JP2021502070A - 抗ror1免疫療法によってがんを処置するための組成物および方法 - Google Patents
抗ror1免疫療法によってがんを処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本願は、米国特許法第119(e)条に準拠して、2017年11月3日付で提出された米国仮特許出願第62/581,284号に基づく優先権を主張する。同米国仮特許出願の全記載内容を引用により本明細書に援用する。
本願は、ASCII様式にて電子的に提出された配列表を含み、この配列表の全体を引用により本明細書に援用する。このASCIIのコピー(2018年10月25日作成)のファイル名は「SequenceListing.txt」であり、サイズは90.0キロバイトである。
本発明は、アメリカ国立衛生研究所と米国保健福祉省の一機関との共同研究開発契約(Cooperative Research and Development Agreement)の実現によってなされたものである。米国政府は、本発明において一定の権利を有する。
本願は、がんの分野、特に、ROR1抗原結合ドメイン、このROR1抗原結合ドメインを含有するキメラ抗原受容体(CAR)、およびその使用方法に関する。
がんは、人間の健康にとって非常に致死率の高い脅威の1つである。がんは、米国だけで毎年130万人近くが新たに罹患し、死亡原因としては心血管疾患に続いて第2位であり、死亡例の4例に1例はがんによるものである。こうした死亡例のほとんどは固形腫瘍が原因である。いくつかの特定のがんの医学的処置は著しく進歩したが、すべてのがんを合わせた5年生存率は、過去20年間で約10%しか改善されていない。がんまたは悪性腫瘍の転移および増殖は急速かつ制御不可能であるため、処置が極めて困難である。
新規の抗ROR1抗体、またはその抗原結合ドメイン、およびこのようなROR1抗原結合ドメインを含有するキメラ抗原受容体(CAR)、および、この受容体を発現する宿主細胞(たとえば、T細胞)、およびこの受容体をコードする核酸分子が、本明細書中において提供される。このCARは、形質導入T細胞上での表面発現が高く、細胞溶解の程度が高く、かつ形質導入T細胞がin vivoにおいて増殖および持続する。さらに、たとえば、対象におけるがんを処置するための、開示されるCAR、宿主細胞、および核酸分子の使用方法が提供される。
定義
本明細書中において使用される場合、単数形「a」、「an」、および「the」は、文脈上明らかな矛盾がない限り、単数形と複数形の両方を指す。たとえば、用語「an antigen(抗原)」は、1つまたは複数の抗原を含み、「少なくとも1つの抗原」という言葉と同等であるとみなし得る。本明細書中において使用される場合、用語「comprises」は「includes」を意味する。したがって、「comprising an antigen」は、他の要素を除外しない「including an antigen」を意味する。「および/または」という言葉は、「および」または「または」を意味する。さらに、特に記載がない限り、核酸またはポリペプチドに与えられる任意のおよびすべての塩基の大きさまたはアミノ酸の大きさならびにすべての分子量または分子質量の値は、近似値であり、説明目的で提供されることが理解される。本明細書中に記載されるものと類似または同等の多くの方法および材料を使用できるが、特に好適な方法および材料が以下に記載される。万一矛盾がある場合には、本明細書(用語の説明を含む)が支配する。これに加えて、材料、方法、および例示は、例証することのみを目的とし、限定を意図しない。多様な実施形態の確認を容易にするために、以下に用語の説明が提供される。
本明細書中に開示されるCARは、ROR1に結合できる少なくとも1つのROR1抗原結合ドメインと、少なくとも1つの膜貫通ドメインと、少なくとも1つの細胞内ドメインとを含む。
一実施形態において、CARは、抗原結合ドメインまたは部位とも称される標的特異的結合要素を含む。ドメインの選択は、標的細胞の表面を定めるリガンドの種類および数に依存する。たとえば、抗原結合ドメインは、特定の疾患状態に関連する標的細胞上において細胞表面マーカーとして働くリガンドを認識するように選択されてよい。したがって、CARにおける抗原結合ドメインのリガンドとして働き得る細胞表面マーカーの例は、ウイルス感染、細菌感染、および寄生虫感染、自己免疫疾患、およびがん細胞に関連するものを含む。
膜貫通ドメインに関して、CARは、当該CARの細胞外ROR1抗原結合ドメインに融合した1つ以上の膜貫通ドメインを含む。
CARにおいて、細胞外ドメインと膜貫通ドメインとの間、または細胞内ドメインと膜貫通ドメインとの間に、スペーサドメインが配置されていてよい。スペーサドメインとは、膜貫通ドメインを細胞外ドメインと、および/または膜貫通ドメインを細胞内ドメインと結合させるように働く、任意のオリゴペプチドまたはポリペプチドを意味する。スペーサドメインは、アミノ酸上限300個まで、好ましくはアミノ酸10〜100個、最も好ましくはアミノ酸25〜50個を含む。
CARの細胞質ドメインまたは細胞内シグナル伝達ドメインは、CARが導入さ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」は、細胞の特殊機能を指す。たとえば、T細胞のエフェクター機能は、細胞溶解活性、またはサイトカインの分泌を含むヘルパー活性であり得る。よって、用語「細胞内シグナル伝達ドメイン」は、エフェクター機能シグナルを伝達し細胞が特殊機能を果たすように仕向ける、タンパク質部分を指す。通常は細胞内シグナル伝達ドメインの全体を使用できるが、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を切断した一部が使用される場合、この切断部分がエフェクター機能シグナルを伝達できる限りは、これを完全な鎖の代わりに使用してよい。したがって、用語「細胞内シグナル伝達ドメイン」の意味には、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切断部分が含まれる。
本明細書中に開示されるCARの機能的部分もまた、本発明の範囲内に明白に含まれる。用語「機能的部分」は、CARに言及して使用される場合、本明細書中に開示されるCARの1種以上の任意の部分または断片を指し、この部分または断片は、当該CAR(親CAR)の生物学的活性を保持する。機能的部分は、たとえば、親CARと類似する程度に、親CARと同程度に、または親CARよりも高程度に、標的細胞の認識、または疾患の検出、処置、もしくは予防を行なう能力を保持する、CAR部分を包含する。親CARに関して、機能的部分は、たとえば、親CARの約10%、25%、30%、50%、68%、80%、90%、95%、またはそれ以上を含み得る。
一実施形態は、本明細書中に開示される抗原の1つ以上に特異的に結合する、CAR、CARを発現するT細胞、抗体、またはその抗原結合ドメインもしくは一部分をさらに提供する。本明細書中において使用される場合、「CARを発現するT細胞」または「CAR T細胞」は、CARを発現するT細胞を意味し、たとえばCARの抗体由来標的ドメインによって決定される、抗原特異性を有する。
本明細書中に開示される抗原の1つ以上に対して特異的な、CAR、CARを発現するT細胞、またはモノクローナル抗体、またはその抗原結合断片は、当業者に周知の多くの手段のうち任意の手段を使用して、エフェクター分子または検出可能なマーカーなどの剤に結合されていてよい。共有結合による手段および非共有結合による手段のいずれを使用してもよい。結合体は、本明細書中に開示される抗原の1つ以上に対して特異的に結合する抗体または抗原結合断片と、エフェクター分子または検出可能なマーカーとが共有結合している分子を含むが、これらに限定されない。当技術分野における当業者には、化学療法剤、抗血管新生剤、毒素、125I、32P、14C、3H、および35Sなどの放射性剤、ならびに、他の標識、標的部位、およびリガンドなどを含む(がこれらに限定されない)多様なエフェクター分子および検出可能なマーカーを使用できるということが理解される。
本発明の一実施形態によって、本明細書中に記載されるCAR、抗体、またはその抗原結合部分(その機能的部分および機能的バリアントを含む)のうち任意のものをコードするヌクレオチド配列を含む核酸がさらに提供される。本発明に係る核酸は、本明細書中に記載されるリーダー配列、抗原結合ドメイン、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うち任意のものをコードするヌクレオチド配列を含んでよい。
本明細書中に開示されるCARを哺乳動物における疾患の処置または予防方法において使用してよいことが意図される。この点において、一実施形態は、哺乳動物におけるがんの処置または予防方法を提供し、これは、哺乳動物に、CAR、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/またはその抗原結合部分、および/または医薬組成物を、哺乳動物におけるがんの処置または予防に有効な量にて投与する工程を含む。
本明細書中に開示される1つ以上の抗原に特異的に結合する、開示されるCAR、またはCARを発現するT細胞、抗体、抗原結合断片、結合体、CAR、またはCARを発現するT細胞のうち1種以上を、担体(製薬学的に許容される担体など)中に含む、バイオ医薬組成物または生物組成物(以下、「組成物」)が、本明細書中において、遺伝子療法、免疫療法、および/または細胞療法における使用を目的として提供される。この組成物は、対象への投与のために単位投薬形態にて調製されてよい。投与の量およびタイミングは、所望される転帰を達成するために、処置担当臨床医によって判断される。この組成物は、全身(静脈内など)または局所(腫瘍内など)への投与を目的として配合されてよい。一例において、開示されるCAR、またはCARを発現するT細胞、抗体、抗原結合断片、結合体は、静脈内投与などの非経口投与を目的として配合される。本明細書中に開示されるCAR、またはCARを発現するT細胞、結合体、抗体、または抗原結合断片を含む組成物は、たとえば、腫瘍(たとえば、神経芽細胞腫であるが、これに限定されない)の処置および検出に有用である。いくつかの例において、この組成物は、癌の処置または検出に有用である。本明細書中に開示されるCAR、またはCARを発現するT細胞、結合体、抗体、または抗原結合断片を含む組成物は、たとえば病理学的血管新生の検出にも有用である。
一態様において、本明細書中に開示されるCARを使用するキットがさらに提供される。たとえば、対象における腫瘍を処置するための、または本明細書中に開示されるCARの1種以上を発現するCAR T細胞を作製するためのキットである。こうしたキットは、典型的には、本明細書中に開示される抗体、抗原結合断片、結合体、核酸分子、CAR、またはCARを発現するT細胞を含んでよい。開示される抗体、抗原結合断片、結合体、核酸分子、CAR、またはCARを発現するT細胞のうち1種を超えるものが、キット中に含まれてよい。
本発明が、以下の実施例によってさらに例証されるが、これらの実施例は、本発明の範囲を限定すると解釈されるべきではない。逆に、様々な他の実施形態、改変、および等価物に頼らなければならず、こうした他の実施形態、改変、および等価物は、本発明の精神および/または付属の請求項の範囲から逸脱することなく、本明細書の記載を読んだ後、当業者の念頭に浮かび得るということが明瞭に理解される。
材料および方法:
a)ヒトROR1に対する完全ヒトScFc(分析のためのFcドメインを有するScFv)バインダの作製
健康なドナー50人の末梢血B細胞から構築されたナイーブヒトScFv(免疫グロブリンの組換え一本鎖可変断片)ファージディスプレイライブラリ(およその多様性として、ユニークな特異性が1010)(Z.Y.ZhuおよびD.S.Dimitrov、データは未発表)を使用して、組換えヒトROR1タンパク質のためのScFvを選択した。ファージディスプレイさせた1012個のScFvの増幅ライブラリを、5μg、3μg、および1μgにて被覆したROR1と共に、体積5×100μl(96ウェルプレートの5つのウェル中に等しく分配)にて、1回目、2回目、および3回目のバイオパニングの間、各回につき2時間ずつ、室温でインキュベートした。各回のインキュベーションの後、1回目の後には5回、以降の回の後には10回、0.05% Tween20(PBST)含有リン酸緩衝生理食塩水でウェルを洗浄して、非特異的に結合したファージを除去し、結合したファージは37℃において1時間かけてTG1コンピテントセルと混合し、感染した細胞から当該ファージを増幅して次の回のバイオパニングにおいて使用した。3回目のバイオパニングの実施後、感染したTG1細胞から380個のクローンを無作為に選び、その1つ1つを、96ウェルプレート中の100μg/ml カルベニシリンおよび0.2%グルコースを含有する2YT培地150μl中に接種した。この細菌培養物の600nmでの光学濃度(OD600)が0.5に達した後、感染多重度(MOI)が10のヘルパーファージM13K07および50μg/ml(最終濃度)のカナマイシンを培地に添加し、プレートを30℃においてさらに一晩、250rpmの振とう器中にてインキュベートした。ファージ上清を3%脱脂乳(PBS中)と体積比4:1にて混合して、酵素結合免疫吸着検定法(ELISA)に使用し、ROR1結合親和性の高いScFvを提示するファージのクローンを特定した。96ウェルプレートの各ウェルに50ngずつ被覆した組換えヒトROR1と共に、上清を室温で2時間インキュベートし、PBSTで5回洗浄した(4℃において一晩インキュベートした後、3%脱脂乳(PBS中)でブロッキングし、0.05% Tween20を含有するPBSで3回洗浄した)。ROR1結合ファージを、西洋ワサビペルオキシダーゼ標識ヤギ抗M13抗体を使用して検出した。この標的抗体と共にインキュベートした後、ウェルを洗浄することによって、非特異的に結合した抗体を除去し、3,3’,5,5’−テトラメチルベンジジン(TMB)基質を添加し、溶液の吸光度を450nmにおいて測定した(A450)。A450が1.0を超えたROR1結合クローンを選択して、さらなる特徴づけに供した。
選択したクローンのVHおよびVLのDNA配列を決定し、クローンによってコードされる、固有の配列を有するScFvを、以下に記載される通りに発現させ、精製した。当該クローンから抽出したプラスミドを使用して、HB2151細胞を形質転換した。新たに形質転換させた細胞の入ったプレートから単一コロニーを選び、これを、100μg/mlのアンピシリンおよび0.2%グルコースを含有する2YT培地200ml中に接種して、250rpmにて振とうしながら37℃においてインキュベートした。この培養物の600nmにおけるODが0.90に達したときに、イソプロピル−β−d−チオガラクトピラノシドを最終濃度0.5mMとなるように添加して、培養物を30℃においてさらに一晩インキュベートした。8,000×gにおいて20分間遠心分離して細菌ペレットを採取し、これを、0.5mU ポリミキシンB(Sigma−Aldrich、St.Louis、MO)を含有するPBSバッファー中に再懸濁した。50rpmにて回転させながら室温において30分間インキュベートした後、再懸濁したペレットを25,000×gで4℃において25分間遠心分離し、上清を使用して、Ni−NTA樹脂を用いて、業者のプロトコール(Qiagen)のとおりに、ScFvを精製した。
PBS中に2μg/mlにて希釈した組換えヒトROR1 50μlを、4℃において一晩かけて96ウェルプレートに被覆した。HisタグおよびFlagタグを有する精製ScFvを段階希釈して、標的タンパク質で被覆したウェル中に添加した。洗浄後、1:3000にて希釈したHRP標識抗Flag抗体を、1時間かけて室温において添加した。洗浄後、3,3,5,5’−テトラメチルベンジジン(TMB)基質を添加し、室温において10分間インキュベートした後、1N H2SO4を添加して反応を停止させ、450nmでのO.D.を読み取って、ScFvの相対的なROR1結合能力を定量した。
組換えヒトROR1に対して特異的な2つのScFvクローンを特定して、ヒト抗ROR1 ScFvバインダ ScFv4およびScFv9として分類した。結合結果が極めて少ないということは、当該2つのバインダが、CARおよび免疫グロブリン治療用コンストラクトに組み入れることのできる、完全にユニークでありかつ重要な、新しいROR1結合部位であることを示す。LTG1941、LTG1942、LTG2528、およびLTG2529 ヒト抗ROR1バインダを発現するキメラ抗原受容体の作製が、下記の実施例2中に概説される。
ホモ・サピエンスROR1(受容体チロシンキナーゼ様オーファン受容体1)は、よく研究されているがん胚細胞表面糖タンパク質であり、慢性リンパ球性白血病(CLL)、および、肉腫の一部、癌、または肺の腺癌などの様々な固形腫瘍において発現している。再発または抵抗性の慢性リンパ球性白血病に対する抗ROR1抗体UC−961(シルムツズマブ(Cirtuzumab))の第1相研究が、現在進行中である(資金援助、Thomas Kipps、NCT02222688)。この第1級の研究の結果が待たれる。ROR1に特異的なCAR−Tを用いた第1相臨床試験も初期段階である(資金援助、フレッドハッチンソン癌研究所、NCT02706392)。本出願人らは、我々の研究を一定基準に基づいて評価するため、かつ我々のコンストラクトの活性を実証するために、発表されたROR1バインダを我々のコントロール(LTG1943、LTG2527)として含めた(Hudecekら,2013,Clin Cancer Res 19:3153−3164を参照)。最近では抗CD19 CARが市販されていることを含めて、T細胞に基づく療法の現時点での進歩を考慮すると、ROR1を発現するCLLおよび他の悪性腫瘍に対しての、本明細書中に提示されるCARコンストラクトを特徴とする、細胞に基づく免疫療法の開発は、ヒト配列に由来する結合部位を使用してヒトの疾患を処置するための革新的で新規のアプローチである。
(a)細胞株
すべての細胞株および試薬は、特記しない限り、American Tissue Culture Collection(ATCC、Manassass、VA)から購入したものである。急性リンパ球性白血病細胞株REHおよびマントル細胞リンパ腫株Jeko−1(ACC−553 DSMZ、Leibniz Institute DSMZ、Braunschwieg、ドイツ)、ならびに慢性骨髄性白血病株K562は、10%熱失活ウシ胎児血清(FBS、Hyclone、Logan、UT)および2mM L−Glutamax(Thermo Fisher Scientific、Grand Island、NY)を添加したRPMI−1640培地中で培養した。
ROR1 CARコンストラクトを、フレーム中の各scFvをCD8のヒンジドメインおよび膜貫通ドメイン(aa 141182〜191、UniProt番号P01732)のいずれか、またはIgG4ヒンジドメイン(aa 99〜110、UniProt配列番号P01861)と結合させ、続いて、CD8膜貫通ドメイン(aa 183〜203、UniProt配列番号P01732)、4−1BB(CD137、aa 214〜255、UniProt配列番号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、参照配列番号:NP_000725.1.)と結合させることによって、作製した。T細胞膜へのCARの輸送を促進するために、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からのリーダー配列を、すべてのコンストラクトに含めた。CARコンストラクトの配列は、コドン最適化して、第3世代レンチウイルスプラスミドバックボーン中にクローニングした(Lentigen Technology社、Gaithersburg、MD)。
CD4+およびCD8+細胞の免疫磁気ビーズ選択を製造元のプロトコールのとおりに使用して(Miltenyi Biotec、Bergisch Gladbach、ドイツ)、健康な志願者からのヒト初代T細胞を全血またはバフィーコート(民間供給元から購入、ドナーの同意を書面で得てある)から精製した。200IU/mlのIL−2を添加したTexMACS培地中において、T細胞を密度0.3〜2×106個/mlにて培養し、CD3/CD28 MACS(登録商標)GMP T細胞TransAct試薬(Miltenyi Biotec)を用いて活性化して、2日目に、CARコンストラクトをコードするレンチウイルスベクターを用いて、10μg/mlプロタミン硫酸塩(Sigma−Aldrich、St.Louis、MO)の存在下において一晩かけて形質導入し、3日目に培地を交換した。200IU/mlのIL−2を添加したTexMACS培地中において培養物を繁殖させてから、8〜12日目に回収した。
細胞介在性の細胞毒性を調べるために(CTLアッセイ)、ホタルルシフェラーゼを安定的に形質導入した標的細胞5,000個を、多様なエフェクター標的比(E:T)にてCAR T細胞と組み合わせて、一晩インキュベートした。SteadyGlo試薬(Promega、Madison WI)を各ウェルに添加し、得られた発光を、EnSpireプレートリーダー(Perkin Elmer、Shelton、Connecticut)で分析し、1秒あたりのカウントとして記録した(試料CPS)。標的のみのウェル(最大CPS)と、標的のみのウェルに1% Tween−20を添加したもの(最小CPS)とを使用して、アッセイ範囲を決定した。特異的溶解の割合を、(1−(試料CPS−最小CPS)/(最大CPS−最小CPS))として計算した。E:T比10にてエフェクターおよび腫瘍細胞株を同時インキュベーションした後で回収した上清に対して、サイトカイン放出アッセイを行なった。サイトカインIFNg、続いてIL−2を、ELISAによって3通りで測定した(Thermo Fischer、Waltham、MA)。
細胞の染色にあたり、CAR Tを形質導入した細胞50万個を培養物から回収して、0.5%ウシ血清アルブミン(Miltenyi Biotec)を添加した冷AutoMACSバッファー中において2回洗浄し、ROR1−Fcペプチド(R&D、Minneapolis、MN)、続いて抗Fc−AF647結合体で染色することによって、CAR表面発現を検出した(Jackson ImmunoResearch、West Grove、PA)。非形質導入細胞をネガティブコントロールとして使用した。すべての研究において、7AAD染色によって死細胞を除外した(BD Biosciences、San Jose、CA)。細胞を2回洗浄し、200μlの染色バッファー中に再懸濁した後、フローサイトメトリーによって定量分析した。MACSQuant(登録商標)10 Analyzer(Miltenyi Biotec)を使用してフローサイトメトリー分析を行ない、FlowJoソフトウェア(Ashland、OR)を使用してデータプロットを生成した。
GMCSFRに由来するリーダーペプチド、抗ヒトROR1 ScFv、CD8またはIgG4ヒンジ、CD8膜貫通ドメイン、4−1BB共刺激(costimulatiory)ドメイン、およびCD3z活性化ドメインの配列をフレーム中で組み合わせることによって、ROR1腫瘍抗原を標的とする完全ヒトCAR Tコンストラクトを設計した。このCAR Tコンストラクトの概略図、ならびに設計したコンストラクトおよび各ScFv標的ドメインのリストが提供される(図1および表1)。同一条件下において増殖させた非形質導入T細胞(UTD)を、コントロールとして含めた。
以下に列記される核酸およびアミノ酸配列は、37C.F.R.1.822で規定されるように、ヌクレオチド塩基の標準的な文字省略およびアミノ酸の3文字コードを使用して示される。各核酸配列について一方の鎖のみが示されるが、示された鎖に言及する場合にはその相補鎖が含まれることが理解される。付属の配列表において:
配列番号1 抗ROR1バインダ:ScFV4 のヌクレオチド配列
CAGGTGCAGCTGCAGGAGTCCGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATACCCGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACACCTGGGGGGTGATGCTTTTGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGGAGGCGGATCCCTGCCTGTGCTGACTCAGCCCCCCTCGGTGTCAGTGGCCCCAGGACAGACGGCCAGGATTACCTGTGGGGGGAACAACATTGGAAGTAAAAGTGTGCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCTATGATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTACTTCTGTCAGTCTTATGATAGCAGCAATCCCGTGGTATTCGGCGGAGGGACCCAGCTCACCGTTTTA
配列番号2 抗ROR1バインダ:ScFV4 のアミノ酸配列
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTIPVDTSKNQFSLKLSSVTAADTAVYYCARHLGGDAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSLPVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISGTQAMDEADYFCQSYDSSNPVVFGGGTQLTVL
配列番号3 ROR1−CAR DNA SEQ LTG1941(LP−ScFV4−CD8H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTTCAGCTGCAAGAATCAGGACCTGGGCTTGTCAAACCATCTGAAACCCTCAGCTTGACTTGTACCGTATCAGGAGGGTCAATTTCAAGCTCATCCTACTATTGGGGATGGATCAGACAACCACCCGGGAAAGGGCTCGAGTGGATAGGGTCCATATATTACAGCGGATCTACATACTACAACCCGTCATTGAAGTCCAGGGTAACGATTCCGGTGGACACTAGCAAGAATCAGTTTAGCCTCAAGTTGAGCAGTGTAACTGCTGCGGACACGGCGGTATATTATTGTGCTCGACACCTCGGTGGAGATGCTTTTGACATATGGGGTCAAGGGACAACAGTCACCGTTAGCTCAGGTGGAGGGGGTAGCGGGGGGGGCGGATCTGGGGGAGGCGGTTCATTGCCCGTACTTACACAGCCACCCTCTGTCAGCGTCGCACCTGGACAAACCGCTCGCATCACCTGTGGCGGAAATAATATAGGTTCCAAGTCTGTTCATTGGTATCAGCAGAAACCGGGACAGGCCCCCGTCCTTGTGGTGTATGATGATTCTGATAGGCCATCTGGTATCCCAGAACGGTTTTCAGGTAGCAATTCAGGGAATACTGCCACTCTCACTATTAGCGGTACTCAAGCTATGGATGAGGCCGACTATTTTTGCCAGAGCTACGACTCTAGTAACCCAGTCGTGTTCGGGGGAGGGACCCAGTTGACCGTGCTGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号4 ROR1−CAR AA SEQ LTG1941(LP−ScFV4−CD8H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQVQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTIPVDTSKNQFSLKLSSVTAADTAVYYCARHLGGDAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSLPVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISGTQAMDEADYFCQSYDSSNPVVFGGGTQLTVLAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号5 ROR1−CAR DNA SEQ LTG2528(LP−ScFV4−IgG4H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTTCAGCTGCAAGAATCAGGACCTGGGCTTGTCAAACCATCTGAAACCCTCAGCTTGACTTGTACCGTATCAGGAGGGTCAATTTCAAGCTCATCCTACTATTGGGGATGGATCAGACAACCACCCGGGAAAGGGCTCGAGTGGATAGGGTCCATATATTACAGCGGATCTACATACTACAACCCGTCATTGAAGTCCAGGGTAACGATTCCGGTGGACACTAGCAAGAATCAGTTTAGCCTCAAGTTGAGCAGTGTAACTGCTGCGGACACGGCGGTATATTATTGTGCTCGACACCTCGGTGGAGATGCTTTTGACATATGGGGTCAAGGGACAACAGTCACCGTTAGCTCAGGTGGAGGGGGTAGCGGGGGGGGCGGATCTGGGGGAGGCGGTTCATTGCCCGTACTTACACAGCCACCCTCTGTCAGCGTCGCACCTGGACAAACCGCTCGCATCACCTGTGGCGGAAATAATATAGGTTCCAAGTCTGTTCATTGGTATCAGCAGAAACCGGGACAGGCCCCCGTCCTTGTGGTGTATGATGATTCTGATAGGCCATCTGGTATCCCAGAACGGTTTTCAGGTAGCAATTCAGGGAATACTGCCACTCTCACTATTAGCGGTACTCAAGCTATGGATGAGGCCGACTATTTTTGCCAGAGCTACGACTCTAGTAACCCAGTCGTGTTCGGGGGAGGGACCCAGTTGACCGTGCTGGCGGCCGCAGAGTCAAAATACGGTCCTCCGTGCCCTCCGTGTCCGATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号6 ROR1−CAR AA SEQ LTG2528(LP−ScFV4−IgG4H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQVQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTIPVDTSKNQFSLKLSSVTAADTAVYYCARHLGGDAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSLPVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISGTQAMDEADYFCQSYDSSNPVVFGGGTQLTVLAAAESKYGPPCPPCPIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号7 抗ROR1バインダ:ScFV9 のヌクレオチド配列
CAGGCGGCCCAGGTACAGCTGCAGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAGGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGTTATAATGATGCTTTTGATATCTGGGGCCAAGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGGTGGCGGATCCAATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGACGGTAACCATCTCCTGCACCCGCAGCAGTGGCAGCATTGCCAGCAACTATGTGCAGTGGTACCAGCAGCGCCCGGGCAGTGCCCCCACCATTGTGATCTATGAGGATGATCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCCATCGACACCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGCAGAGTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGAGCCCGGCAATGGGGTATTCGGCGGAGGGACCAAGGTCACCGTCCTA
配列番号8 抗ROR1バインダ:ScFV9 のアミノ酸配列
QAAQVQLQQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGWINPNSGGTNYAQRFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCASYNDAFDIWGQGTLVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTIVIYEDDQRPSGVPDRFSGSIDTSSNSASLTISGLQSEDEADYYCQSYEPGNGVFGGGTKVTVL
配列番号9 ROR1−CAR DNA SEQ LTG1942(LP−ScFV9−CD8H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAGGCGGCCCAGGTACAGCTGCAGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAGGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGTTATAATGATGCTTTTGATATCTGGGGCCAAGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGGTGGCGGATCCAATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGACGGTAACCATCTCCTGCACCCGCAGCAGTGGCAGCATTGCCAGCAACTATGTGCAGTGGTACCAGCAGCGCCCGGGCAGTGCCCCCACCATTGTGATCTATGAGGATGATCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCCATCGACACCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGCAGAGTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGAGCCCGGCAATGGGGTATTCGGCGGAGGGACCAAGGTCACCGTCCTAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号10 ROR1−CAR AA SEQ LTG1942(LP−ScFV9−CD8H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQAAQVQLQQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGWINPNSGGTNYAQRFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCASYNDAFDIWGQGTLVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTIVIYEDDQRPSGVPDRFSGSIDTSSNSASLTISGLQSEDEADYYCQSYEPGNGVFGGGTKVTVLAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号11 ROR1−CAR DNA SEQ LTG2529(LP−ScFV9−IgG4H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAGGCGGCCCAGGTACAGCTGCAGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAGGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGTTATAATGATGCTTTTGATATCTGGGGCCAAGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGGTGGCGGATCCAATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGACGGTAACCATCTCCTGCACCCGCAGCAGTGGCAGCATTGCCAGCAACTATGTGCAGTGGTACCAGCAGCGCCCGGGCAGTGCCCCCACCATTGTGATCTATGAGGATGATCAAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGGCTCCATCGACACCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGCAGAGTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGAGCCCGGCAATGGGGTATTCGGCGGAGGGACCAAGGTCACCGTCCTAGCGGCCGCAGAGTCAAAATACGGTCCTCCGTGCCCTCCGTGTCCGATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号12 ROR1−CAR AA SEQ LTG2529(LP−ScFV9−IgG4H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQAAQVQLQQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGWINPNSGGTNYAQRFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCASYNDAFDIWGQGTLVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTIVIYEDDQRPSGVPDRFSGSIDTSSNSASLTISGLQSEDEADYYCQSYEPGNGVFGGGTKVTVLAAAESKYGPPCPPCPIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号13 コントロール抗ROR1バインダのヌクレオチド配列:
CAAGAACAGCTTGTAGAGTCCGGCGGTAGATTGGTGACACCGGGGGGGAGCCTTACCCTGTCTTGTAAGGCATCTGGGTTCGATTTCAGTGCGTATTATATGAGCTGGGTTCGGCAGGCGCCCGGGAAGGGGCTGGAATGGATAGCCACTATATACCCGTCATCCGGCAAGACTTACTACGCGACTTGGGTAAACGGGAGGTTTACGATAAGCTCAGATAACGCCCAAAACACGGTTGATCTCCAAATGAATAGCTTGACCGCCGCTGATAGGGCGACCTATTTCTGTGCGCGGGACTCTTACGCTGATGACGGGGCCCTCTTCAATATATGGGGACCGGGAACGCTCGTAACCATATCATCTGGAGGAGGTGGGAGCGGAGGCGGAGGGTCAGGTGGGGGCGGGAGCGAACTCGTACTTACACAATCTCCAAGCGTAAGCGCAGCGTTGGGGAGTCCAGCAAAGATCACCTGCACTTTGTCAAGCGCCCACAAAACGGATACGATAGATTGGTATCAGCAACTCCAAGGTGAAGCGCCACGATATCTCATGCAGGTACAGAGCGACGGGAGTTATACTAAGAGGCCCGGGGTCCCAGACAGATTCAGTGGCAGCAGTTCAGGTGCCGACAGATACCTGATAATACCCTCAGTTCAAGCCGATGATGAAGCCGATTACTACTGTGGGGCTGACTACATAGGTGGGTATGTTTTCGGGGGCGGCACTCAATTGACAGTTACAGGG
配列番号14 コントロール抗ROR1バインダのアミノ酸配列:
QEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYYATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTISSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAPRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGGGTQLTVTG
配列番号15 ROR1−CAR DNA SEQ コントロールLTG1943(LP−コントロールScFv−CD8H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGAACAGCTTGTAGAGTCCGGCGGTAGATTGGTGACACCGGGGGGGAGCCTTACCCTGTCTTGTAAGGCATCTGGGTTCGATTTCAGTGCGTATTATATGAGCTGGGTTCGGCAGGCGCCCGGGAAGGGGCTGGAATGGATAGCCACTATATACCCGTCATCCGGCAAGACTTACTACGCGACTTGGGTAAACGGGAGGTTTACGATAAGCTCAGATAACGCCCAAAACACGGTTGATCTCCAAATGAATAGCTTGACCGCCGCTGATAGGGCGACCTATTTCTGTGCGCGGGACTCTTACGCTGATGACGGGGCCCTCTTCAATATATGGGGACCGGGAACGCTCGTAACCATATCATCTGGAGGAGGTGGGAGCGGAGGCGGAGGGTCAGGTGGGGGCGGGAGCGAACTCGTACTTACACAATCTCCAAGCGTAAGCGCAGCGTTGGGGAGTCCAGCAAAGATCACCTGCACTTTGTCAAGCGCCCACAAAACGGATACGATAGATTGGTATCAGCAACTCCAAGGTGAAGCGCCACGATATCTCATGCAGGTACAGAGCGACGGGAGTTATACTAAGAGGCCCGGGGTCCCAGACAGATTCAGTGGCAGCAGTTCAGGTGCCGACAGATACCTGATAATACCCTCAGTTCAAGCCGATGATGAAGCCGATTACTACTGTGGGGCTGACTACATAGGTGGGTATGTTTTCGGGGGCGGCACTCAATTGACAGTTACAGGGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号16 ROR1−CAR AA SEQ コントロールLTG1943(LP−コントロールScFv−CD8H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYYATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTISSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAPRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGGGTQLTVTGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号17 ROR1−CAR DNA SEQ コントロールLTG2527(LP−コントロールScFv−IgG4H/CD8TM−41BB−CD3ゼータ)
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGAACAGCTTGTAGAGTCCGGCGGTAGATTGGTGACACCGGGGGGGAGCCTTACCCTGTCTTGTAAGGCATCTGGGTTCGATTTCAGTGCGTATTATATGAGCTGGGTTCGGCAGGCGCCCGGGAAGGGGCTGGAATGGATAGCCACTATATACCCGTCATCCGGCAAGACTTACTACGCGACTTGGGTAAACGGGAGGTTTACGATAAGCTCAGATAACGCCCAAAACACGGTTGATCTCCAAATGAATAGCTTGACCGCCGCTGATAGGGCGACCTATTTCTGTGCGCGGGACTCTTACGCTGATGACGGGGCCCTCTTCAATATATGGGGACCGGGAACGCTCGTAACCATATCATCTGGAGGAGGTGGGAGCGGAGGCGGAGGGTCAGGTGGGGGCGGGAGCGAACTCGTACTTACACAATCTCCAAGCGTAAGCGCAGCGTTGGGGAGTCCAGCAAAGATCACCTGCACTTTGTCAAGCGCCCACAAAACGGATACGATAGATTGGTATCAGCAACTCCAAGGTGAAGCGCCACGATATCTCATGCAGGTACAGAGCGACGGGAGTTATACTAAGAGGCCCGGGGTCCCAGACAGATTCAGTGGCAGCAGTTCAGGTGCCGACAGATACCTGATAATACCCTCAGTTCAAGCCGATGATGAAGCCGATTACTACTGTGGGGCTGACTACATAGGTGGGTATGTTTTCGGGGGCGGCACTCAATTGACAGTTACAGGGGCGGCCGCAGAGTCAAAATACGGTCCTCCGTGCCCTCCGTGTCCGATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号18 ROR1−CAR AA SEQ コントロールLTG2527(LP−コントロールScFv−IgG4H/CD8TM−41BB−CD3ゼータ)
MLLLVTSLLLCELPHPAFLLIPQEQLVESGGRLVTPGGSLTLSCKASGFDFSAYYMSWVRQAPGKGLEWIATIYPSSGKTYYATWVNGRFTISSDNAQNTVDLQMNSLTAADRATYFCARDSYADDGALFNIWGPGTLVTISSGGGGSGGGGSGGGGSELVLTQSPSVSAALGSPAKITCTLSSAHKTDTIDWYQQLQGEAPRYLMQVQSDGSYTKRPGVPDRFSGSSSGADRYLIIPSVQADDEADYYCGADYIGGYVFGGGTQLTVTGAAAESKYGPPCPPCPIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号19 リーダー/シグナルペプチド配列(LP)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCG
配列番号20 リーダー/シグナルペプチド配列(LP)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIP
配列番号21 DNA CD8膜貫通ドメインのヌクレオチド配列
ATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGC
配列番号22 CD8膜貫通ドメインのアミノ酸配列
IWAPLAGTCGVLLLSLVITLYC
配列番号23 DNA CD8ヒンジドメインのヌクレオチド配列
ACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTAC
配列番号24 CD8ヒンジドメインのアミノ酸配列
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY
配列番号25 CD8アルファのアミノ酸番号137〜206のヒンジおよび膜貫通領域のアミノ酸配列(NCBI REFSEQ:NP__001759.3)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC
配列番号26 4−1BBのシグナル伝達ドメインのヌクレオチド配列
AAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTG
配列番号27 4−1BBのシグナル伝達ドメインのアミノ酸配列
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
配列番号28 CD3−ゼータの細胞内シグナル伝達ドメインのヌクレオチド配列
CGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号29 CD3−ゼータのアミノ酸配列
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号30 CD3−ゼータの細胞内シグナル伝達ドメイン、バリアント、のヌクレオチド配列
CGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATAAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号31 CD3−ゼータシグナル伝達ドメイン、バリアント、のアミノ酸配列
RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号32 ScFV CD19(FMC63)のヌクレオチド配列
GACATTCAGATGACTCAGACCACCTCTTCCTTGTCCGCGTCACTGGGAGACAGAGTGACCATCTCGTGTCGCGCAAGCCAGGATATCTCCAAGTACCTGAACTGGTACCAACAGAAGCCCGACGGGACTGTGAAGCTGCTGATCTACCACACCTCACGCCTGCACAGCGGAGTGCCAAGCAGATTCTCCGGCTCCGGCTCGGGAACCGATTACTCGCTTACCATTAGCAACCTCGAGCAGGAGGACATCGCTACCTACTTCTGCCAGCAAGGAAATACCCTGCCCTACACCTTCGGCGGAGGAACCAAATTGGAAATCACCGGCGGAGGAGGCTCCGGGGGAGGAGGTTCCGGGGGCGGGGGTTCCGAAGTGAAGCTCCAGGAGTCCGGCCCCGGCCTGGTGGCGCCGTCGCAATCACTCTCTGTGACCTGTACCGTGTCGGGAGTGTCCCTGCCTGATTACGGCGTGAGCTGGATTCGGCAGCCGCCGCGGAAGGGCCTGGAATGGCTGGGTGTCATCTGGGGATCCGAGACTACCTACTACAACTCGGCCCTGAAGTCCCGCCTGACTATCATCAAAGACAACTCGAAGTCCCAGGTCTTTCTGAAGATGAACTCCCTGCAAACTGACGACACCGCCATCTATTACTGTGCTAAGCACTACTACTACGGTGGAAGCTATGCTATGGACTACTGGGGGCAAGGCACTTCGGTGACTGTGTCAAGC
配列番号33 ScFV CD19(FMC63)のアミノ酸配列
DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS
配列番号34 抗CD33 ScFV(LTG1936)のヌクレオチド配列
CAGGTGCAGCTGGTGCAATCTGGGGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGATTCAGTTTTCCCACCTACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCGAGACTAGTTGGAGATGGCTACAATACGGGGGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGTGGTGGCGGTAGCGGTGGTGGCGGATCCGATATTGTGATGACCCACACTCCACTCTCTCTGTCCGTCACCCCTGGACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAGAGCCTCCTGCATAGTAATGGAAAGACCTATTTGTATTGGTACCTGCAGAAGCCAGGCCAGCCTCCACAGCTCCTGATCTATGGAGCTTCCAACCGGTTCTCTGGAGTGCCAGACAGGTTCAGTGGCAGCGGGTCAGGGACAGATTTCACACTGAAAATCAGCCGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAAGTATACAGCTTCCTATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
配列番号35 抗CD33 ScFV(LTG1936)のアミノ酸配列
QVQLVQSGAEVKKPGESLRISCKGSGFSFPTYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARLVGDGYNTGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIVMTHTPLSLSVTPGQPASISCKSSQSLLHSNGKTYLYWYLQKPGQPPQLLIYGASNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQSIQLPITFGQGTRLEIK
配列番号36 抗メソテリンScFV(LTG1904)のヌクレオチド配列
GAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCGGCGGAGGCACCCAGCTGACCGTCCTCGGT
配列番号37 抗メソテリンScFV(LTG1904)のアミノ酸配列
EVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDLSSVAGPFNYWGQGTLVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHLVFGGGTQLTVLG
配列番号38 IgG4H(ヒンジ)のヌクレオチド配列
GAGTCAAAATACGGTCCTCCGTGCCCTCCGTGTCCG
配列番号39 IgG4H(ヒンジ)のアミノ酸配列
ESKYGPPCPPCP
配列番号40 CD8 TM(膜貫通)に結合したIgG4Hのヒンジドメインのヌクレオチド配列
GAGTCAAAATACGGTCCTCCGTGCCCTCCGTGTCCGATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGC
配列番号41 CD8 TM(膜貫通)に結合したIgG4Hのヒンジドメインのアミノ酸配列
ESKYGPPCPPCPIYIWAPLAGTCGVLLLSLVITLYC
Claims (48)
- 配列番号1または配列番号7を含むヌクレオチド配列でコードされるROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメインと、少なくとも1つの膜貫通ドメインと、少なくとも1つの細胞内シグナル伝達ドメインとを含むキメラ抗原受容体(CAR)をコードする、単離された核酸分子。
- コードされる前記少なくとも1つのROR1抗原結合ドメインは、ROR1に結合する抗体の少なくとも1つの一本鎖可変断片を含む、請求項1に記載の単離された核酸分子。
- コードされる前記少なくとも1つのROR1抗原結合ドメインは、ROR1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1に記載の単離された核酸分子。
- コードされる前記少なくとも1つのROR1抗原結合ドメイン、前記少なくとも1つの細胞内シグナル伝達ドメイン、またはその両方は、リンカーまたはスペーサドメインによって、前記膜貫通ドメインに結合される、請求項1に記載の単離された核酸分子。
- コードされる前記リンカーまたはスペーサドメインは、IgG4、CD8、またはCD28の細胞外ドメインに由来し、かつ、膜貫通ドメインに結合している、請求項4に記載の単離された核酸分子。
- コードされる前記細胞外のROR1抗原結合ドメインは、リーダーペプチドをコードするリーダーヌクレオチド配列の後ろに位置する、請求項1に記載の単離された核酸分子。
- 前記リーダーヌクレオチド配列は、配列番号20のリーダーアミノ酸配列をコードする配列番号19を含むヌクレオチド配列を含む、請求項6に記載の単離された核酸分子。
- 前記膜貫通ドメインは、T細胞受容体のアルファ、ベータ、もしくはゼータ鎖、CD8、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD83、CD86、CD134、CD137、CD154、およびTNFRSF19、またはこれらの任意の組み合わせを含むタンパク質の膜貫通ドメインを含む、請求項1に記載の単離された核酸分子。
- 前記細胞外のROR1抗原結合ドメインをコードする核酸配列は、配列番号1、3、5、7、9、もしくは11を含むヌクレオチド配列(nucleic sequence)、またはこれらとの同一性が85%、90%、95%、96%、97%、98%、もしくは99%である配列を含む、請求項1に記載の単離された核酸分子。
- コードされる前記少なくとも1つの細胞内シグナル伝達ドメインは、CD3ゼータ細胞内ドメインをさらに含む、請求項1に記載の単離された核酸分子。
- コードされる前記少なくとも1つの細胞内シグナル伝達ドメインは、前記CD3ゼータ細胞内ドメインよりもN末端側に位置している、請求項10に記載の単離された核酸分子。
- コードされる前記少なくとも1つの細胞内シグナル伝達ドメインは、共刺激ドメイン、一次シグナル伝達ドメイン、またはこれらの任意の組み合わせを含む、請求項1に記載の単離された核酸分子。
- コードされる前記少なくとも1つの共刺激ドメインは、OX40、CD70、CD27、CD28、CD5、ICAM−1、LFA−1(CD11a/CD18)、ICOS(CD278)、DAP10、DAP12、および4−1BB(CD137)、またはこれらの任意の組み合わせの機能的シグナル伝達ドメインを含む、請求項12に記載の単離された核酸分子。
- 請求項1に記載の単離された核酸分子によりコードされるキメラ抗原受容体(CAR)。
- 配列番号2または8のアミノ酸配列を含むROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメインと、少なくとも1つの膜貫通ドメインと、少なくとも1つの細胞内シグナル伝達ドメインとを含む、請求項14に記載のCAR。
- 前記ROR1抗原結合ドメインは、ROR1に結合する抗体の少なくとも1つの一本鎖可変断片を含む、請求項15に記載のCAR。
- 前記ROR1抗原結合ドメインは、ROR1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15に記載のCAR。
- 前記膜貫通ドメインは、T細胞受容体のアルファ、ベータ、もしくはゼータ鎖、CD8、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、およびTNFRSF19、またはこれらの任意の組み合わせを含むタンパク質の膜貫通ドメインを含む、請求項15に記載のCAR。
- 前記CD8膜貫通ドメインは、配列番号22のアミノ酸配列、または配列番号22のアミノ酸配列との同一性が85%、90%、95%、96%、97%、98%、もしくは99%であるアミノ酸配列を含む、請求項18に記載のCAR。
- 前記配列番号2もしくは8のアミノ酸配列を含むROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメイン、および前記少なくとも1つの細胞内シグナル伝達ドメイン、またはその両方は、リンカーまたはスペーサドメインによって、前記膜貫通ドメインに結合される、請求項15に記載のCAR。
- 前記リンカーまたはスペーサドメインは、IgG4、CD8、またはCD28の細胞外ドメインに由来し、かつ、膜貫通ドメインに結合している、請求項20に記載のCAR。
- 前記少なくとも1つの細胞内シグナル伝達ドメインは、共刺激ドメインおよび一次シグナル伝達ドメインを含む、請求項15に記載のCAR。
- 前記少なくとも1つの細胞内シグナル伝達ドメインは、OX40、CD70、CD27、CD28、CD5、ICAM−1、LFA−1(CD11a/CD18)、ICOS(CD278)、DAP10、DAP12、および4−1BB(CD137)、またはこれらの組み合わせからなる群より選択されるタンパク質の機能的シグナル伝達ドメインを含む共刺激ドメインを含む、請求項22に記載のCAR。
- 請求項1に記載の核酸分子を含むベクター。
- 前記ベクターは、DNAベクター、RNAベクター、プラスミドベクター、コスミドベクター、ヘルペスウイルスベクター、麻疹ウイルスベクター、レンチウイルスベクター、アデノウイルスベクター、またはレトロウイルスベクター、またはこれらの組み合わせからなる群より選択される、請求項24に記載のベクター。
- プロモーターをさらに含む、請求項24に記載のベクター。
- 前記プロモーターは、誘導性プロモーター、構成的プロモーター、組織特異的プロモーター、自殺プロモーター、またはこれらの任意の組み合わせである、請求項26に記載のベクター。
- 請求項24に記載のベクターを含む細胞。
- 前記細胞はT細胞である、請求項28に記載の細胞。
- 前記T細胞はCD8+ T細胞である、請求項29に記載の細胞。
- 前記細胞はヒト細胞である、請求項28に記載の細胞。
- 請求項24に記載のベクターをT細胞に形質導入する工程を含む、細胞作製方法。
- in vitro転写されたRNAまたは合成されたRNAを細胞中に導入する工程を含み、前記RNAは請求項1に記載の核酸分子を含む、RNA操作細胞の集団の発生方法。
- 哺乳動物への抗腫瘍免疫の提供方法であって、請求項28に記載の細胞の有効量を前記哺乳動物に投与する工程を含む、方法。
- 哺乳動物におけるがんの処置または予防方法であって、前記哺乳動物に、請求項15に記載のCARを、前記哺乳動物におけるがんの処置または予防に有効な量にて投与する工程を含む、方法。
- 抗腫瘍有効量のヒトのT細胞の集団を含む医薬組成物であって、前記T細胞は、キメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARは、配列番号2または8のアミノ酸配列を含むROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメイン、少なくとも1つのリンカードメイン、少なくとも1つの膜貫通ドメイン、少なくとも1つの細胞内シグナル伝達ドメインを含み、かつ、前記T細胞は、がんを有するヒトのT細胞である、医薬組成物。
- 前記少なくとも1つの膜貫通ドメインは、T細胞受容体のアルファ、ベータ、もしくはゼータ鎖、CD8、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、およびCD154、またはこれらの任意の組み合わせを含むタンパク質の膜貫通ドメインを含む、請求項36に記載の医薬組成物。
- 前記T細胞は、血液がんを有するヒトのT細胞である、請求項36に記載の医薬組成物。
- 前記血液がんは白血病またはリンパ腫である、請求項38に記載の医薬組成物。
- 前記白血病は、慢性リンパ球性白血病(CLL)、急性リンパ球性白血病(ALL)、または慢性骨髄性白血病(CML)である、請求項39に記載の医薬組成物。
- 前記リンパ腫は、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39に記載の医薬組成物。
- 前記血液がんは多発性骨髄腫である、請求項38に記載の医薬組成物。
- 前記ヒトのがんは、口腔(coral)および咽頭がん(舌、口、咽頭、頭頸部)、消化器がん(食道、胃、小腸、結腸、直腸、肛門、肝臓、肝内胆管(interhepatic bile duct)、胆嚢、膵臓)、呼吸器がん(喉頭、肺、および気管支)、骨および関節がん、軟部組織がん、皮膚がん(黒色腫、基底細胞癌、および扁平上皮癌)を含む成人癌、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、星状細胞腫、神経膠芽細胞腫、神経膠腫)、ならびに、乳房、生殖器系(子宮頸部、子宮体部、卵巣、外陰部、膣、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)、脳および他の神経系のがん、またはこれらの任意の組み合わせを含む、請求項36に記載の医薬組成物。
- 腫瘍抗原の発現上昇に関連する疾患、障害、または状態を有する哺乳動物の処置方法であって、前記方法は、抗腫瘍有効量のT細胞の集団を含む医薬組成物を対象に投与する工程を含み、前記T細胞は、キメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARは、配列番号2または8のアミノ酸配列を含むROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメイン、少なくとも1つのリンカーまたはスペーサードメイン、少なくとも1つの膜貫通ドメイン、少なくとも1つの細胞内シグナル伝達ドメインを含み、前記T細胞は、がんを有する前記対象のT細胞である、方法。
- それを必要とする対象におけるがんの処置方法であって、前記方法は、抗腫瘍有効量のT細胞の集団を含む医薬組成物を前記対象に投与する工程を含み、前記T細胞は、キメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARは、配列番号2または8のアミノ酸配列を含むROR1抗原結合ドメインを含む少なくとも1つの細胞外の抗原結合ドメイン、少なくとも1つのリンカーまたはスペーサードメイン、少なくとも1つの膜貫通ドメイン、少なくとも1つの細胞内シグナル伝達ドメインを含み、前記T細胞は、がんを有する前記対象のT細胞である、方法。
- 前記少なくとも1つの膜貫通ドメインは、T細胞受容体のアルファ、ベータ、もしくはゼータ鎖、CD8、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、およびCD154、またはこれらの任意の組み合わせを含むタンパク質の膜貫通ドメインを含む、請求項44または45に記載の方法。
- キメラ抗原受容体発現細胞の作製プロセスであって、前記プロセスは、請求項1に記載の単離された核酸を細胞中に導入する工程を含む、プロセス。
- 前記細胞は、T細胞、またはT細胞を含有する細胞集団である、請求項47に記載のキメラ抗原受容体発現細胞の作製プロセス。
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