を使用する細胞傷害性T細胞アッセイにおいて、エフェクターT細胞集団を使用した。単一CAR構成成分(20_19−28zもしくは22−BBz)またはDuoSet(20_19−28z+22−BBz)を用いて形質導入したヒトT細胞を、4つの異なるエフェクター標的比(表示のとおり20:1、10:1、5:1、2.5:1)で細胞傷害性T細胞アッセイにおいて使用した(図8を参照されたい)。CAR−T標的として使用された白血病細胞株は:Raji(3つ全ての標的抗原を発現する)、REH(3つ全ての標的抗原を発現する)、K562(対照、標的を発現しない)、K562−CD19(CD19を発現する)、K562−CD20(CD20を発現する)およびK562−CD22(CD22を発現する)であった。DuoCAR形質導入細胞(20−19−28z+22−BBz)だけが両方の白血病細胞株(RajiおよびREH)、および3つ全ての単一発現K562標的細胞株(K562−CD19、K562−CD20、K562−CD22)に対して高い細胞溶解活性を示した。これは、DuoCARテクノロジーが同じエフェクターT細胞集団において、3つの白血病抗原を同時に独自に標的化できることを実証し、それにより1つまたは2つよりも多い標的抗原を同時に標的化できることによる優れた抗新生物活性を実証し、それにより悪性腫瘍がエスケープ変異体(1つまたは2つの抗原が喪失したまたは下方制御されている細胞クローン。これは免疫アブレーションからエスケープした)を生成する可能性を減少させた。最終結果は、結果的には再発である抗原喪失バリアントのエスケープおよび増殖に起因する、患者についてのさらに高い治癒率である。
DuoCAR産生方法
本出願に記載されるDuoCARテクノロジーは、遺伝子ベクターによってコードされる1つよりも多い膜貫通タンパク質から2つよりも多い抗原特異性を発現する治療的リンパ球、本実施例ではヒトT細胞の集団を生成する。本実施例では、これは2つの別々の手段によって達成される。図9は、「未形質導入」「共形質導入」および「共トランスフェクション」と表示される3つのデータ列を含有している。図9は、図7においてと同様に生成されたデータの2つの列を含有し、ここで第1列はCD20−およびCD19−特異的な特異的結合の発現についてフローサイトメトリーによって分析され、第2列はCD22−およびCD19−結合活性の発現についてフローサイトメトリーによって分析している。データの第1の列は、未形質導入ヒトT細胞を示している。結合活性は、CAR由来結合活性のCD19、CD20またはCD22組換えタンパク質指標については示されておらず、DuoCAR発現が無いことを実証している。第2の列では、「共形質導入」を、DuoCARを生成するために使用した。このデータセットでは、2つのLVを活性化T細胞を同時に形質導入するために使用した。図7においてと同様に、DuoCARを含むDuoSet中の1つのCARは、CD28シグナル伝達およびCD3ゼータシグナル伝達モチーフに連結されたタンデムCD20およびCD19バインダーであり;他のCARは、CD22バインダーであり4−1BBおよびCD3ゼータシグナル伝達モチーフに連結されていた。列1中の第2象限(Q2)は、CD20およびCD19−scFv活性についてのユニタリ染色の非常に特異的なパターンを示している。これは、両方のバインダーが同じ表面糖タンパク質上にあるためであり、それによりそれらは同じ強度で共発現され、見られる非常に特異的な直線のパターンを生じている。共形質導入データの第2列では、2つの糖タンパク質が各細胞上で均一なパターンで発現されない場合に、さらに伝統的なパターンが見られる。それにより、4つの異なる集団のパターンが見られる。下左の象限では、いずれのバインダーも発現していない細胞が見られる。上左の象限では、CD22 CARだけを発現している細胞が見られる。下右の象限では、CD20_CD19タンデムCARだけを発現している細胞が見られる。最後に、上右の象限では、DuoCARを含むCAR DuoSetの両方のメンバーを発現している細胞が見られる。
本出願は、「配列表」という表題のPDFファイルによって米国特許商標庁に電子出願された配列表を含有する。その配列表は参照により本明細書に組み込まれる。
以下に列記した核酸およびアミノ酸配列は、37C.F.R.1.822において定義されたのと同様に、ヌクレオチド塩基に関する標準的な文字略語およびアミノ酸に関する3文字コードを使用して示す。それぞれの核酸配列の一本鎖のみを示すが、示した鎖に関する何らかの参照によって相補鎖が含まれると理解される。添付の配列表中:
配列番号1は、CD20反応性scFv結合ドメインLTG1495)のヌクレオチド配列である。
GAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAA
配列番号2は、CD20反応性scFv結合ドメイン(LTG1495)のアミノ酸配列である。
EVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIK
配列番号3は、CAR LTG1495(LP−1495−CD8 TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTCCTTCTCGTGACCTCCCTGCTTCTCTGCGAACTGCCCCATCCTGCCTTCCTGCTGATTCCCGAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号4は、CAR LTG1495(LP−1495−CD8 TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号5は、リーダー/シグナルペプチド配列のヌクレオチド配列である。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCG
配列番号6は、リーダー/シグナルペプチド配列のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIP
配列番号7は、CD22反応性scFv結合ドメインLTG2200)のヌクレオチド配列である。
CAGGTACAGCTCCAGCAGAGTGGCCCAGGGCTCGTGAAGCCAAGCCAGACGCTGTCCCTGACTTGTGCAATTTCAGGGGATTCAGTTTCATCAAATAGCGCGGCGTGGAATTGGATTCGACAATCTCCTTCCCGAGGGTTGGAATGGCTTGGACGAACATATTACAGATCCAAATGGTATAACGACTATGCGGTATCAGTAAAGTCAAGAATAACCATTAACCCCGACACAAGCAAGAACCAATTCTCTTTGCAGCTTAACTCTGTCACGCCAGAAGACACGGCAGTCTATTATTGCGCTCGCGAGGTAACGGGTGACCTGGAAGACGCTTTTGACATTTGGGGGCAGGGTACGATGGTGACAGTCAGTTCAGGGGGCGGTGGGAGTGGGGGAGGGGGTAGCGGGGGGGGAGGGTCAGACATTCAGATGACCCAGTCCCCTTCATCCTTGTCTGCCTCCGTCGGTGACAGGGTGACAATAACATGCAGAGCAAGCCAAACAATCTGGAGCTATCTCAACTGGTACCAGCAGCGACCAGGAAAAGCGCCAAACCTGCTGATTTACGCTGCTTCCTCCCTCCAATCAGGCGTGCCTAGTAGATTTAGCGGTAGGGGCTCCGGCACCGATTTTACGCTCACTATAAGCTCTCTTCAAGCAGAAGATTTTGCGACTTATTACTGCCAGCAGTCCTATAGTATACCTCAGACTTTCGGACAGGGTACCAAGTTGGAGATTAAGGCGGCCGCA
配列番号8は、CD22反応性scFv結合ドメイン(LTG2200)のアミノ酸配列である。
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIKAAA
配列番号9は、CAR LTG2200(LP−2200−CD8 TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTTCTTTTGGTGACTTCCCTTTTGCTGTGCGAGTTGCCACACCCCGCCTTCCTGCTTATTCCCCAGGTACAGCTCCAGCAGAGTGGCCCAGGGCTCGTGAAGCCAAGCCAGACGCTGTCCCTGACTTGTGCAATTTCAGGGGATTCAGTTTCATCAAATAGCGCGGCGTGGAATTGGATTCGACAATCTCCTTCCCGAGGGTTGGAATGGCTTGGACGAACATATTACAGATCCAAATGGTATAACGACTATGCGGTATCAGTAAAGTCAAGAATAACCATTAACCCCGACACAAGCAAGAACCAATTCTCTTTGCAGCTTAACTCTGTCACGCCAGAAGACACGGCAGTCTATTATTGCGCTCGCGAGGTAACGGGTGACCTGGAAGACGCTTTTGACATTTGGGGGCAGGGTACGATGGTGACAGTCAGTTCAGGGGGCGGTGGGAGTGGGGGAGGGGGTAGCGGGGGGGGAGGGTCAGACATTCAGATGACCCAGTCCCCTTCATCCTTGTCTGCCTCCGTCGGTGACAGGGTGACAATAACATGCAGAGCAAGCCAAACAATCTGGAGCTATCTCAACTGGTACCAGCAGCGACCAGGAAAAGCGCCAAACCTGCTGATTTACGCTGCTTCCTCCCTCCAATCAGGCGTGCCTAGTAGATTTAGCGGTAGGGGCTCCGGCACCGATTTTACGCTCACTATAAGCTCTCTTCAAGCAGAAGATTTTGCGACTTATTACTGCCAGCAGTCCTATAGTATACCTCAGACTTTCGGACAGGGTACCAAGTTGGAGATTAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号10は、CAR LTG2200(LP−2200−CD8 TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAASSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号11は、DNA CD8膜貫通ドメインのヌクレオチド配列である。
ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGC
配列番号12は、CD8膜貫通ドメインのアミノ酸配列である。
IWAPLAGTCGVLLLSLVITLYC
配列番号13は、DNA CD8ヒンジドメインのヌクレオチド配列である。
ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTTGCCTGCGATATCTAC
配列番号14は、CD8ヒンジドメインのアミノ酸配列である。
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY
配列番号15は、CD8アルファ(NCBI RefSeq:NP.sub.−−001759.3)のヒンジおよび膜貫通領域のアミノ酸番号137から206のアミノ酸配列である。
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC
配列番号16は、ヒトIgG CL配列のアミノ酸配列である。
GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
配列番号17は、4−1BBのDNAシグナル伝達ドメインのヌクレオチド配列である。
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAG AAGAAGAAGAAGGAGGATGTGAACTG
配列番号18は、4−1BBのシグナル伝達ドメインのアミノ酸配列である。
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
配列番号19は、CD3−ゼータのDNAシグナル伝達ドメインのヌクレオチド配列である。
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC
配列番号20は、CD3ゼータのアミノ酸配列である。
RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号21は、CAR LTG1562(LP−CD19バインダー−CD8リンカー−CD4tm−4−1BB−CD3−ゼータ)のヌクレオチド配列である。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGATATTCAGATGACCCAGACCACCAGCAGCCTGAGCGCGAGCCTGGGCGATCGCGTGACCATTAGCTGCCGCGCGAGCCAGGATATTAGCAAATATCTGAACTGGTATCAGCAGAAACCGGATGGCACCGTGAAACTGCTGATTTATCATACCAGCCGCCTGCATAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGCAGCGGCACCGATTATAGCCTGACCATTAGCAACCTGGAACAGGAAGATATTGCGACCTATTTTTGCCAGCAGGGCAACACCCTGCCGTATACCTTTGGCGGCGGCACCAAACTGGAAATTACCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGAAGTGAAACTGCAGGAAAGCGGCCCGGGCCTGGTGGCGCCGAGCCAGAGCCTGAGCGTGACCTGCACCGTGAGCGGCGTGAGCCTGCCGGATTATGGCGTGAGCTGGATTCGCCAGCCGCCGCGCAAAGGCCTGGAATGGCTGGGCGTGATTTGGGGCAGCGAAACCACCTATTATAACAGCGCGCTGAAAAGCCGCCTGACCATTATTAAAGATAACAGCAAAAGCCAGGTGTTTCTGAAAATGAACAGCCTGCAGACCGATGATACCGCGATTTATTATTGCGCGAAACATTATTATTATGGCGGCAGCTATGCGATGGATTATTGGGGCCAGGGCACCAGCGTGACCGTGAGCAGCGCGGCGGCGCCGGCGCCGCGCCCGCCGACCCCGGCGCCGACCATTGCGAGCCAGCCGCTGAGCCTGCGCCCGGAAGCGTGCCGCCCGGCGGCGGGCGGCGCGGTGCATACCCGCGGCCTGGATTTTGTGCAGCCGATGGCGCTGATTGTGCTGGGCGGCGTGGCGGGCCTGCTGCTGTTTATTGGCCTGGGCATTTTTTTTTGCGTGCGCTGCCGCCCGCGCCGCAAAAAACTGCTGTATATTTTTAAACAGCCGTTTATGCGCCCGGTGCAGACCACCCAGGAAGAAGATGGCTGCAGCTGCCGCTTTCCGGAAGAAGAAGAAGGCGGCTGCGAACTGCGCGTGAAATTTAGCCGCAGCGCGGATGCGCCGGCGTATCAGCAGGGCCAGAACCAGCTGTATAACGAACTGAACCTGGGCCGCCGCGAAGAATATGATGTGCTGGATAAACGCCGCGGCCGCGATCCGGAAATGGGCGGCAAACCGCGCCGCAAAAACCCGCAGGAAGGCCTGTATAACGAACTGCAGAAAGATAAAATGGCGGAAGCGTATAGCGAAATTGGCATGAAAGGCGAACGCCGCCGCGGCAAAGGCCATGATGGCCTGTATCAGGGCCTGAGCACCGCGACCAAAGATACCTATGATGCG CTGCATATGCAGGCGCTGCCGCCGCGC
配列番号22は、CAR LTG1562(LP−CD19バインダー−CD8リンク−CD4tm−4−1BB−CD3−ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFVQPMALIVLGGVAGLLLFIGLGIFFCVRCRPRRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号23は、CD20_19−反応性scFv結合ドメイン(LTG1497二重特異性バインダー)のヌクレオチド配列である。
GAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGGAGGCGGCGGCAGCGGCGGGGGAGGGTCCGGAGGGGGTGGTTCTGGTGGAGGAGGATCGGGAGGCGGTGGCAGCGACATTCAGATGACTCAGACCACCTCCTCCCTGTCCGCCTCCCTGGGCGACCGCGTGACCATCTCATGCCGCGCCAGCCAGGACATCTCGAAGTACCTCAACTGGTACCAGCAGAAGCCCGACGGAACCGTGAAGCTCCTGATCTACCACACCTCCCGGCTGCACAGCGGAGTGCCGTCTAGATTCTCGGGTTCGGGGTCGGGAACTGACTACTCCCTTACTATTTCCAACCTGGAGCAGGAGGATATTGCCACCTACTTCTGCCAACAAGGAAACACCCTGCCGTACACTTTTGGCGGGGGAACCAAGCTGGAAATCACTGGCAGCACATCCGGTTCCGGGAAGCCCGGCTCCGGAGAGGGCAGCACCAAGGGGGAAGTCAAGCTGCAGGAATCAGGACCTGGCCTGGTGGCCCCGAGCCAGTCACTGTCCGTGACTTGTACTGTGTCCGGAGTGTCGCTCCCGGATTACGGAGTGTCCTGGATCAGGCAGCCACCTCGGAAAGGATTGGAATGGCTCGGAGTCATCTGGGGTTCCGAAACCACCTATTACAACTCGGCACTGAAATCCAGGCTCACCATTATCAAGGATAACTCCAAGTCACAAGTGTTCCTGAAGATGAATAGCCTGCAGACTGACGACACGGCGATCTACTATTGCGCCAAGCACTACTACTACGGCGGATCCTACGCTATGGACTACTGGGGCCAGGGGACCAGCGTGACCGTGTCATCCGCGGCCGCA
配列番号24は、CD20_19−反応性scFv結合ドメイン(LTG1497二重特異性バインダー)のアミノ酸配列である。
EVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAA
配列番号25は、CAR LTG1497(LP−LTG1497−CD8 TM−41BB−CD3ゼータ)または(LP−CD20 VH−(GGGGS)3−CD20 VL−(GGGGS)5−CD19VL−ウィットロウリンカー−CD19 VH−CD8ヒンジ+TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTCCTTCTCGTGACCTCCCTGCTTCTCTGCGAACTGCCCCATCCTGCCTTCCTGCTGATTCCCGAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGGAGGCGGCGGCAGCGGCGGGGGAGGGTCCGGAGGGGGTGGTTCTGGTGGAGGAGGATCGGGAGGCGGTGGCAGCGACATTCAGATGACTCAGACCACCTCCTCCCTGTCCGCCTCCCTGGGCGACCGCGTGACCATCTCATGCCGCGCCAGCCAGGACATCTCGAAGTACCTCAACTGGTACCAGCAGAAGCCCGACGGAACCGTGAAGCTCCTGATCTACCACACCTCCCGGCTGCACAGCGGAGTGCCGTCTAGATTCTCGGGTTCGGGGTCGGGAACTGACTACTCCCTTACTATTTCCAACCTGGAGCAGGAGGATATTGCCACCTACTTCTGCCAACAAGGAAACACCCTGCCGTACACTTTTGGCGGGGGAACCAAGCTGGAAATCACTGGCAGCACATCCGGTTCCGGGAAGCCCGGCTCCGGAGAGGGCAGCACCAAGGGGGAAGTCAAGCTGCAGGAATCAGGACCTGGCCTGGTGGCCCCGAGCCAGTCACTGTCCGTGACTTGTACTGTGTCCGGAGTGTCGCTCCCGGATTACGGAGTGTCCTGGATCAGGCAGCCACCTCGGAAAGGATTGGAATGGCTCGGAGTCATCTGGGGTTCCGAAACCACCTATTACAACTCGGCACTGAAATCCAGGCTCACCATTATCAAGGATAACTCCAAGTCACAAGTGTTCCTGAAGATGAATAGCCTGCAGACTGACGACACGGCGATCTACTATTGCGCCAAGCACTACTACTACGGCGGATCCTACGCTATGGACTACTGGGGCCAGGGGACCAGCGTGACCGTGTCATCCGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号26は、CAR LTG1497(LP−LTG1497−CD8 TM−41BB−CD3ゼータ)または(LP−CD20 VH−(GGGGS)3−CD20 VL−(GGGGS)5−CD19VL−ウィットロウリンカー−CD19 VH−CD8ヒンジ+TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号27は、CD19のためのscFVのヌクレオチド配列である。
GACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATTAGTAAATATTTAAATTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTACCATACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAAGAAGATATTGCCACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGATCACAGGTGGCGGTGGCTCGGGCGGTGGTGGGTCGGGTGGCGGCGGATCTGAGGTGAAACTGCAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCATTACCCGACTATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGGAGTGGCTGGGAGTAATATGGGGTAGTGAAACCACATACTATAATTCAGCTCTCAAATCCAGACTGACCATCATCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATTTACTACTGTGCCAAACATTATTACTACGGTGGTAGCTATGCTATGGACTACTGGGGCCAAGGAACCTCAGTCACCGTCTCCTCA
配列番号28は、CD19のためのscFVのアミノ酸配列である。
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS
配列番号29は、CAR LTG 1494(LP−CD19バインダー−CD8リンク−CD8tm−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTTCTCCTGGTCACCTCCCTGCTCCTCTGCGAACTGCCTCACCCTGCCTTCCTTCTGATTCCTGACACTGACATTCAGATGACTCAGACCACCTCTTCCTTGTCCGCGTCACTGGGAGACAGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATCTCCAAGTACCTGAACTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCTGCTGATCTACCACACCTCACGCCTGCACAGCGGAGTGCCAAGCAGATTCTCCGGCTCCGGCTCGGGAACCGATTACTCGCTTACCATTAGCAACCTCGAGCAGGAGGACATCGCTACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTACACCTTCGGCGGAGGAACCAAATTGGAAATCACCGGCTCCACGAGCGGCTCCGGGAAGCCTGGTTCCGGGGAAGGCTCCACTAAGGGTGAAGTGAAGCTCCAGGAGTCCGGCCCCGGCCTGGTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCGTGTCGGGAGTGTCCCTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCGCCGCGGAAGGGCCTGGAATGGCTGGGTGTCATCTGGGGATCCGAGACTACCTACTACAACTCGGCCCTGAAGTCCCGCCTGACTATCATCAAAGACAACTCGAAGTCCCAGGTCTTTCTGAAGATGAACTCCCTGCAAACTGACGACACCGCCATCTATTACTGTGCTAAGCACTACTACTACGGTGGAAGCTATGCTATGGACTACTGGGGCCAGGGGACATCCGTGACAGTCAGCTCCGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号30は、CAR LTG 1494(LP−CD19バインダー−CD8リンク−CD8tm−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPDTDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号31は、CAR LTG1538(LP−CD19バインダー−CD8リンク−CD8tm−シグナル(LTI再操作されたCD19 CAR)のヌクレオチド配列である。
ATGCTTCTCCTGGTCACCTCCCTGCTCCTCTGCGAACTGCCTCACCCTGCCTTCCTTCTGATTCCTGACATTCAGATGACTCAGACCACCTCTTCCTTGTCCGCGTCACTGGGAGACAGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATCTCCAAGTACCTGAACTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCTGCTGATCTACCACACCTCACGCCTGCACAGCGGAGTGCCAAGCAGATTCTCCGGCTCCGGCTCGGGAACCGATTACTCGCTTACCATTAGCAACCTCGAGCAGGAGGACATCGCTACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTACACCTTCGGCGGAGGAACCAAATTGGAAATCACCGGCGGAGGAGGCTCCGGGGGAGGAGGTTCCGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGTCCGGCCCCGGCCTGGTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCGTGTCGGGAGTGTCCCTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCGCCGCGGAAGGGCCTGGAATGGCTGGGTGTCATCTGGGGATCCGAGACTACCTACTACAACTCGGCCCTGAAGTCCCGCCTGACTATCATCAAAGACAACTCGAAGTCCCAGGTCTTTCTGAAGATGAACTCCCTGCAAACTGACGACACCGCCATCTATTACTGTGCTAAGCACTACTACTACGGTGGAAGCTATGCTATGGACTACTGGGGGCAAGGCACTTCGGTGACTGTGTCAAGCGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号32は、CAR LTG1538(LP−CD19バインダー−CD8リンク−CD8tm−シグナル(LTI再操作されたCD19 CAR)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号33は、CD19_20反応性scFv結合ドメイン(LTG1496)のヌクレオチド配列である。
GACATTCAGATGACTCAGACCACCTCCTCCCTGTCCGCCTCCCTGGGCGACCGCGTGACCATCTCATGCCGCGCCAGCCAGGACATCTCGAAGTACCTCAACTGGTACCAGCAGAAGCCCGACGGAACCGTGAAGCTCCTGATCTACCACACCTCCCGGCTGCACAGCGGAGTGCCGTCTAGATTCTCGGGTTCGGGGTCGGGAACTGACTACTCCCTTACTATTTCCAACCTGGAGCAGGAGGATATTGCCACCTACTTCTGCCAACAAGGAAACACCCTGCCGTACACTTTTGGCGGGGGAACCAAGCTGGAAATCACTGGCAGCACATCCGGTTCCGGGAAGCCCGGCTCCGGAGAGGGCAGCACCAAGGGGGAAGTCAAGCTGCAGGAATCAGGACCTGGCCTGGTGGCCCCGAGCCAGTCACTGTCCGTGACTTGTACTGTGTCCGGAGTGTCGCTCCCGGATTACGGAGTGTCCTGGATCAGGCAGCCACCTCGGAAAGGATTGGAATGGCTCGGAGTCATCTGGGGTTCCGAAACCACCTATTACAACTCGGCACTGAAATCCAGGCTCACCATTATCAAGGATAACTCCAAGTCACAAGTGTTCCTGAAGATGAATAGCCTGCAGACTGACGACACGGCGATCTACTATTGCGCCAAGCACTACTACTACGGCGGATCCTACGCTATGGACTACTGGGGCCAGGGGACCAGCGTGACCGTGTCATCCGGAGGCGGCGGCAGCGGCGGGGGAGGGTCCGGAGGGGGTGGTTCTGGTGGAGGAGGATCGGGAGGCGGTGGCAGCGAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGCGGCCGCA
配列番号34は、CD19_20反応性scFv結合ドメイン(LTG1496)のアミノ酸配列である。
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKAAA
配列番号35は、CAR LTG1496(LP−LTG1496−CD8 TM−41BB−CD3ゼータ)または(LP−CD19 VL−ウィットロウリンカー−CD19 VH(GGGGS)5 CD20 VH (GGGGS)3−CD20 VL CD8ヒンジ+TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTCCTTCTCGTGACCTCCCTGCTTCTCTGCGAACTGCCCCATCCTGCCTTCCTGCTGATTCCCGACATTCAGATGACTCAGACCACCTCCTCCCTGTCCGCCTCCCTGGGCGACCGCGTGACCATCTCATGCCGCGCCAGCCAGGACATCTCGAAGTACCTCAACTGGTACCAGCAGAAGCCCGACGGAACCGTGAAGCTCCTGATCTACCACACCTCCCGGCTGCACAGCGGAGTGCCGTCTAGATTCTCGGGTTCGGGGTCGGGAACTGACTACTCCCTTACTATTTCCAACCTGGAGCAGGAGGATATTGCCACCTACTTCTGCCAACAAGGAAACACCCTGCCGTACACTTTTGGCGGGGGAACCAAGCTGGAAATCACTGGCAGCACATCCGGTTCCGGGAAGCCCGGCTCCGGAGAGGGCAGCACCAAGGGGGAAGTCAAGCTGCAGGAATCAGGACCTGGCCTGGTGGCCCCGAGCCAGTCACTGTCCGTGACTTGTACTGTGTCCGGAGTGTCGCTCCCGGATTACGGAGTGTCCTGGATCAGGCAGCCACCTCGGAAAGGATTGGAATGGCTCGGAGTCATCTGGGGTTCCGAAACCACCTATTACAACTCGGCACTGAAATCCAGGCTCACCATTATCAAGGATAACTCCAAGTCACAAGTGTTCCTGAAGATGAATAGCCTGCAGACTGACGACACGGCGATCTACTATTGCGCCAAGCACTACTACTACGGCGGATCCTACGCTATGGACTACTGGGGCCAGGGGACCAGCGTGACCGTGTCATCCGGAGGCGGCGGCAGCGGCGGGGGAGGGTCCGGAGGGGGTGGTTCTGGTGGAGGAGGATCGGGAGGCGGTGGCAGCGAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号36は、CAR LTG1496(LP−LTG1496−CD8 TM−41BB−CD3ゼータ)または(LP−CD19 VL−ウィットロウリンカー−CD19 VH(GGGGS)5 CD20 VH (GGGGS)3−CD20 VL CD8ヒンジ+TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号37は、メソテリン反応性scFv結合ドメイン(LTG1904)のヌクレオチド配列である。
GAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCGGCGGAGGCACCCAGCTGACCGTCCTCGGT
配列番号38は、メソテリン反応性scFv結合ドメイン(LTG1904)のアミノ酸配列である。
EVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDLSSVAGPFNYWGQGTLVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHLVFGGGTQLTVLG
配列番号39は、CAR LTG1904(LP−LTG1904−CD8 TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCGGCGGAGGCACCCAGCTGACCGTCCTCGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号40は、CAR LTG1904(LP−LTG1904−CD8 TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDLSSVAGPFNYWGQGTLVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHLVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号41は、CD33反応性1本鎖結合ドメインVH−4(LTG1906)のヌクレオチド配列である。
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATGAGCTGGGTCCGCCAGGCTCCAAGACAAGGGCTTGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGCGGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACAGCCACGTATTACTGTGCGAAAGAAAATGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA
配列番号42は、CD33反応性1本鎖結合ドメインVH−4(LTG1906)のアミノ酸配列である。
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPRQGLEWVANIKQDGSEKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTATYYCAKENVDWGQGTLVTVSS
配列番号43は、CAR LTG1906(LP−VH4−CD8 TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATGAGCTGGGTCCGCCAGGCTCCAAGACAAGGGCTTGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGCGGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACAGCCACGTATTACTGTGCGAAAGAAAATGTGGACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号44は、CAR LTG1906(LP−VH4−CD8 TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPRQGLEWVANIKQDGSEKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTATYYCAKENVDWGQGTLVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号45は、TSLPR−反応性scFv結合ドメイン(LTG1789)のヌクレオチド配列である。
ATGGCACTGCCCGTGACCGCCCTGCTTCTGCCGCTTGCACTTCTGCTGCACGCCGCTAGGCCCCAAGTCACCCTCAAAGAGTCAGGGCCAGGAATCCTCAAGCCCTCACAGACTCTGTCTCTTACTTGCTCATTCAGCGGATTCAGCCTTTCCACCTCTGGTATGGGCGTGGGGTGGATTAGGCAACCTAGCGGAAAGGGGCTTGAATGGCTGGCCCACATCTGGTGGGACGACGACAAGTACTACAACCCCTCACTGAAGTCCCAGCTCACTATTTCCAAAGATACTTCCCGGAATCAGGTGTTCCTCAAGATTACCTCTGTCGACACCGCTGATACCGCCACTTACTATTGTTCACGCAGACCGAGAGGTACCATGGACGCAATGGACTACTGGGGACAGGGCACCAGCGTGACCGTGTCATCTGGCGGTGGAGGGTCAGGAGGTGGAGGTAGCGGAGGCGGTGGGTCCGACATTGTCATGACCCAGGCCGCCAGCAGCCTGAGCGCTTCACTGGGCGACAGGGTGACCATCAGCTGTCGCGCATCACAAGATATCTCTAAGTATCTTAATTGGTACCAGCAAAAGCCGGATGGAACCGTGAAGCTGCTGATCTACTACACCTCACGGCTGCATTCTGGAGTGCCTAGCCGCTTTAGCGGATCTGGGTCCGGTACTGACTACAGCCTCACCATTAGAAACCTTGAACAGGAGGACATCGCAACTTATTTCTGCCAACAGGTCTATACTCTGCCGTGGACCTTCGGCGGAGGTACCAAACTGGAGATTAAGTCCGG
配列番号46は、TSLPR−反応性scFv結合ドメイン(LTG1789)のアミノ酸配列である。
MALPVTALLLPLALLLHAARPQVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKSQLTISKDTSRNQVFLKITSVDTADTATYYCSRRPRGTMDAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQAASSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTIRNLEQEDIATYFCQQVYTLPWTFGGGTKLEIKS
配列番号47は、CAR LTG1789(LP−3G11−CD8 TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGGCACTGCCCGTGACCGCCCTGCTTCTGCCGCTTGCACTTCTGCTGCACGCCGCTAGGCCCCAAGTCACCCTCAAAGAGTCAGGGCCAGGAATCCTCAAGCCCTCACAGACTCTGTCTCTTACTTGCTCATTCAGCGGATTCAGCCTTTCCACCTCTGGTATGGGCGTGGGGTGGATTAGGCAACCTAGCGGAAAGGGGCTTGAATGGCTGGCCCACATCTGGTGGGACGACGACAAGTACTACAACCCCTCACTGAAGTCCCAGCTCACTATTTCCAAAGATACTTCCCGGAATCAGGTGTTCCTCAAGATTACCTCTGTCGACACCGCTGATACCGCCACTTACTATTGTTCACGCAGACCGAGAGGTACCATGGACGCAATGGACTACTGGGGACAGGGCACCAGCGTGACCGTGTCATCTGGCGGTGGAGGGTCAGGAGGTGGAGGTAGCGGAGGCGGTGGGTCCGACATTGTCATGACCCAGGCCGCCAGCAGCCTGAGCGCTTCACTGGGCGACAGGGTGACCATCAGCTGTCGCGCATCACAAGATATCTCTAAGTATCTTAATTGGTACCAGCAAAAGCCGGATGGAACCGTGAAGCTGCTGATCTACTACACCTCACGGCTGCATTCTGGAGTGCCTAGCCGCTTTAGCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号48は、CAR LTG1789(LP−3G11−CD8 TM−41BB−CD3ゼータ)のアミノ酸配列である。
MALPVTALLLPLALLLHAARPQVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKSQLTISKDTSRNQVFLKITSVDTADTATYYCSRRPRGTMDAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQAASSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTIRNLEQEDIATYFCQQVYTLPWTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号49は、CAR LTG1563(LP−CD19−TNFRSF19TM−41BB−CD3ゼータ)のヌクレオチド配列である。
ATGCTGCTGCTGGTCACCAGCCTGCTGCTGTGCGAGCTCCCTCACCCCGCCTTTCTGCTTATCCCGGACATTCAGATGACACAGACCACCTCGAGCTTGTCCGCGTCGCTGGGCGATCGCGTGACCATCTCCTGCCGGGCCTCCCAAGACATTTCAAAGTATCTCAACTGGTACCAGCAGAAGCCGGACGGAACCGTGAAACTGCTGATCTACCATACCAGCCGCCTGCACTCCGGCGTGCCGTCCCGCTTCTCCGGATCGGGTTCCGGAACTGACTACTCACTGACTATCTCCAACTTGGAACAAGAGGACATCGCCACTTACTTCTGTCAACAAGGAAATACCCTTCCCTACACCTTCGGGGGGGGTACCAAGCTGGAGATCACTGGGGGCGGAGGCTCCGGTGGAGGCGGATCCGGCGGTGGAGGGAGCGAAGTCAAGCTGCAGGAATCAGGACCAGGACTCGTGGCGCCATCCCAGTCCCTGTCGGTGACCTGTACTGTCTCCGGAGTCAGCCTCCCCGATTACGGAGTGTCATGGATTAGGCAACCCCCAAGAAAAGGGCTGGAATGGCTCGGAGTGATCTGGGGCTCCGAAACCACCTACTACAACTCGGCGCTGAAGTCCCGGCTGACCATCATCAAGGACAACTCCAAGAGCCAAGTGTTCTTGAAGATGAACAGCTTGCAGACCGACGATACCGCAATCTACTACTGTGCCAAGCACTATTACTACGGGGGGTCTTACGCCATGGACTACTGGGGACAGGGCACCTCCGTGACTGTGTCGTCCGCGGCCGCGCCCGCCCCTCGGCCCCCGACTCCTGCCCCGACGATCGCTTCCCAACCTCTCTCGCTGCGCCCGGAAGCATGCCGGCCCGCCGCCGGTGGCGCTGTCCACACTCGCGGACTGGACTTTGATACCGCACTGGCGGCCGTGATCTGTAGCGCCCTGGCCACCGTGCTGCTGGCGCTGCTCATCCTTTGCGTGATCTACTGCAAGCGGCAGCCTAGGCGAAAGAAGCTCCTCTACATTTTCAAGCAACCCTTCATGCGCCCCGTGCAAACCACCCAGGAGGAGGATGGATGCTCATGCCGGTTCCCTGAGGAAGAAGAGGGCGGTTGCGAGCTCAGAGTGAAATTCAGCCGGTCGGCTGACGCCCCGGCGTACCAGCAGGGCCAGAACCAGCTGTACAATGAGCTCAACCTGGGGCGCCGCGAAGAGTACGACGTGCTGGACAAGAGGAGAGGCAGAGATCCGGAAATGGGCGGAAAGCCAAGGCGGAAGAACCCGCAGGAAGGTCTTTACAACGAACTGCAGAAGGACAAGATGGCCGAGGCCTACTCCGAGATTGGGATGAAGGGAGAAAGACGGAGGGGAAAGGGACATGACGGACTTTACCAGGGCCTGAGCACTGCCACGAAGGACACCTATGATGCCCTGCACATGCAGGCGCTGCCGCCTCGG
配列番号50は、CAR LTG1563(LP−CD19−TNFRSF19TM−41BB−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFDTALAAVICSALATVLLALLILCVIYCKRQPRRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号51は、CAR LTG2228(LP−CD20_CD19−CD8TM−CD28−CD3ゼータ)のアミノ酸配列である。
ATGCTCCTTCTCGTGACCTCCCTGCTTCTCTGCGAACTGCCCCATCCTGCCTTCCTGCTGATTCCCGAGGTGCAGTTGCAACAGTCAGGAGCTGAACTGGTCAAGCCAGGAGCCAGCGTGAAGATGAGCTGCAAGGCCTCCGGTTACACCTTCACCTCCTACAACATGCACTGGGTGAAACAGACCCCGGGACAAGGGCTCGAATGGATTGGCGCCATCTACCCCGGGAATGGCGATACTTCGTACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGCCGACAAGAGCTCCTCCACCGCGTATATGCAGTTGAGCTCCCTGACCTCCGAGGACTCCGCCGACTACTACTGCGCACGGTCCAACTACTATGGAAGCTCGTACTGGTTCTTCGATGTCTGGGGGGCCGGCACCACTGTGACCGTCAGCTCCGGGGGCGGAGGATCCGGTGGAGGCGGAAGCGGGGGTGGAGGATCCGACATTGTGCTGACTCAGTCCCCGGCAATCCTGTCGGCCTCACCGGGCGAAAAGGTCACGATGACTTGTAGAGCGTCGTCCAGCGTGAACTACATGGATTGGTACCAAAAGAAGCCTGGATCGTCACCCAAGCCTTGGATCTACGCTACATCTAACCTGGCCTCCGGCGTGCCAGCGCGGTTCAGCGGGTCCGGCTCGGGCACCTCATACTCGCTGACCATCTCCCGCGTGGAGGCTGAGGACGCCGCGACCTACTACTGCCAGCAGTGGTCCTTCAACCCGCCGACTTTTGGAGGCGGTACTAAGCTGGAGATCAAAGGAGGCGGCGGCAGCGGCGGGGGAGGGTCCGGAGGGGGTGGTTCTGGTGGAGGAGGATCGGGAGGCGGTGGCAGCGACATTCAGATGACTCAGACCACCTCCTCCCTGTCCGCCTCCCTGGGCGACCGCGTGACCATCTCATGCCGCGCCAGCCAGGACATCTCGAAGTACCTCAACTGGTACCAGCAGAAGCCCGACGGAACCGTGAAGCTCCTGATCTACCACACCTCCCGGCTGCACAGCGGAGTGCCGTCTAGATTCTCGGGTTCGGGGTCGGGAACTGACTACTCCCTTACTATTTCCAACCTGGAGCAGGAGGATATTGCCACCTACTTCTGCCAACAAGGAAACACCCTGCCGTACACTTTTGGCGGGGGAACCAAGCTGGAAATCACTGGCAGCACATCCGGTTCCGGGAAGCCCGGCTCCGGAGAGGGCAGCACCAAGGGGGAAGTCAAGCTGCAGGAATCAGGACCTGGCCTGGTGGCCCCGAGCCAGTCACTGTCCGTGACTTGTACTGTGTCCGGAGTGTCGCTCCCGGATTACGGAGTGTCCTGGATCAGGCAGCCACCTCGGAAAGGATTGGAATGGCTCGGAGTCATCTGGGGTTCCGAAACCACCTATTACAACTCGGCACTGAAATCCAGGCTCACCATTATCAAGGATAACTCCAAGTCACAAGTGTTCCTGAAGATGAATAGCCTGCAGACTGACGACACGGCGATCTACTATTGCGCCAAGCACTACTACTACGGCGGATCCTACGCTATGGACTACTGGGGCCAGGGGACCAGCGTGACCGTGTCATCCGCGGCCGCGACTACCACTCCTGCACCACGGCCACCTACCCCAGCCCCCACCATTGCAAGCCAGCCACTTTCACTGCGCCCCGAAGCGTGTAGACCAGCTGCTGGAGGAGCCGTGCATACCCGAGGGCTGGACTTCGCCTGTGACATCTACATCTGGGCCCCATTGGCTGGAACTTGCGGCGTGCTGCTCTTGTCTCTGGTCATTACCCTGTACTGCCGGTCGAAGAGGTCCAGACTCTTGCACTCCGACTACATGAACATGACTCCTAGAAGGCCCGGACCCACTAGAAAGCACTACCAGCCGTACGCCCCTCCTCGGGATTTCGCCGCATACCGGTCCAGAGTGAAGTTCAGCCGCTCAGCCGATGCACCGGCCTACCAGCAGGGACAGAACCAGCTCTACAACGAGCTCAACCTGGGTCGGCGGGAAGAATATGACGTGCTGGACAAACGGCGCGGCAGAGATCCGGAGATGGGGGGAAAGCCGAGGAGGAAGAACCCTCAAGAGGGCCTGTACAACGAACTGCAGAAGGACAAGATGGCGGAAGCCTACTCCGAGATCGGCATGAAGGGAGAACGCCGGAGAGGGAAGGGTCATGACGGACTGTACCAGGGCCTGTCAACTGCCACTAAGGACACTTACGATGCGCTCCATATGCAAGCTTTGCCCCCGCGG
配列番号52は、CAR LTG2228(LP−CD20_CD19−CD8TM−CD28−CD3ゼータ)のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPEVQLQQSGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGQGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSADYYCARSNYYGSSYWFFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPAILSASPGEKVTMTCRASSSVNYMDWYQKKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSFNPPTFGGGTKLEIKGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Claims (37)
- 各ベクターが機能的CARをコードする少なくとも2つのベクターをコードする1または複数の単離された核酸分子を含む免疫療法組成物であって、前記ベクターの内の1つにおける少なくとも1つの結合ドメイン(複数可)が同一でなく、それによりベクターの組合せが2つ以上の同一でない結合ドメインの発現を生じ、各ベクターによりコードされた結合ドメイン(複数可)が膜貫通ドメインおよび1または複数の同一でない細胞内シグナル伝達モチーフに共有結合で連結されている、免疫療法組成物。
- (a)細胞中で機能的である核酸配列をそれぞれが含む少なくとも2つのベクターを含む免疫療法組成物であって、
(b)各ベクターが機能的CARをコードし;
(c)各CARが少なくとも1つの結合ドメイン、単一膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフから構成され;
(d)前記ベクターの内の1つにおける前記少なくとも1つの結合ドメインが同一でなく;ならびに
(e)前記少なくとも1つの結合ドメイン、単一膜貫通ドメイン、少なくとも1つのリンカードメインおよび少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合で連結されており、ベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、
免疫療法組成物。 - (a)細胞中で機能的である核酸配列をそれぞれが含む少なくとも2つのベクターを含む免疫療法組成物であって、
(b)各ベクターが機能的CARをコードし;
(c)各CARが少なくとも1つの結合ドメイン、単一膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフを含み;
(d)各ベクター中の前記少なくとも1つの結合ドメイン(複数可)が同一でなく;
(e)少なくとも1つのシグナル伝達モチーフ組合せが前記各ベクターの間で同一でなく;
(f)前記少なくとも1つの結合ドメイン、単一膜貫通ドメイン、および少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合で連結されており、2つ以上のベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、
免疫療法組成物。 - 各ベクターが1つよりも多い機能的CARをコードする、請求項1から3に記載の免疫療法組成物。
- 前記リンパ球集団(複数可)が自家T細胞または末梢血由来リンパ球の混合物を含む、請求項2または3に記載の免疫療法組成物。
- CARの少なくとも1つの細胞外抗原結合性ドメインが、抗原に結合する抗体の少なくとも1つの単鎖可変断片を含む、請求項2または3に記載の免疫療法組成物。
- CARの少なくとも1つの細胞外抗原結合性ドメインが、抗原に結合する抗体の少なくとも1つの重鎖可変領域を含む、請求項2または3に記載の免疫療法組成物。
- CARの少なくとも1つの細胞外抗原結合性ドメイン、CARの少なくとも1つの細胞内シグナル伝達ドメイン、またはその両方が、リンカーまたはスペーサードメインによって膜貫通ドメインに接続されている、請求項2または3に記載の免疫療法組成物。
- CARの細胞外抗原結合性ドメインにリーダーペプチドが先行する、請求項2または3に記載の免疫療法組成物。
- CARの細胞外抗原結合性ドメインが、CD19、CD20、CD22、ROR1、TSLPR、メソセリン、CD33、CD38、CD123(IL3RA)、CD138、BCMA(CD269)、GPC2、GPC3、FGFR4、c−Met、PSMA、糖脂質F77、EGFRvIII、GD−2、NY−ESO−1 TCR、MAGE A3 TCR、またはそれらの任意の組合せを含む抗原を標的化する、請求項2または3に記載の免疫療法組成物。
- CARの細胞外抗原結合性ドメインが、抗CD19 scFV抗原結合性ドメイン、抗CD20 scFV抗原結合性ドメイン、抗CD22 scFV抗原結合性ドメイン、抗ROR1 scFV抗原結合性ドメイン、抗TSLPR scFV抗原結合性ドメイン、抗メソセリンscFV抗原結合性ドメイン、抗CD33 scFV抗原結合性ドメイン、抗CD38 scFV抗原結合性ドメイン、抗CD123(IL3RA)scFV抗原結合性ドメイン、抗CD138 scFV抗原結合性ドメイン、抗BCMA(CD269)scFV抗原結合性ドメイン、抗GPC2 scFV抗原結合性ドメイン、抗GPC3 scFV抗原結合性ドメイン、抗FGFR4 scFV抗原結合性ドメイン、抗c−Met scFV抗原結合性ドメイン、抗PMSA scFV抗原結合性ドメイン、抗糖脂質F77 scFV抗原結合性ドメイン、抗EGFRvIII scFV抗原結合性ドメイン、抗GD−2 scFV抗原結合性ドメイン、抗NY−ESo−1 TCR scFV抗原結合性ドメイン、抗MAGE A3 TCR scFV抗原結合性ドメイン、または85%、90%、95%、96%、97%、98%もしくは99%の同一性を有するそのアミノ酸配列、あるいはそれらの任意の組合せを含む、請求項2または3に記載の免疫療法組成物。
- CARのリンカーまたはスペーサードメインが、CD8の細胞外ドメインに由来し、膜貫通ドメインに連結されている、請求項2または3に記載の免疫療法組成物。
- CARが、T細胞受容体のアルファ、ベータもしくはゼータ鎖、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、CD271、TNFRSF19、またはそれらの任意の組合せからなる群から選択されるタンパク質の膜貫通ドメインを含む膜貫通ドメインをさらに含む、請求項2または3に記載の免疫療法組成物。
- 少なくとも1つの細胞内シグナル伝達ドメインが、CD3ゼータ細胞内ドメインをさらに含む、請求項2または3に記載の免疫療法組成物。
- 少なくとも1つの細胞内シグナル伝達ドメインが、CD3ゼータ細胞内ドメインに対してC末端側に配置されている、請求項2または3に記載の免疫療法組成物。
- 少なくとも1つの細胞内シグナル伝達ドメインが、共刺激ドメイン、一次シグナル伝達ドメイン、またはそれらの任意の組合せを含む、請求項2または3に記載の免疫療法組成物。
- 少なくとも1つの共刺激ドメインが、OX40、CD70、CD27、CD28、CD5、ICAM−1、LFA−1(CD11a/CD18)、ICOS(CD278)、DAP10、DAP12および4−1BB(CD137)の機能的シグナル伝達ドメイン、またはそれらの任意の組合せを含む、請求項16に記載の免疫療法組成物。
- 単一ウイルスベクターが、組込みのためのCRISPRシステムとの組合せで、全てのキメラ抗原受容体(例えばアデノ、SV40、ヘルペスベクター、POXベクターまたはコスミドベクター)をコードするために使用される、請求項1〜3のいずれか1項に記載の免疫療法組成物。
- 各ベクターがRNAまたはDNAベクターである、請求項1〜3のいずれか1項に記載の免疫療法組成物。
- 少なくとも1つのベクターが前記細胞における核酸の発現を調節する核酸分子を発現する、請求項1〜3のいずれか1項に記載の免疫療法組成物。
- 前記核酸分子が内因性遺伝子の発現を阻害するまたは欠失させる、請求項20に記載の免疫療法組成物。
- ヒトリンパ球細胞の集団の抗腫瘍有効量を含む医薬組成物であって、前記集団の前記細胞が、各ベクターが機能的CARをコードする少なくとも2つのベクターをコードする核酸分子を含む細胞を含み、前記ベクターの内の1つにおける少なくとも1つの結合ドメイン(複数可)が同一でなく、それによりベクターの組合せが2つ以上の同一でない結合ドメインの発現を生じ、各ベクターによりコードされた結合ドメイン(複数可)が膜貫通ドメインおよび1または複数の同一でない細胞内シグナル伝達モチーフに共有結合的に連結されている、医薬組成物。
- ヒトリンパ球細胞の集団の抗腫瘍有効量を含む医薬組成物であって、前記集団の前記細胞が(a)2つ以上のベクターをコードする核酸分子を含む細胞を含み;(b)各ベクターが機能的CARをコードし;(c)各CARが少なくとも1つの結合ドメイン、少なくとも1つの膜貫通ドメイン、少なくとも1つのリンカードメインおよび少なくとも1つの細胞内シグナル伝達モチーフから構成され;(d)前記ベクターの内の1つにおける前記少なくとも1つの結合ドメインが同一でなく;ならびに(e)前記少なくとも1つの結合ドメイン、単一膜貫通ドメイン、少なくとも1つのリンカードメインおよび少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合的に連結されており、ベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、医薬組成物。
- ヒトリンパ球細胞の集団の抗腫瘍有効量を含む医薬組成物であって、前記集団の前記細胞が(a)2つ以上のベクターをコードする核酸分子を含む細胞を含み;(b)各ベクターが機能的CARをコードし;(c)各CARが少なくとも1つの結合ドメイン、少なくとも1つの膜貫通ドメイン、少なくとも1つのリンカードメインおよび少なくとも1つの細胞内シグナル伝達モチーフを含み;(d)各ベクター中の前記少なくとも1つの結合ドメイン(複数可)が同一でなく;(e)少なくとも1つのシグナル伝達モチーフ組合せが前記各ベクター間で同一でなく;ならびに(f)前記少なくとも1つの結合ドメイン、単一膜貫通ドメイン、少なくとも1つのリンカードメインおよび少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合的に連結されており、2つ以上のベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、医薬組成物。
- リンパ球細胞が、血液学的がんを有するヒトのT細胞である、請求項23または24に記載の医薬組成物。
- 血液学的がんが、白血病またはリンパ腫である、請求項23または24に記載の医薬組成物。
- 白血病が、慢性リンパ性白血病(CLL)、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)または慢性骨髄性白血病(CML)である、請求項23または24に記載の医薬組成物。
- リンパ腫が、マントル細胞リンパ腫、非ホジキンリンパ腫またはホジキンリンパ腫である、請求項23または24に記載の医薬組成物。
- 血液学的がんが多発性骨髄腫である、請求項23または24に記載の医薬組成物。
- ヒトがんが、口腔および咽頭がん(舌、口、咽頭、頭頸部)、消化器系がん(食道、胃、小腸、結腸、直腸、肛門、肝臓、肝内胆管、胆嚢、膵臓)、呼吸器系がん(喉頭、肺および気管支)、骨および関節のがん、軟組織がん、皮膚がん(黒色腫、基底細胞癌および扁平上皮癌)、小児腫瘍(神経芽細胞腫、横紋筋肉腫、骨肉腫、ユーイング肉腫)、中枢神経系の腫瘍(脳腫瘍、星状細胞腫、神経膠芽腫、神経膠腫)、ならびに乳房、生殖系(子宮頸部、子宮体、卵巣、外陰部、腟、前立腺、精巣、陰茎、子宮内膜)、泌尿器系(膀胱、腎臓および腎盂、尿管)、眼および眼窩、内分泌系(甲状腺)ならびに脳および他の神経系のがん、またはそれらの任意の組合せを含む成人癌を含む、請求項23または24に記載の医薬組成物。
- 腫瘍抗原の上昇した発現と関連する疾患、障害または状態を有する哺乳動物を処置する方法であって、各ベクターが機能的CARをコードする少なくとも2つのベクターおよび薬学的に許容される賦形剤を含む医薬組成物を対象に投与するステップを含み、前記ベクターの内の1つにおける少なくとも1つの結合ドメイン(複数可)が同一でなく、それによりベクターの組合せが2つ以上の同一でない結合ドメインの発現を生じ、各ベクターによりコードされた結合ドメイン(複数可)が膜貫通ドメインおよび1または複数の同一でない細胞内シグナル伝達モチーフに共有結合的に連結されており、ベクターの前記組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、方法。
- 腫瘍抗原の上昇した発現と関連する疾患、障害または状態を有する哺乳動物を処置する方法であって、(a)2つ以上のベクターをコードする核酸分子を含み、;(b)各ベクターが機能的CARをコードし;(c)各CARが少なくとも1つの結合ドメイン、少なくとも1つの膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフから構成され;(d)前記ベクターの内の1つの前記少なくとも1つの結合ドメインが同一でなく;ならびに(e)前記少なくとも1つの結合ドメイン、単一膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合的に連結されており、ベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、医薬組成物を対象に投与するステップを含む方法。
- 腫瘍抗原の上昇した発現と関連する疾患、障害または状態を有する哺乳動物を処置する方法であって、(a)2つ以上のベクターをコードする核酸分子を含み;(b)各ベクターが機能的CARをコードし;(c)各CARが少なくとも1つの結合ドメイン、少なくとも1つの膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフを含み;(d)各ベクター中の前記少なくとも1つの結合ドメイン(複数可)が同一でなく;(e)少なくとも1つのシグナル伝達モチーフ組合せが前記各ベクター間で同一でなく;ならびに(f)前記少なくとも1つの結合ドメイン、単一膜貫通ドメインおよび少なくとも1つの細胞内シグナル伝達モチーフが前記各ベクターにおいて共有結合的に連結されており、2つ以上のベクターの組合せが1または複数のリンパ球集団を遺伝子改変するために使用される、医薬組成物を対象に投与するステップを含む方法。
- 遺伝子改変されるリンパ球が自家リンパ球であり、前記自家または同種リンパ球が、悪性疾患の再発を予防するように患者に直接、注入により戻される、請求項31〜33のいずれか1項に記載の方法。
- 遺伝子改変されるリンパ球が自家T細胞であり、前記自家T細胞が、腫瘍の安定化、低減、排除、緩解またはがんもしくはがんの再発の排除を生じる患者特異的抗腫瘍T細胞のin vivo増殖、持続を患者特異的に促進するために患者に直接、注入により戻される、請求項31〜33のいずれか1項に記載の方法。
- T細胞が、特異的活性化またはメモリー関連表面マーカーを発現することによって事前選択されている、請求項31〜33のいずれか1項に記載の方法。
- T細胞および樹状細胞が造血幹細胞ドナーに由来し、この手順が造血幹細胞移植の状況で実施される、請求項31〜33のいずれか1項に記載の方法。
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