JP2022513682A - 抗cd38免疫療法によりがんを処置するための組成物および方法 - Google Patents
抗cd38免疫療法により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
本発明は、アメリカ合衆国保健福祉省の機関であるアメリカ国立衛生研究所とのCooperative Research and Development Agreementの実施において創出された。米国政府は本発明に対し一定の権利を有する。
本出願は、がんの分野、特に、CD38抗原結合性ドメイン、およびこのようなCD38抗原結合性ドメインを含むキメラ抗原受容体(CAR)、およびその使用方法に関する。
がんは、ヒトの健康に対する最も致命的な脅威の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。
新規の抗CD38抗体またはその抗原結合性ドメイン、およびこのようなCD38抗原結合性ドメインを含むキメラ抗原受容体(CAR)、および受容体を発現する宿主細胞(例えばT細胞)、および受容体をコードする核酸分子が本明細書で提供される。CARは、エフェクター細胞表面に発現される単一分子からなる場合と、またはエフェクター細胞発現シグナル伝達モジュールおよび可溶性標的化モジュールからなる場合があり、例えば可溶性標的化モジュールが細胞発現シグナル伝達モジュールに結合すると、完全に機能的なCARが形成される。CARは、形質導入T細胞での高い表面発現、高度の細胞溶解ならびに形質導入T細胞のin vivoでの増殖および持続を示す。例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、および核酸分子を使用する方法も提供される。
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CARは、CD38に結合することが可能な少なくとも1つのCD38抗原結合性ドメイン、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を含む。
一実施形態では、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。
膜貫通ドメインに関して、CARは、CARの細胞外CD33抗原結合性ドメインに融合された1つまたは複数の膜貫通ドメインを含む。
CARでは、ヒンジドメインとも呼ばれるスペーサードメインは、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配置され得る。スペーサードメインは、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CAR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CAR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%またはそれ超を構成し得る。
一実施形態は、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。
CAR、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CAR、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。
本明細書で開示されるCAR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、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/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。
担体(例えば、医薬的に許容される担体)中に、開示されたCAR、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、CAR、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CAR、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CAR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CAR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、CAR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。
本発明は以下の実施例によってさらに例証され、これらの実施例は決して本発明の範囲に制約を課すものとして解釈すべきではない。反対に、その様々な他の実施形態、変更形態、および均等物に頼らなければならず、これらは本明細書の記載を読んだ後、本発明の精神および/または添付の特許請求の範囲から逸脱せずに、当業者の念頭に浮かび得ることは容易に理解される。
材料および方法:
大型酵母ディスプレイヒトナイーブ単鎖可変断片(ScFv)抗体ライブラリーを使用して、本明細書に記載される抗ヒトCD38抗体を単離した。ライブラリーは、60以上の個人からのヒト抗体遺伝子レパートリーのコレクションを使用して構築された。3ラウンドの磁気活性化セルソーティング(MACS)を行って、CD38-Fcと名付けられた、ヒトIgG1 Fcと融合した組換えヒトCD38細胞外ドメインへのヒトScFvバインダーを富化した。酵母ライブラリーパニングの第1のラウンドでは、酵母ディスプレイScFvライブラリー(5×1010細胞)を、15ml PBSA(ダルベッコのリン酸緩衝生理食塩水(PBS)緩衝液中の0.1%ウシ血清アルブミン(BSA)からなる)中の5μg/mL CD38-Fcとともに、室温でローテーター上に1.5時間インキュベートした。25ml PBSAで2回洗浄した後、酵母ライブラリーミックスを100μLプロテインGマイクロビーズ(Miltenyi Biotec)とともに、室温でローテーター上に30分間インキュベートした。1回洗浄した後、ライブラリーミックスを50mlのPBSAに再懸濁し、MACS細胞分離カラム(LSカラム)にロードした。10mlのPBSAで3回洗浄した後、ScFvバインダーをカラムに提示した酵母は、その後、2mlのPBSAで2回溶出した。これらの溶出酵母細胞を組み合わせて、50mlのSDCAA培地(1Lの水中、20gのD-グルコース、6.7gのアミノ酸を含まないBD Difco(商標)酵母窒素ベース、5gのBacto(商標)カザミノ酸、5.4gのNa2.HPO4、8.56gのNaH2PO4.H2O)に再懸濁し、225rpm、30℃で20時間振とうしながら増幅させた。その後、増幅されたプールをSGCAA培地(SDCAA培地の同じ組成からなるが、グルコースの代わりにガラクトースを含む)中で誘導し、225rpm、30℃でさらに16時間振とうし、次のラウンドのパニングに使用した。同じプロセスをさらに2回繰り返して、CD38-Fc特異的バインダーを富化した。
AMLには処置選択肢がほとんどなく、処置関連の毒性と処置後の疾患再発が一般的である。さらに、マウス由来の抗体などの非ヒト配列を使用する免疫療法は、患者に治療の拒絶または副作用をもたらし得る。AMLの新しいCAR T処置法を開発するため、完全ヒトScFv標的化ドメインを組み込んだ15のCD38を標的化するCAR T構築物を設計し、抗腫瘍活性を評価した。
(a)細胞株
MM細胞株MM1.SおよびRPMI-8226、ならびにヒト胎児腎臓系統293Tは、American Tissue Culture Collection(ATCC,Manassas,VA)から購入した。ホタルルシフェラーゼ(Lentigen)をコードするレンチウイルスベクターを野生型腫瘍株に安定に形質導入することで、ルシフェラーゼを発現する細胞株の単一細胞クローンを生成した。全血を、ドナーの書面による同意を得て、オクラホマ血液研究所(OBI)の健康なボランティアから収集した。処理済みバフィーコートはOBI(Oklahoma City,OK)から購入した。CD4陽性およびCD8陽性のヒトT細胞を、CD4-およびCD8-MicroBeads(Miltenyi Biotec,Bergisch Gladbach,Germany)の1:1混合物を製造業者のプロトコールに従って使用して、陽性選択によりバフィーコートから精製した。
CARの抗原結合性ドメイン、scFv、配列は、ヒト抗CD38 ScFvに由来していた。バインダー配列をインフレームで、CD8a連結および膜貫通ドメイン(aa123-191、Ref配列ID NP001759.3)、次いで4-1BB(CD137、aa214-255、UniProt配列ID Q07011)シグナル伝達ドメインおよびCD3ゼータシグナル伝達ドメイン(CD247、aa52-163、Ref配列ID:NP_000725.1)に連結することにより、CAR T構築物を生成した。重鎖および軽鎖がモノクローナル抗体ダラツムマブに由来する、本明細書でM8DRと呼ばれる対照ScFvを、それぞれVH-VLまたはVL-VHの配向で組み込んだCAR陽性対照構築物LTG2525およびLTG2526を、同様の方法で構築した。CAR構築物配列を第3世代の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。HEK293T細胞の一過性トランスフェクションによりレンチウイルスベクター(LV)を含む上清を生成し、レンチウイルスベクターを含む上清を遠心処理することによりベクターをペレットにして、-80℃で保存した。
健康なボランティアからのヒト初代T細胞を、製造業者のプロトコール(Miltenyi Biotec,Bergisch Gladbach,Germany)に従って、CD4+およびCD8+細胞の免疫磁気ビーズ選択を使用して、全血またはバフィーコート(ドナーの書面による同意を得て、商業プロバイダーから購入)から精製した。T細胞を、密度0.3~2×106細胞/mlで、30IU/ml IL-2を添加したTexMACS(商標)培地で培養し、CD3/CD28MACS(登録商標)GMP T細胞TransAct試薬(Miltenyi Biotec)で活性化し、2日目に10μg/ml硫酸プロタミン(Sigma-Aldrich,St,Louis,MO)存在下で一晩、CAR構築物をコードするレンチウイルスベクターを形質導入し、3日目に培地を交換した。培養物は、30IU/ml IL-2を添加したTexMACS(商標)培地で、8~10日目の採取まで繁殖させた。
細胞媒介性の細胞傷害性を決定するため(CTLアッセイ)、ホタルルシフェラーゼが安定に形質導入された標的細胞5,000個を種々の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試薬(Promega,Madison WI)を各ウェルに添加し、生じた発光を秒あたりのカウントとして定量化した(試料CPS)。標的のみのウェル(最大CPS)および1% Tween-20を加えた標的のみのウェル(最小CPS)を使用してアッセイ範囲を決定した。特異的な溶解のパーセントを(1-(試料CPS-最小CPS)/(最大CPS-最小CPS))として算出した。E:T比が10:1の共培養からの上清を除去し、IFNγおよびTNFα濃度についてELISA(eBioscience,San Diego,CA)により分析した。
細胞染色では、CAR T形質導入細胞50万個を培養液から採取し、0.5%ウシ血清アルブミン(Miltenyi Biotec)を添加した低温のAutoMACS緩衝液で2回洗浄して、CD38-Hisペプチド(Thermo Fisher Scientific,Waltham,Massachusetts)、その後二次抗-His-PE検出試薬(Miltenyi Biotec,Bergisch Gladbach,Germany)で染色することによりCAR表面発現を検出した。ベンダーのプロトコールに従って、VioBlueフルオロフォア(Miltenyi Biotec)とコンジュゲートされた抗CD4抗体を必要に応じて使用した。陰性対照として非形質導入細胞を使用した。全ての研究で、死滅した細胞は7AAD染色(BD Biosciences,San Jose,CA)により除外した。細胞を2回洗浄し、フローサイトメトリーによる定量分析前に染色緩衝液200μlで再懸濁させた。MACSQuant(登録商標)10 Analyzer(Miltenyi Biotec)でフローサイトメトリー分析を実施し、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。
この実施例は、MMおよび他のCD38+悪性腫瘍の処置のための腫瘍抗原CD38を標的化するCAR T細胞の創出、ならびに腫瘍微小環境におけるCD38発現腫瘍サプレッサー細胞の死滅について記載する。各CARは、ヒト酵母ディスプレイライブラリー由来のヒトScFvバインダー、CD8ヒンジおよび膜貫通ドメイン、4-1BB共刺激ドメイン、ならびにCD3z活性化ドメインで構成されていた(図1)。
本出願は、タイトル「配列表」のPDFファイルにより、アメリカ合衆国特許商標庁に電子的に提出された配列表を含む。配列表は参照により組み込まれる。
以下に列挙す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、ヌクレオチド塩基用の標準的な略語、およびアミノ酸用の1文字または3文字コードを使用して示される。各核酸配列のうち一方の鎖のみが示されているが、相補鎖は、示される鎖を参照することによって含まれるものと理解される。添付の配列表では:
配列番号1 CD38 hScFvバインダーM3801のヌクレオチド配列
GAAGTGCAATTGGTCCAAAGCGGTGCAGAAGTCAAGAAACCTGGTTCGAGCGTGAAAGTGTCCTGCAAGGCCTCTGGCGGCACCTTCTCATCCTACGCCATTAGCTGGGTCCGCCAAGCCCCGGGCCAGGGACTTGAGTGGATGGGCGGAATCATCCCTATCTTCGGGACCGCCAATTACGCCCAGAAGTTCCAGGGCCGCGTGACCATCACCGCGGACAAGTCCACATCAACCGCCTATATGGAGCTCTCGTCGCTGAGATCAGAGGACACTGCTGTCTACTACTGTGCGAGGGCCCCATACGACGATGCATTCGACATCTGGGGACAGGGTACCATGGTCACTGTGTCCAGCGGGGGCGGAGGCTCCGGGGGGGGCGGATCGGGGGGCGGCGGATCCAACTTCATGCTGACCCAGCCGCACTCGGTGTCAGAGAGCCCCGGAAAGACTGTGACCATTAGCTGCACCCGGTCCAGCGGAAGCATCGCCTCCAACTACGTGCAGTGGTACCAGCAGCGGCCGGGCTCCGCGCCGACCACTGTGATCTACGAAGATAACCAGCGCCCCTCCGGTGTCCCTGGACGGTTCTCCGGATCCATTGACACCTCGTCCAACTCCGCCTCGCTGACGATCTCCGGACTGGAGACTGAAGATGAAGCTGTGTACTACTGCCAATCCTACGACTCCGGATTTCCCTACGCCGTGTTCGGTGGCGGGACCCAGCTCACCGTGCTGGGA
配列番号2 CD38 hScFvバインダーM3801のアミノ酸配列
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAPYDDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPGRFSGSIDTSSNSASLTISGLETEDEAVYYCQSYDSGFPYAVFGGGTQLTVLG
配列番号3 CD38 hScFvバインダーM3802のヌクレオチド配列
GAAGTGCAACTCGTCGAATCTGGTGGAGGATCCGTGCAGCCTGGTGGAAGCCTGAGACTGTCGTGTGCCGCCTCCGAGTTCACCTTCTCCTCGTACTGGATGCACTGGGTCAGACAGGCGCCCGGAAAGGGCCTGGAATGGGTGGCCGTGATCTCATACGACGGCGCGAAGAAGTACTACGCCGATTCCGTGAAGGGCCGCTTTACCATTTCCCGGGACAATTCAAAGAACACCCTCTACCTTCAAATGAACTCCCTGAGGGCCGAGGATACTGCAGTCTACTACTGCGCTCGGGATGACGGGAGCGGGGGCTTCGACTACTGGGGACAGGGAACCCTCGTGACTGTGTCATCCGGTGGCGGCGGCTCCGGAGGCGGCGGTTCCGGGGGGGGGGGATCCGACATCGTGATGACGCACACTCCTCTGTCGCTGTCCGTGACCCCCGGCCAGCCTGCCTCAATCTCGTGCAAGAGCTCCCAGTCGCTGCTGCATAGCGATGGAAAGACCTACCTGTATTGGTACCTTCAAAAGCCGGGACAGCCGCCGCAGTTGCTGATCTATGAAGTCAGCAACCGCTTCTCGGGAGTGCCCGACCGCTACTCCGGCTCGGGGAGCGGAACCGACTTCACCCTGAAAATTTCCCGGGTCGAGGCAGAGGACGTGGGAGTGTACTACTGCATGCAAAGCATTCAGTTGCCACTGACTTTCGGTGGAGGAACCAAGCTCGAAATCAAA
配列番号4 CD38 hScFvバインダーM3802のアミノ酸配列
EVQLVESGGGSVQPGGSLRLSCAASEFTFSSYWMHWVRQAPGKGLEWVAVISYDGAKKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDGSGGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTHTPLSLSVTPGQPASISCKSSQSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGVPDRYSGSGSGTDFTLKISRVEAEDVGVYYCMQSIQLPLTFGGGTKLEIK
配列番号5 CD38 hScFvバインダーM3803のヌクレオチド配列
GAAGTGCAATTGGTGCAGAGCGGTGGAGGACTTGTGAAACCTGGTGGATCCCTGAGACTTTCCTGTGCCGCTTCGGGCTTCACCTTCTCGGACTACTACATGTCCTGGATTCGCCAGGCCCCTGGAAAGGGACTGGAATGGGTGTCATACATCAGCTCCTCCGGTTCCACCATCTACTATGCCGATTCCGTGAAGGGCAGATTCACCATCTCGCGCGACAACGCCAAGAACACTCTCTATCTGCAAATGAACTCACTGCGGGCTGAGGACACCGCGGTCTACTACTGCGCCCGGGACCTCAGCGGAAAGTCCAGCGGATGGTCCCATTACTTCGATTACTGGGGACAGGGAACCCTGGTCACCGTGTCCAGCGGCGGGGGGGGCTCGGGTGGCGGCGGCTCCGGCGGCGGCGGGAGCAACTTCATGCTGACTCAGCCCCACTCCGTGTCCGAGAGCCCGGGAAAGACCGTGACTATTTCGTGCACACGGTCCTCCGGGAGCATTGCGAACAACTACGTGCAGTGGTACCAGCAGCGGCCCGATAGGGCCCCAACCACTGTGATCTACGAAGATGACCAGCGGCCGTCTGGAGTCCCGGACCGCTTCTCGGGGTCCATCGACTCATCATCCAATTCCGCATCGCTGACGATCAGCGGACTGAAGATCGAGGACGAAGCCGATTACTACTGCCAGTCCTACGACGGCACCAACTGGGTCTTTGGGGGTGGAACCAAGCTGACTGTGCTCGGA
配列番号6 CD38 hScFvバインダーM3803のアミノ酸配列
EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARDLSGKSSGWSHYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIANNYVQWYQQRPDRAPTTVIYEDDQRPSGVPDRFSGSIDSSSNSASLTISGLKIEDEADYYCQSYDGTNWVFGGGTKLTVLG
配列番号7 CD38 hScFvバインダーM3804のヌクレオチド配列
GAAGTGCAACTTGTCGAAAGCGGTGGAGGTCTTGTCCAACCTGGTCGCTCCCTGAGGCTCTCGTGTGCCGCGAGCGGATTCACCTTCTCATCGTACGCTATGTCCTGGGTCAGACAGGCTCCTGGAAAGGGCCTGGAATGGGTGGCCGTGATCTCCTACGACGGCAGCAACAAGTATTACGCCGACTCAGTGAAGGGCCGGTTCACCATTTCCCGGGACAACAGCAAGAACACCCTGTACTTGCAAATGAACTCCCTGCGGGCCGAGGATACCGCGGTGTACTACTGCGCCCACCTCCGCTTTGGATACGGAATGGATGTCTGGGGACAGGGAACTACCGTGACCGTGTCGTCCGGGGGGGGGGGAAGCGGCGGCGGGGGATCGGGTGGCGGCGGATCCCAGACTGTGGTCACCCAAGAGCCTTCACTGACCGTGTCCCCGGGTGGCACCGTGACGCTGACTTGCGCGTCATCTACCGGGGCCGTGACCTCGGACCACTACCCCTGCTGGTTCCAGCAGAAACCCGGACATCCACCGAGAGCCCTGGTGTACTCCACTGACACCATCCACTCCTGGACTCCGGCCCGGTTCTCCGGAAGCCTCCTGGGCGGGAAGGCCGCACTGACAGTGTCCGGAGTGCAGCCCGAGGATGAAGCCGACTACTACTGTCTGCTCTACTATGGGGGAGCACGCGTGTTCGGTGGCGGCACTCAGCTGACCGTGCTGGGA
配列番号8 CD38 hScFvバインダーM3804のアミノ酸配列
EVQLVESGGGLVQPGRSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAHLRFGYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSDHYPCWFQQKPGHPPRALVYSTDTIHSWTPARFSGSLLGGKAALTVSGVQPEDEADYYCLLYYGGARVFGGGTQLTVLG
配列番号9 CD38 hScFvバインダーM3806のヌクレオチド配列
CAAGTGCAACTCGTCCAATCCGGAGCTGAAGTCAAGAAGCCAGGATCTTCCGTGAAAGTGTCGTGCAAGGCCTCCGGGGGAACATTCTCCTCATATGCGATCAGCTGGGTCCGCCAGGCTCCGGGACAGGGCTTGGAGTGGATGGGTATCATTAACCCTTCGGGCGGCTCAACTAGCTACGCCCAGAAGTTCCAGGGCAGAGTGACCATGACCAGGGACACCAGCACTTCGACGGTGTACATGGAACTGTCCTCACTGCGGTCCGAGGACACCGCCGTGTACTACTGCGCCCGGGAGTATTCCTCCTCCCGCGTGGACGCCTTCGATATCTGGGGACAGGGTACCATGGTCACTGTGTCGTCCGGCGGCGGCGGAAGCGGGGGTGGCGGGAGCGGTGGCGGCGGATCCAGCTACGAACTCACCCAGCCGCCGTCAGTGTCCGTGAGCCCGGGACAGACCGCAACCATTACTTGTTCCGGGGATGACCTGGGATCCAAATACGTGTGCTGGTACCAACAGAAGCCTGGTCACTCGCCCGTGCTGATCATCTACGACGACTCAGACCGGCCCAGCGGCATCCCCGAGAGATTTTCCGGATCCAACAGCGGAAACACCGCCACTCTGACTATTTCGCGCGTCGAGGCCGGCGACGAAGCGGATTACTACTGCCAAGTCTGGGACAGCTCCTCGGATCATGCCGTGTTCGGGGGCGGAACCCAGCTTACCGTGCTGGGG
配列番号10 CD38 hScFvバインダーM3806のアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREYSSSRVDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSYELTQPPSVSVSPGQTATITCSGDDLGSKYVCWYQQKPGHSPVLIIYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFGGGTQLTVLG
配列番号11 CD38 hScFvバインダーM3808のヌクレオチド配列
GAAGTGCAGTTGGTGGAGAGCGGTGGAGGACTTGTGCAACCTGGTGGATCCCTGAGATTGTCGTGTGCCGCCTCCGGTTTCACCTTCTCCTCGTACTGGATGAGCTGGGTCCGCCAGGCACCCGGGAAGGGACTGGAATGGGTGGCGGACATTAAGGATGACGGCTCCGAGCGGTACTACGTGGACTCCGTGAAGGGCCGGTTCACTATCTCAAGAGACAATGCCAAGAACAGCCTGTACCTCCAAATGAACTCGCTGCGGGCCGAGGATACCGCAGTGTATTACTGCGCCCGCGACGTGTGGGCTGGGATGGATGTCTGGGGCCAGGGGACCACTGTCACTGTGTCTAGCGGGGGCGGCGGAAGCGGCGGCGGCGGATCCGGTGGTGGCGGAAGCGACATTCAGCTGACCCAGTCCCCATCATTCCTGTCCGCCTCCGTGGGCGACAGGGTCACTATCACTTGCCAAGCCAGCCAGGACATCTCCAACTACCTGAACTGGTACCAGCAGAAGCCTGGAAAAGCTCCGAAGCTCCTCATCTACGACGCCTCGAACCTCGAAACCGGAGTGCCCTCACGGTTTTCCGGATCGGGATCGGGGACCGATTTCTCCTTCACCATTTCATCCCTGCAACCCGAGGACATCGCGACCTACTACTGCCAACAGACATACTCCCCGCCGATTACGTTCGGACAGGGAACCCGCCTGGAAATCAAG
配列番号12 CD38 hScFvバインダーM3808のアミノ酸配列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVADIKDDGSERYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDVWAGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFSFTISSLQPEDIATYYCQQTYSPPITFGQGTRLEIK
配列番号13 リーダー/シグナルペプチド配列のヌクレオチド配列
atgctgctgctggtgaccagcctgctgctgtgcgaactgccgcatccggcgtttctgctgattccg
配列番号14 リーダー/シグナルペプチド配列のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIP
配列番号15 CD38 hScFvバインダーM3809のヌクレオチド配列
CAAGTCCAACTCGTCCAGTCCGGTGCCGAAGTCAAGAAGCCTGGCTCATCCGTGAAAGTGTCCTGCAAAGCATCGGGCGGAACCTTCTCCTCCTATGCCATTTCCTGGGTCCGCCAGGCACCGGGCCAGGGTCTGGAGTGGATGGGCGGGATTATCCCTATCTTCGGAACTGCCAACCACGCCCAAAAGTTCCAGGGACGCGTGACCATTACCGCCGATGAATCAACCTCAACCGCCTACATGGAACTGTCCAGCTTGAGGTCCGAGGACACCGCCGTGTACTACTGCGCGTTCATGATGGTGCCGGAGTACTACTTTGACTACTGGGGCCAGGGAACCCTTGTGACCGTGTCGTCCGGTGGTGGCGGATCCGGGGGGGGGGGATCTGGGGGCGGCGGAAGCGATATCCAGATGACCCAGTCGCCATCGAGCCTGTCCGCTTCCGTGGGCGACAGAGTGACGATCACTTGCCGGGCTTCACAAGGCATCAGAAATGACCTGGGCTGGTATCAGCAGAAGCCCGGAGAAGCGCCCAAGCGGCTGATCTACGCGGCCAGCACCCTGCAAAACGGAGTGCCTTCGCGGTTCTCCGGGAGCGGCTCCGGAACTGACTTCACTCTGACTATTAACAGCCTCCAGCCCGAGGATTTCGCCACATACTACTGTCAGCAGTACAACAGCTACCCGTACACCTTCGGACAGGGAACTAAGCTCGAAATCAAG
配列番号16 CD38 hScFvバインダーM3809のアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANHAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAFMMVPEYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGEAPKRLIYAASTLQNGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK
配列番号17 CD38 hScFvバインダーM3810のヌクレオチド配列
AAAGTGCAACTCCAAGAAAGCGGCCCCGGACTTGTCAAACCGTCCCAGACTCTCTCCCTGACCTGTGCCGTCAGCGGTGGCTCAATTTCGAGCGGTGGCTACTACTGGTCCTGGATCAGGCAGCATCCGGGAAAGGGCTTGGAGTGGATTGGATACATCTACTACTCCGGGTCCACCTACTACAATCCCTCGCTGAAGTCGAGAGTCACCATCAGCGTGGACACCTCCAAGAACCAGTTTAGCCTGAAGCTGTCCTCAGTGACCGCAGCTGACACCGCCGTGTACTACTGCGCCCGCGGCGGAGTGATGGGCGGAGACTTCGACTACTGGGGACAGGGAACCCTGGTCACTGTGTCCAGCGGGGGGGGGGGATCCGGCGGCGGCGGTTCCGGTGGCGGAGGGTCCCAGTCAGTGCTGACTCAGCCACCTTCCGTGTCTGTGTCGCCCGGACAAACCGCCAGCATCACGTGCTCCGGCGACAACCTCGGTGATCACTATGTGTGCTGGTACCAACAGCGGCCGGGGCAGTCACCGGTGCTGATTATGTACGAGGATACTAAGCGCCCTTCCGGAATCCCTGACCGGTTCTCGGGAAGCAACTCCGGAAACACCGCCACCCTGACCATCTCCGGAACCCAGACAATGGATGAAGCGGACTACTATTGCGTGGCGTGGGACGATTCGCTGTCCGGCTGGGTGTTCGGCGGGGGAACTCAGCTGACTGTGCTCGGA
配列番号18 CD38 hScFvバインダーM3810のアミノ酸配列
KVQLQESGPGLVKPSQTLSLTCAVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGVMGGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSVSPGQTASITCSGDNLGDHYVCWYQQRPGQSPVLIMYEDTKRPSGIPDRFSGSNSGNTATLTISGTQTMDEADYYCVAWDDSLSGWVFGGGTQLTVLG
配列番号19 CD38 hScFvバインダーM3811のヌクレオチド配列
CAACTCCAACTCCAAGAATCTGGACCAGGCCTCGTGAAGCCCTCCCAAACTCTGTCCCTGACCTGTACCGTGTCGGGTGGAAGCATTTCGAGCGGTGGATACTACTGGTCCTGGATCAGGCAGCATCCTGGAAAGGGACTGGAGTGGATTGGGTACATCTACTACTCCGGCTCAACCTACTACAACCCGTCCTTGAAATCGCGCGTGACGATCTCCGTGGACACTTCAAAGAACCAGTTCAGCCTGAAGCTTTCCTCCGTGACCGCGGCCGATACAGCGGTGTACTACTGCGCTCGGGATCAGAGCGTGGCCGACCCTGGTGGCGGCTACTACTACTACGGAATGGATGTCTGGGGACAGGGAACCACCGTGACTGTGTCCAGCGGGGGCGGCGGATCCGGGGGGGGGGGATCGGGCGGCGGCGGTTCGCAGTCCGTGCTGACCCAGCCACCTAGCGTGTCAGTGGCACCGGGACAGACCGCCTCCATTTCCTGCGGGGGAAATGACTTCGGTAGCCGCTCCGTGTCATGGTATCACCAGAAGCCGGGACAGGCCCCGGTGCTGGTCATCTATGACGACAACGACAGACCCTCGGGCATCCCCGAACGGTTTTCGGGAAGCACCTCCGGAGACACTGCCACCCTGACCATCTCCCGGGTCGAGGTCGGCGATGAAGCCGATTACTACTGCCAAGTCTGGGACGACGACTCCGACCACTGGGTGTTCGGCGGCGGAACTAAGCTGACTGTGCTGGGG
配列番号20 CD38 hScFvバインダーM3811のアミノ酸配列
QLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDQSVADPGGGYYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSVAPGQTASISCGGNDFGSRSVSWYHQKPGQAPVLVIYDDNDRPSGIPERFSGSTSGDTATLTISRVEVGDEADYYCQVWDDDSDHWVFGGGTKLTVLG
配列番号21 CD38 hScFvバインダーM3812のヌクレオチド配列
CAAGTGCAACTCCAACAATCGGGCCCCGGACTCGTGAAACCGTCCCAGACTCTGTCCCTTACTTGCGTGATTTCCGGGGACTCCGTGAGCTCAAACTCGGCGGCCTGGAACTGGATTAGACAGTCCCCTTCCCGGGGTCTGGAATGGCTGGGCCGGACTTACTACCGGTCGAAGTGGCACAACGATTACGCAGTCAGCGTCGAGAGCCGCATCATCGTGAACCCGGACACCTCAAAGAACCAGTTCAGCCTGCAACTGAATTCCGTGACCCCCGAGGACACCGCTGTGTACTACTGCGCCCGCGACCCCGGATACTTCTATGGACTGGACGTCTGGGGACAGGGGACCATGGTCACCGTGTCGAGCGGCGGCGGCGGATCCGGTGGCGGGGGATCCGGCGGTGGCGGATCCAACTTCATGTTGACTCAGCCGCATTCGGTGTCGGAGTCCCCTGGAAAGACAGTCACCATCCCATGTACCCGGAGCAGCGGAACTATCGCCGACTACTACGTGCAGTGGTACCAGCAGCGCCCTGATTCCTCACCGATCATTGTGATCTATGACGACAACCAGAGGCCCTCCGGGGTGCCGGATAGATTCAGCGGATCCATTGACTCCTCGTCCAACTCTGCCTCACTGACGATCTCCGGGCTCAAGACCGAAGATGAAGCGGCCTACTACTGCCAGTCATACGACTCCACCAACCACTGGGTGTTTGGTGGCGGAACTAAGCTGACCGTGCTGGGA
配列番号22 CD38 hScFvバインダーM3812のアミノ酸配列
QVQLQQSGPGLVKPSQTLSLTCVISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWHNDYAVSVESRIIVNPDTSKNQFSLQLNSVTPEDTAVYYCARDPGYFYGLDVWGQGTMVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTIPCTRSSGTIADYYVQWYQQRPDSSPIIVIYDDNQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEAAYYCQSYDSTNHWVFGGGTKLTVLG
配列番号23 CD38 hScFvバインダーM3815のヌクレオチド配列
CAAGTCACACTCAAAGAATCCGGACCGGTGCTCGTGAAGCCTACTGAAACCTTGACCCTGACATGCACCTTTTCCGGGTTCTCCCTGAGCACCTCGGGAGTCGGAGTGGCGTGGATTAGGCAGCCGCCAGGAAAAGACCTCGAGTGGCTCGCCCTTATCTACTGGGACGATGACAAGCGCTACTCACCCTCACTGGAGAGCAGACTGACGATCACCAAGGATACCTCGAAGAACCAAGTGGCCCTGACTATGTCCGACATGGACCCTGTGGACACCGCGACTTACTACTGCGCCCGGGGCGATTACTGGGGACGGCTGGACTACTGGGGACAGGGAACTCTGGTCACCGTGTCCAGCGGCGGCGGTGGTTCAGGGGGTGGCGGCAGCGGGGGGGGCGGATCGGATATCCAGCTTACCCAGTCGCCGTCCTCCCTCTCTGCATCGATTGGCGACCGCGTGACTATTACGTGTCAGGCCTCCGAGGACATCAACAACTACCTGAACTGGTACCAGCAGAAGCCCGGAAAGGCCCCAAAGCTGCTGATCTACGACGCTAGCAACTTGGAAACCGGAGTGCCGTCCCGGTTCTCCGGATCCGGGAGCGGTACCGACTTCACCTTCACCATCAACTCCCTGCAACCCGAGGATATTGCCACCTATTACTGCCAACAGTTCGACAATATGCCTCTGACTTTCGGGGGCGGCACTAAGCTCGAAATCAAG
配列番号24 CD38 hScFvバインダーM3815のアミノ酸配列
QVTLKESGPVLVKPTETLTLTCTFSGFSLSTSGVGVAWIRQPPGKDLEWLALIYWDDDKRYSPSLESRLTITKDTSKNQVALTMSDMDPVDTATYYCARGDYWGRLDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASIGDRVTITCQASEDINNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTINSLQPEDIATYYCQQFDNMPLTFGGGTKLEIK
配列番号25 CD38 hScFvバインダーM3815 Pのヌクレオチド配列
CAAGTCACTCTGAAAGAATCCGGTCCCGTGCTCGTCAAACCCACCGAAACCCTGACCCTGACCTGTACTTTCTCCGGATTTTCCCTCTCAACCTCCGGCGTGGGCGTGGCCTGGATTCGGCAGCCTCCCGGAAAGGATTTGGAGTGGCTGGCCCTGATCTACTGGGATGACGATAAGCGCTACTCCCCATCCCTCGAGTCCCGGCTGACTATCACTAAGGACACCTCCAAGAATCAAGTCGCCCTTACTATGTCGGACATGGACCCTGTGGACACCGCTACGTACTACTGCGCTCGGGGAGACTATTGGGGGCGCCTGGACTACTGGGGACAGGGAACCCTCGTGACCGTGTCGTCTGGGGGCGGCGGACCGGGTGGCGGAGCGTCCGGGGGCGGTGGATCGGACATCCAGCTGACACAGAGCCCCAGCAGCCTGAGCGCCTCGATTGGCGACAGAGTGACCATTACGTGCCAGGCATCCGAGGACATCAACAACTACCTGAACTGGTACCAGCAGAAGCCTGGGAAGGCCCCAAAGCTGCTGATCTACGACGCCTCCAACCTGGAAACCGGAGTGCCGTCAAGGTTCAGCGGCTCGGGATCAGGAACCGATTTCACTTTCACCATCAACAGCTTGCAGCCGGAAGATATCGCGACCTACTACTGCCAACAGTTCGACAACATGCCGCTGACTTTCGGTGGCGGGACCAAGCTTGAGATTAAG
配列番号26 CD38 hScFvバインダーM3815 Pのアミノ酸配列
Q V T L K E S G P V L V K P T E T L T L T C T F S G F S L S T S G V G V A W I R Q P P G K D L E W L A L I Y W D D D K R Y S P S L E S R L T I T K D T S K N Q V A L T M S D M D P V D T A T Y Y C A R G D Y W G R L D Y W G Q G T L V T V S S G G G G P G G G A S G G G G S D I Q L T Q S P S S L S A S I G D R V T I T C Q A S E D I N N Y L N W Y Q Q K P G K A P K L L I Y D A S N L E T G V P S R F S G S G S G T D F T F T I N S L Q P E D I A T Y Y C Q Q F D N M P L T F G G G T K L E I K
配列番号27 DNA CD8膜貫通ドメインのヌクレオチド配列
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc accctttact gc
配列番号28 CD8膜貫通ドメインのアミノ酸配列
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
Val Ile Thr Leu Tyr Cys
配列番号29 DNA CD8ヒンジドメインのヌクレオチド配列
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg
gacttcgcct gtgat
配列番号30 CD8ヒンジドメインのアミノ酸配列
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
配列番号31 CD8.アルファ(NCBI RefSeq:NP.sub.--001759.3)のアミノ酸番号118~178ヒンジ領域のアミノ酸配列
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
配列番号32 ヒトIgG CL配列のアミノ酸配列
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
配列番号33 4-1BBのDNAシグナル伝達ドメインのヌクレオチド配列
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt
gaactg
配列番号34 4-1BBのシグナル伝達ドメインのアミノ酸配列
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
配列番号35 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
agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc
tacgacgccc ttcacatgca ggccctgccc cctcgc
配列番号36 CD3ゼータのアミノ酸配列
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
配列番号37 ScFv CD19のヌクレオチド配列
gacatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcaccatcagttgca gggcaagtca ggacattagt aaatatttaa attggtatca gcagaaacca gatggaactg ttaaactcct gatctaccat acatcaagat tacactcagg agtcccatca aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccgtacac gttcggaggg gggaccaagc tggagatcac aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc ggatctgagg tgaaactgca ggagtcagga cctggcctgg tggcgccctc acagagcctg tccgtcacat gcactgtctc aggggtctca ttacccgact atggtgtaag ctggattcgc cagcctccac gaaagggtct ggagtggctg ggagtaatat ggggtagtga aaccacatac tataattcag ctctcaaatc cagactgacc atcatcaagg acaactccaa gagccaagtt ttcttaaaaa tgaacagtct gcaaactgat gacacagcca tttactactg tgccaaacat tattactacg gtggtagcta tgctatggac tactggggcc aaggaacctc agtcaccgtc tcctca
配列番号38 ScFv CD19のアミノ酸配列
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
配列番号39 GMCSFリーダーペプチドのヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCG
配列番号40 GMCSFリーダーペプチドのアミノ酸配列
MLLLVTSLLLCELPHPAFLLIP
配列番号41 TNFRSF19リーダーペプチドのヌクレオチド配列
GGCTCTGAAAGTGCTGTTGGAACAAGAAAAGACCTTCTTCACCTTGCTCGTGTTGCTGGGGTACCTGTCCTGCAAAGTCACCTGT
配列番号42 TNFRSF19リーダーペプチドのアミノ酸配列
MALKVLLEQEKTFFTLLVLLGYLSCKVTC
配列番号43 CD8アルファリーダーペプチドのヌクレオチド配列
atggcgctgccggtgaccgcgctgctgctgccgctggcgctgctgctgcatgcggcgcgc
ccg
配列番号44 CD8アルファリーダーペプチドのアミノ酸配列
MALPVTALLLPLALLLHAARP
配列番号45 CD28共刺激ドメインのヌクレオチド配列
CGGTCGAAGAGGTCCAGACTCTTGCACTCCGACTACATGAACATGACTCCTAGAAGGCCCGGACCCACTAGAAAGCACTACCAGCCGTACGCCCCTCCTCGGGATTTCGCCGCATACCGG TCC
配列番号46 CD28共刺激ドメインのアミノ酸配列
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
配列番号47 CD3ゼータ活性化ドメインのヌクレオチド配列
AGAGTGAAGTTCAGCCGCTCAGCCGATGCACCGGCCTACCAGCAGGGACAGAACCAGCTCTACAACGAGCTCAACCTGGGTCGGCGGGAAGAATATGACGTGCTGGACAAACGGCGCGGCAGAGATCCGGAGATGGGGGGAAAGCCGAGGAGGAAGAACCCTCAAGAGGGCCTGTACAACGAACTGCAGAAGGACAAGATGGCGGAAGCCTACTCCGAGATCGGCATGAAGGGAGAACGCCGGAGAGGGAAGGGTCATGACGGACTGTACCAGGGCCTGTCAACTGCCACTAAGGACACTTACGATGCGCTCCATATGCAAGCTTTGCCCCCGCGG
配列番号48 CD3ゼータ活性化ドメインのアミノ酸配列
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号49 TNFRSF19ヒンジおよび膜貫通ドメインのヌクレオチド配列(膜貫通ドメインを下線で示す)
GCGGCCGCGGTCGGATTCCAAGACATGGAATGCGTGCCCTGCGGCGACCCGCCACCTCCTTACGAGCCGCACTGCGCATCGAAGGTCAACCTCGTGAAGATCGCGAGCACCGCGTCCTCACCCCGGGATACTGCTCTGGCCGCCGTGATTTGTTCCGCCTTGGCCACCGTGCTTCTGGCCCTGCTGATCCTCTGTGTGATC
配列番号50 TNFRSF19ヒンジおよび膜貫通ドメインのアミノ酸配列(膜貫通ドメインを下線で示す)
A A A V G F Q D M E C V P C G D P P P P Y E P H C A S K V N L V K I A S T A S S P R D T A L A A V I C S A L A T V L L A L L I L C V I
配列番号51 TNFRSF19膜貫通ドメインのヌクレオチド配列
GCCGCCGTGATTTGTTCCGCCTTGGCCACCGTGCTTCTGGCCCTGCTGATCCTCTGTGTGATC
配列番号52 TNFRSF19膜貫通ドメインのアミノ酸配列
A A V I C S A L A T V L L A L L I L C V I
配列番号53 TNFRSF19ヒンジドメインのヌクレオチド配列
GCGGCCGCGGTCGGATTCCAAGACATGGAATGCGTGCCCTGCGGCGACCCGCCACCTCCTTACGAGCCGCACTGCGCATCGAAGGTCAACCTCGTGAAGATCGCGAGCACCGCGTCCTCACCCCGGGATACTGCTCTG
配列番号54 TNFRSF19ヒンジドメインのアミノ酸配列
A A A V G F Q D M E C V P C G D P P P P Y E P H C A S K V N L V K I A S T A S S P R D T A L
配列番号55 短縮型TNFRSF19ヒンジドメインのヌクレオチド配列
TACGAGCCTCACTGCGCCAGCAAAGTCAACTTGGTGAAGATCGCGAGCACTGCCTCGTCCCCTCGGGACACTGCTCTGGC
配列番号56 短縮型TNFRSF19ヒンジドメインのアミノ酸配列
Y E P H C A S K V N L V K I A S T A S S P R D T A L
配列番号57 TNFRSF19膜貫通ドメインに融合されたCD8aヒンジドメインのヌクレオチド配列(膜貫通配列を下線で示す)
GCGGCCGCGCCCGCCCCTCGGCCCCCGACTCCTGCCCCGACGATCGCTTCCCAACCTCTCTCGCTGCGCCCGGAAGCATGCCGGCCCGCCGCCGGTGGCGCTGTCCACACTCGCGGACTGGACTTTGATACCGCACTGGCGGCCGTGATCTGTAGCGCCCTGGCCACCGTGCTGCTGGCGCTGCTCATCCTTTGCGTGATCTACTGCAAGCGGCAGCCTAGG
配列番号58 TNFRSF19膜貫通ドメインに融合されたCD8aヒンジドメインのアミノ酸配列(膜貫通配列を下線で示す)
A A A P A P R P P T P A P T I A S Q P L S L R P E A C R P A A G G A V H T R G L D F D T A L A A V I C S A L A T V L L A L L I L C V I Y C K R Q P R
配列番号59 CD28共刺激ドメインのヌクレオチド配列
CGGTCGAAGAGGTCCAGACTCTTGCACTCCGACTACATGAACATGACTCCTAGAAGGCCCGGACCCACTAGAAAGCACTACCAGCCGTACGCCCCTCCTCGGGATTTCGCCGCATACCGGTCC
配列番号60 CD28共刺激ドメインのアミノ酸配列
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
配列番号61 CD3ゼータバージョン2のヌクレオチド配列
cgcgtgaaatttagccgcagcgcggatgcgccggcgtatcagcagggccagaaccagctg
tataacgaactgaacctgggccgccgcgaagaatatgatgtgctggataaacgccgcggc
cgcgatccggaaatgggcggcaaaccgcgccgcaaaaacccgcaggaaggcctgtataac
gaactgcagaaagataaaatggcggaagcgtatagcgaaattggcatgaaaggcgaacgc
cgccgcggcaaaggccatgatggcctgtatcagggcctgagcaccgcgaccaaagatacc
tatgatgcgctgcatatgcaggcgctgccgccgcgc
配列番号62 CD3ゼータバージョン2のアミノ酸配列
R V K F S R S A D A P A Y Q Q G Q N Q L Y N E L N L G R R E E Y D V L D K R R G R D P E M G G K P R R K N P Q E G L Y N E L Q K D K M A E A Y S E I G M K G E R R R G K G H D G L Y Q G L S T A T K D T Y D A L H M Q A L P P R
配列番号63 フューリンP2Aフューリンのヌクレオチド配列
CGCGCGAAACGCAGCGGCAGCGGCGCGACCAACTTTAGCCTGCTGAAACAGGCGGGCGAT GTGGAAGAAAACCCGGGCCCGCGAGCAAAGAGG
配列番号64 フューリンP2Aフューリンのアミノ酸配列(フューリン配列を下線で示す)
RAKRSGSGATNFSLLKQAGDVEENPGPRAKR
配列番号65 フューリンT2Aのヌクレオチド配列
AGAGCTAAACGCTCTGGGTCTGGTGAAGGACGAGGTAGCCTTCTTACGTGCGGAGACGTGGAGGAAAACCCAGGACCC
配列番号66 フューリンT2Aのアミノ酸配列(フューリン配列を下線で示す)
RAKRSGSGEGRGSLLTCGDVEENPGP
配列番号67 短縮型EGFR(tEGFR)タグのヌクレオチド配列
AGGAAGGTTTGCAATGGAATCGGTATAGGGGAGTTTAAGGATTCACTTAGCATAAACGCTACTAATATTAAACACTTCAAAAACTGTACGAGTATAAGTGGAGATCTTCACATTTTGCCGGTTGCATTCCGAGGCGATTCATTCACCCACACGCCACCGCTTGACCCACAAGAATTGGATATTCTTAAAACCGTTAAAGAAATAACGGGGTTTTTGCTCATTCAAGCGTGGCCAGAAAATCGCACTGACCTCCATGCTTTCGAGAACCTGGAGATTATAAGAGGACGAACTAAGCAGCATGGTCAATTCTCCCTTGCTGTGGTCAGCCTGAACATCACCAGTCTTGGTTTGCGGTCCCTCAAGGAAATTTCAGATGGAGATGTCATCATAAGCGGCAACAAGAATTTGTGCTATGCAAATACCATAAACTGGAAAAAACTGTTTGGCACTTCCGGCCAGAAAACCAAGATTATTTCAAATCGGGGTGAGAACAGCTGCAAAGCCACCGGCCAGGTTTGTCATGCCTTGTGCTCTCCGGAAGGCTGTTGGGGGCCAGAACCCAGGGACTGCGTCAGTTGCAGAAACGTCTCAAGAGGCCGCGAATGCGTTGACAAGTGTAACCTCCTTGAGGGTGAGCCACGAGAGTTTGTTGAGAACAGCGAGTGTATACAATGTCACCCTGAATGTTTGCCCCAGGCTATGAATATAACCTGCACAGGCCGCGGGCCTGATAACTGCATCCAGTGTGCTCATTACATAGATGGACCTCACTGTGTGAAAACCTGCCCGGCCGGAGTTATGGGAGAAAACAACACTCTGGTGTGGAAATACGCTGATGCAGGCCACGTGTGCCACCTTTGTCACCCGAATTGTACATATGGGTGTACCGGTCCTGGACTTGAAGGTTGCCCTACCAATGGCCCTAAAATACCCAGTATCGCAACTGGCATGGTAGGCGCTCTTCTCTTGCTCTTGGTAGTTGCTCTCGGCATAGGTCTTTTTATG
配列番号68 短縮型EGFR(tEGFR)タグのアミノ酸配列
RKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM
配列番号69 CD38 hScFvバインダーM3816のヌクレオチド配列
CAAGTGCAACTCCAAGAATCCGGTCCTGGCCTCGTCAAACCTTCCGAAACACTGTCCCTGACCTGTACCGTGTCCGGAGGGTCGATTAGCTCGTCGTCATACTACTGGGGATGGATCAGACAGCCGCCGGGAAAGGGACTCGAGTGGATCGGGTCCATCTACTACTCGGGTAGCACTTACTACAACCCGTCGCTGAAGTCCCGCGTGACTATTTCCGTGGACACCTCCAAGAACCAGTTCAGCCTGAAGCTGAGCTCCGTGACCGCTGCCGATACCGCAGTGTACTACTGCGCGCGCCGGGGAAGCATCCGCGCCTTTGACATCTGGGGACAGGGAACTATGGTCACGGTGTCCAGCGGCGGTGGCGGATCTGGCGGCGGCGGATCCGGGGGGGGGGGAAGCCAGTCAGTGCTGACTCAGCCGCCTTCGGTGTCCGAGGCGCCCGGCCAGAGGGTCACCATTTCCTGCTCTGGATCGTCCAGCAACATTGGCAACAACGCCGTCAACTGGTACCAGCAGCTGCCCGGGGAAGCCCCCAAGCTGTTGATCTACTACGACGAGTATCTGCCAAGCGGAGTGTCAGACAGATTCTCCGCGTCGAAGTCCGGCACCTCCGCCTCACTTGCAATCTCCGGCCTGCGGTCCGAGGACGAAGCCGATTACTATTGCGCCGCCTGGGACGATAATCTGTCCGGTTGGGTGTTCGGCGGTGGAACCCAGCTTACCGTGCTCGGA
配列番号70 CD38 hScFvバインダーM3816のアミノ酸配列
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGSIRAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSEAPGQRVTISCSGSSSNIGNNAVNWYQQLPGEAPKLLIYYDEYLPSGVSDRFSASKSGTSASLAISGLRSEDEADYYCAAWDDNLSGWVFGGGTQLTVLG
配列番号71 CD38 hScFvバインダーM3817のヌクレオチド配列CAAGTGCAACTCCAAGAATCCGGTCCTGGTCTGGTCAAACCCTCCGAAACTCTGTCCCTGACGTGCACCGTGTCGGGATACTCCATTTCCTCCGGATACTACTGGGGTTGGATCCGCCAGCCTCCGGGAAAAGGCCTGGAATGGGTCGGAACCATCGGGAAGGACGGATCCACTTTCTATTCCCCGTCGCTGAAGTCACGGATCACCATTAGCCAGGACACCTCCAAGAACCAGTTCAGCCTGAAGCTGAACTCCGTGAACGCCGCGGACACTGCCGTCTACTACTGTGCGAAGCACAAGTGGTCCTTCGACTCCGGGAACGATTACTTCGACCACTGGGGCCAGGGGACCCTCGTGACCGTGTCGTCCGGCGGCGGGGGATCCGGTGGCGGGGGAAGCGGCGGCGGCGGATCAGACATTCAGCTGACCCAGTCTCCCTCATCCCTGTCGGCTAGCGTGGGCGATAGAGTGACCATCACATGCCAGGCATCGCAGGACATTTCGAACTATCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCGAAGCTTTTGATCTACGACGCCAGCAACCTGGAGACTGGAGTGCCCAGCCGGTTCAGCGGATCGGGATCCGGTACCGATTTCACCTTTACCATCTCCTCACTGCAACCAGAGGATATCGCCACCTACTACTGCCAGCAGTACCAGAATCTCCCGCTCACTTTCGGACAAGGGACTAGGCTTGAGATCAAG
配列番号72 CD38 hScFvバインダーM3817のアミノ酸配列
QVQLQESGPGLVKPSETLSLTCTVSGYSISSGYYWGWIRQPPGKGLEWVGTIGKDGSTFYSPSLKSRITISQDTSKNQFSLKLNSVNAADTAVYYCAKHKWSFDSGNDYFDHWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYQNLPLTFGQGTRLEIK
配列番号73 CD38 hScFvバインダーM8DR H_Lのヌクレオチド配列
GAGGTACAGTTGCTGGAGAGTGGAGGTGGTCTGGTACAGCCGGGAGGGTCCTTGCGGCTGTCATGCGCAGTTAGCGGATTTACTTTCAACTCCTTCGCCATGTCCTGGGTTAGGCAGGCCCCTGGAAAGGGTCTCGAATGGGTCTCTGCCATCAGTGGGAGTGGAGGTGGCACTTACTATGCTGACAGCGTCAAAGGGCGCTTCACTATTAGTCGAGACAACTCAAAGAATACTCTGTACCTTCAAATGAACTCCCTCCGAGCCGAAGACACTGCCGTATACTTTTGTGCTAAAGACAAAATCCTCTGGTTCGGCGAGCCTGTGTTCGACTACTGGGGACAGGGTACGCTCGTGACCGTGTCATCTGCTAGCGGTGGTGGCGGCTCAGGTGGTGGTGGCTCTGGTGGAGGTGGTAGTGAGATAGTACTGACACAGAGCCCGGCAACTCTTTCTCTCTCACCTGGTGAAAGAGCAACCCTCAGTTGCAGGGCTTCCCAGTCCGTATCTTCTTATCTCGCCTGGTACCAACAGAAACCGGGGCAAGCACCACGACTCTTGATCTATGATGCCTCTAACCGCGCAACAGGGATTCCGGCCCGATTTAGCGGCAGCGGTAGCGGCACGGACTTTACACTGACGATTTCTTCCCTTGAGCCGGAAGACTTTGCTGTGTATTATTGTCAACAACGGTCTAATTGGCCGCCGACGTTTGGACAGGGCACAAAGGTTGAAATAAAG
配列番号74 CD38 hScFvバインダーM8DR H_Lのアミノ酸配列
EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK
配列番号75 CD38 hScFvバインダーM8DR L_Hのヌクレオチド配列
GAAATTGTTTTGACTCAGAGTCCTGCGACATTGAGCTTGAGTCCGGGTGAACGGGCTACTCTTAGTTGCCGCGCCTCACAGTCCGTATCTTCATACCTCGCCTGGTATCAACAGAAGCCGGGGCAGGCCCCTCGCCTGCTTATATATGATGCCAGCAATAGAGCTACTGGAATACCTGCCCGATTTTCTGGGTCTGGAAGTGGGACGGATTTCACACTGACAATATCTTCTCTTGAGCCGGAAGACTTTGCCGTCTATTACTGCCAACAGCGCTCTAACTGGCCGCCCACGTTTGGTCAGGGAACAAAGGTAGAGATAAAGGGGGGCGGTGGCTCCGGTGGGGGAGGGAGCGGAGGAGGTGGTTCTGAAGTCCAGCTTCTCGAATCCGGTGGGGGTCTGGTTCAACCTGGAGGTAGTCTCCGCTTGTCCTGTGCTGTCTCAGGGTTCACATTTAACTCTTTTGCTATGTCTTGGGTTCGGCAAGCTCCTGGCAAGGGCCTGGAGTGGGTGTCCGCTATTAGTGGCTCCGGAGGCGGCACGTACTATGCAGATAGTGTGAAGGGCAGGTTTACTATTTCCCGGGATAACTCTAAGAACACCCTGTACTTGCAGATGAATAGTTTGCGAGCCGAAGACACTGCAGTGTATTTTTGCGCCAAGGATAAAATACTCTGGTTTGGCGAGCCGGTATTTGACTATTGGGGGCAAGGCACACTTGTCACAGTATCCAGC
配列番号76 CD38 hScFvバインダーM8DR L_Hのアミノ酸配列
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS
配列番号77 LTG2089(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAGTGCAATTGGTCCAAAGCGGTGCAGAAGTCAAGAAACCTGGTTCGAGCGTGAAAGTGTCCTGCAAGGCCTCTGGCGGCACCTTCTCATCCTACGCCATTAGCTGGGTCCGCCAAGCCCCGGGCCAGGGACTTGAGTGGATGGGCGGAATCATCCCTATCTTCGGGACCGCCAATTACGCCCAGAAGTTCCAGGGCCGCGTGACCATCACCGCGGACAAGTCCACATCAACCGCCTATATGGAGCTCTCGTCGCTGAGATCAGAGGACACTGCTGTCTACTACTGTGCGAGGGCCCCATACGACGATGCATTCGACATCTGGGGACAGGGTACCATGGTCACTGTGTCCAGCGGGGGCGGAGGCTCCGGGGGGGGCGGATCGGGGGGCGGCGGATCCAACTTCATGCTGACCCAGCCGCACTCGGTGTCAGAGAGCCCCGGAAAGACTGTGACCATTAGCTGCACCCGGTCCAGCGGAAGCATCGCCTCCAACTACGTGCAGTGGTACCAGCAGCGGCCGGGCTCCGCGCCGACCACTGTGATCTACGAAGATAACCAGCGCCCCTCCGGTGTCCCTGGACGGTTCTCCGGATCCATTGACACCTCGTCCAACTCCGCCTCGCTGACGATCTCCGGACTGGAGACTGAAGATGAAGCTGTGTACTACTGCCAATCCTACGACTCCGGATTTCCCTACGCCGTGTTCGGTGGCGGGACCCAGCTCACCGTGCTGGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号78 LTG2089(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAPYDDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTTVIYEDNQRPSGVPGRFSGSIDTSSNSASLTISGLETEDEAVYYCQSYDSGFPYAVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号79 ヒトIgG4ヒンジのヌクレオチド配列
GAGAGCAAATACGGGCCGCCATGTCCCCCGTGTCCG
配列番号80 ヒトIgG4ヒンジのアミノ酸配列
ESKYGPPCPPCP
配列番号81 ヒトIgG4 CH2ドメインのヌクレオチド配列
GCACCACCAGTTGCTGGCCCTAGTGTCTTCTTGTTCCCTCCCAAGCCCAAAGACACCTTGATGATTTCCAGAACTCCTGAGGTTACCTGCGTTGTCGTAGATGTTTCTCAGGAGGACCCAGAGGTCCAATTTAACTGGTACGTTGATGGGGTGGAAGTTCACAATGCGAAGACAAAGCCGCGGGAAGAACAATTTCAGTCCACTTACCGGGTTGTCAGCGTTCTGACGGTATTGCATCAAGACTGGCTTAATGGAAAGGAATATAAGTGTAAGGTGTCCAACAAAGGTTTGCCGAGCAGTATTGAGAAGACCATATCAAAGGCGAAG
配列番号82 ヒトIgG4 CH2ドメインのアミノ酸配列
APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV
DGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA K
配列番号83 ヒトIgG4 CH3ドメインのヌクレオチド配列
GGGCAGCCGCGCGAGCCACAAGTTTACACTTTGCCGCCATCTCAAGAGGAAATGACTAAAAACCAGGTATCCTTGACATGCCTCGTAAAAGGATTTTATCCATCTGATATTGCTGTGGAATGGGAGTCTAACGGGCAGCCGGAAAATAATTACAAAACTACACCACCTGTGCTCGATTCAGATGGAAGTTTCTTCCTTTACAGTAGACTTACGGTGGACAAATCTAGGTGGCAGGAAGGGAATGTGTTTAGTTGTAGTGTAATGCACGAGGCACTTCATAACCACTATACACAGAAGTCACTGAGTTTGAGTCTTGGCAAA
配列番号84 ヒトIgG4 CH3ドメインのアミノ酸配列
GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
配列番号85 ヒトIgG4ヒンジCH2 CH3ドメインのヌクレオチド配列
GAGAGCAAATACGGGCCGCCATGTCCCCCGTGTCCGGCACCACCAGTTGCTGGCCCTAGTGTCTTCTTGTTCCCTCCCAAGCCCAAAGACACCTTGATGATTTCCAGAACTCCTGAGGTTACCTGCGTTGTCGTAGATGTTTCTCAGGAGGACCCAGAGGTCCAATTTAACTGGTACGTTGATGGGGTGGAAGTTCACAATGCGAAGACAAAGCCGCGGGAAGAACAATTTCAGTCCACTTACCGGGTTGTCAGCGTTCTGACGGTATTGCATCAAGACTGGCTTAATGGAAAGGAATATAAGTGTAAGGTGTCCAACAAAGGTTTGCCGAGCAGTATTGAGAAGACCATATCAAAGGCGAAGGGGCAGCCGCGCGAGCCACAAGTTTACACTTTGCCGCCATCTCAAGAGGAAATGACTAAAAACCAGGTATCCTTGACATGCCTCGTAAAAGGATTTTATCCATCTGATATTGCTGTGGAATGGGAGTCTAACGGGCAGCCGGAAAATAATTACAAAACTACACCACCTGTGCTCGATTCAGATGGAAGTTTCTTCCTTTACAGTAGACTTACGGTGGACAAATCTAGGTGGCAGGAAGGGAATGTGTTTAGTTGTAGTGTAATGCACGAGGCACTTCATAACCACTATACACAGAAGTCACTGAGTTTGAGTCTTGGCAAA
配列番号86 ヒトIgG4ヒンジCH2 CH3ドメインのアミノ酸配列
ESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
配列番号87 LTG2090(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAGTGCAACTCGTCGAATCTGGTGGAGGATCCGTGCAGCCTGGTGGAAGCCTGAGACTGTCGTGTGCCGCCTCCGAGTTCACCTTCTCCTCGTACTGGATGCACTGGGTCAGACAGGCGCCCGGAAAGGGCCTGGAATGGGTGGCCGTGATCTCATACGACGGCGCGAAGAAGTACTACGCCGATTCCGTGAAGGGCCGCTTTACCATTTCCCGGGACAATTCAAAGAACACCCTCTACCTTCAAATGAACTCCCTGAGGGCCGAGGATACTGCAGTCTACTACTGCGCTCGGGATGACGGGAGCGGGGGCTTCGACTACTGGGGACAGGGAACCCTCGTGACTGTGTCATCCGGTGGCGGCGGCTCCGGAGGCGGCGGTTCCGGGGGGGGGGGATCCGACATCGTGATGACGCACACTCCTCTGTCGCTGTCCGTGACCCCCGGCCAGCCTGCCTCAATCTCGTGCAAGAGCTCCCAGTCGCTGCTGCATAGCGATGGAAAGACCTACCTGTATTGGTACCTTCAAAAGCCGGGACAGCCGCCGCAGTTGCTGATCTATGAAGTCAGCAACCGCTTCTCGGGAGTGCCCGACCGCTACTCCGGCTCGGGGAGCGGAACCGACTTCACCCTGAAAATTTCCCGGGTCGAGGCAGAGGACGTGGGAGTGTACTACTGCATGCAAAGCATTCAGTTGCCACTGACTTTCGGTGGAGGAACCAAGCTCGAAATCAAAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号88 LTG2090(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGSVQPGGSLRLSCAASEFTFSSYWMHWVRQAPGKGLEWVAVISYDGAKKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDGSGGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTHTPLSLSVTPGQPASISCKSSQSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGVPDRYSGSGSGTDFTLKISRVEAEDVGVYYCMQSIQLPLTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号89 LTG2091(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAGTGCAATTGGTGCAGAGCGGTGGAGGACTTGTGAAACCTGGTGGATCCCTGAGACTTTCCTGTGCCGCTTCGGGCTTCACCTTCTCGGACTACTACATGTCCTGGATTCGCCAGGCCCCTGGAAAGGGACTGGAATGGGTGTCATACATCAGCTCCTCCGGTTCCACCATCTACTATGCCGATTCCGTGAAGGGCAGATTCACCATCTCGCGCGACAACGCCAAGAACACTCTCTATCTGCAAATGAACTCACTGCGGGCTGAGGACACCGCGGTCTACTACTGCGCCCGGGACCTCAGCGGAAAGTCCAGCGGATGGTCCCATTACTTCGATTACTGGGGACAGGGAACCCTGGTCACCGTGTCCAGCGGCGGGGGGGGCTCGGGTGGCGGCGGCTCCGGCGGCGGCGGGAGCAACTTCATGCTGACTCAGCCCCACTCCGTGTCCGAGAGCCCGGGAAAGACCGTGACTATTTCGTGCACACGGTCCTCCGGGAGCATTGCGAACAACTACGTGCAGTGGTACCAGCAGCGGCCCGATAGGGCCCCAACCACTGTGATCTACGAAGATGACCAGCGGCCGTCTGGAGTCCCGGACCGCTTCTCGGGGTCCATCGACTCATCATCCAATTCCGCATCGCTGACGATCAGCGGACTGAAGATCGAGGACGAAGCCGATTACTACTGCCAGTCCTACGACGGCACCAACTGGGTCTTTGGGGGTGGAACCAAGCTGACTGTGCTCGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号90 LTG2091(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARDLSGKSSGWSHYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTISCTRSSGSIANNYVQWYQQRPDRAPTTVIYEDDQRPSGVPDRFSGSIDSSSNSASLTISGLKIEDEADYYCQSYDGTNWVFGGGTKLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号91 LTG2092(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAGTGCAACTTGTCGAAAGCGGTGGAGGTCTTGTCCAACCTGGTCGCTCCCTGAGGCTCTCGTGTGCCGCGAGCGGATTCACCTTCTCATCGTACGCTATGTCCTGGGTCAGACAGGCTCCTGGAAAGGGCCTGGAATGGGTGGCCGTGATCTCCTACGACGGCAGCAACAAGTATTACGCCGACTCAGTGAAGGGCCGGTTCACCATTTCCCGGGACAACAGCAAGAACACCCTGTACTTGCAAATGAACTCCCTGCGGGCCGAGGATACCGCGGTGTACTACTGCGCCCACCTCCGCTTTGGATACGGAATGGATGTCTGGGGACAGGGAACTACCGTGACCGTGTCGTCCGGGGGGGGGGGAAGCGGCGGCGGGGGATCGGGTGGCGGCGGATCCCAGACTGTGGTCACCCAAGAGCCTTCACTGACCGTGTCCCCGGGTGGCACCGTGACGCTGACTTGCGCGTCATCTACCGGGGCCGTGACCTCGGACCACTACCCCTGCTGGTTCCAGCAGAAACCCGGACATCCACCGAGAGCCCTGGTGTACTCCACTGACACCATCCACTCCTGGACTCCGGCCCGGTTCTCCGGAAGCCTCCTGGGCGGGAAGGCCGCACTGACAGTGTCCGGAGTGCAGCCCGAGGATGAAGCCGACTACTACTGTCTGCTCTACTATGGGGGAGCACGCGTGTTCGGTGGCGGCACTCAGCTGACCGTGCTGGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号92 LTG2092(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGRSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAHLRFGYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSDHYPCWFQQKPGHPPRALVYSTDTIHSWTPARFSGSLLGGKAALTVSGVQPEDEADYYCLLYYGGARVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号93 LTG2093(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTGCAACTCGTCCAATCCGGAGCTGAAGTCAAGAAGCCAGGATCTTCCGTGAAAGTGTCGTGCAAGGCCTCCGGGGGAACATTCTCCTCATATGCGATCAGCTGGGTCCGCCAGGCTCCGGGACAGGGCTTGGAGTGGATGGGTATCATTAACCCTTCGGGCGGCTCAACTAGCTACGCCCAGAAGTTCCAGGGCAGAGTGACCATGACCAGGGACACCAGCACTTCGACGGTGTACATGGAACTGTCCTCACTGCGGTCCGAGGACACCGCCGTGTACTACTGCGCCCGGGAGTATTCCTCCTCCCGCGTGGACGCCTTCGATATCTGGGGACAGGGTACCATGGTCACTGTGTCGTCCGGCGGCGGCGGAAGCGGGGGTGGCGGGAGCGGTGGCGGCGGATCCAGCTACGAACTCACCCAGCCGCCGTCAGTGTCCGTGAGCCCGGGACAGACCGCAACCATTACTTGTTCCGGGGATGACCTGGGATCCAAATACGTGTGCTGGTACCAACAGAAGCCTGGTCACTCGCCCGTGCTGATCATCTACGACGACTCAGACCGGCCCAGCGGCATCCCCGAGAGATTTTCCGGATCCAACAGCGGAAACACCGCCACTCTGACTATTTCGCGCGTCGAGGCCGGCGACGAAGCGGATTACTACTGCCAAGTCTGGGACAGCTCCTCGGATCATGCCGTGTTCGGGGGCGGAACCCAGCTTACCGTGCTGGGGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号94 LTG2093(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREYSSSRVDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSYELTQPPSVSVSPGQTATITCSGDDLGSKYVCWYQQKPGHSPVLIIYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHAVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号95 LTG2094(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAGTGCAGTTGGTGGAGAGCGGTGGAGGACTTGTGCAACCTGGTGGATCCCTGAGATTGTCGTGTGCCGCCTCCGGTTTCACCTTCTCCTCGTACTGGATGAGCTGGGTCCGCCAGGCACCCGGGAAGGGACTGGAATGGGTGGCGGACATTAAGGATGACGGCTCCGAGCGGTACTACGTGGACTCCGTGAAGGGCCGGTTCACTATCTCAAGAGACAATGCCAAGAACAGCCTGTACCTCCAAATGAACTCGCTGCGGGCCGAGGATACCGCAGTGTATTACTGCGCCCGCGACGTGTGGGCTGGGATGGATGTCTGGGGCCAGGGGACCACTGTCACTGTGTCTAGCGGGGGCGGCGGAAGCGGCGGCGGCGGATCCGGTGGTGGCGGAAGCGACATTCAGCTGACCCAGTCCCCATCATTCCTGTCCGCCTCCGTGGGCGACAGGGTCACTATCACTTGCCAAGCCAGCCAGGACATCTCCAACTACCTGAACTGGTACCAGCAGAAGCCTGGAAAAGCTCCGAAGCTCCTCATCTACGACGCCTCGAACCTCGAAACCGGAGTGCCCTCACGGTTTTCCGGATCGGGATCGGGGACCGATTTCTCCTTCACCATTTCATCCCTGCAACCCGAGGACATCGCGACCTACTACTGCCAACAGACATACTCCCCGCCGATTACGTTCGGACAGGGAACCCGCCTGGAAATCAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号96 LTG2094(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVADIKDDGSERYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDVWAGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQLTQSPSFLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFSFTISSLQPEDIATYYCQQTYSPPITFGQGTRLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号97 LTG2095(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTCCAACTCGTCCAGTCCGGTGCCGAAGTCAAGAAGCCTGGCTCATCCGTGAAAGTGTCCTGCAAAGCATCGGGCGGAACCTTCTCCTCCTATGCCATTTCCTGGGTCCGCCAGGCACCGGGCCAGGGTCTGGAGTGGATGGGCGGGATTATCCCTATCTTCGGAACTGCCAACCACGCCCAAAAGTTCCAGGGACGCGTGACCATTACCGCCGATGAATCAACCTCAACCGCCTACATGGAACTGTCCAGCTTGAGGTCCGAGGACACCGCCGTGTACTACTGCGCGTTCATGATGGTGCCGGAGTACTACTTTGACTACTGGGGCCAGGGAACCCTTGTGACCGTGTCGTCCGGTGGTGGCGGATCCGGGGGGGGGGGATCTGGGGGCGGCGGAAGCGATATCCAGATGACCCAGTCGCCATCGAGCCTGTCCGCTTCCGTGGGCGACAGAGTGACGATCACTTGCCGGGCTTCACAAGGCATCAGAAATGACCTGGGCTGGTATCAGCAGAAGCCCGGAGAAGCGCCCAAGCGGCTGATCTACGCGGCCAGCACCCTGCAAAACGGAGTGCCTTCGCGGTTCTCCGGGAGCGGCTCCGGAACTGACTTCACTCTGACTATTAACAGCCTCCAGCCCGAGGATTTCGCCACATACTACTGTCAGCAGTACAACAGCTACCCGTACACCTTCGGACAGGGAACTAAGCTCGAAATCAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号98 LTG2095(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANHAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAFMMVPEYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGEAPKRLIYAASTLQNGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCQQYNSYPYTFGQGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号99 LTG2096(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGAAAGTGCAACTCCAAGAAAGCGGCCCCGGACTTGTCAAACCGTCCCAGACTCTCTCCCTGACCTGTGCCGTCAGCGGTGGCTCAATTTCGAGCGGTGGCTACTACTGGTCCTGGATCAGGCAGCATCCGGGAAAGGGCTTGGAGTGGATTGGATACATCTACTACTCCGGGTCCACCTACTACAATCCCTCGCTGAAGTCGAGAGTCACCATCAGCGTGGACACCTCCAAGAACCAGTTTAGCCTGAAGCTGTCCTCAGTGACCGCAGCTGACACCGCCGTGTACTACTGCGCCCGCGGCGGAGTGATGGGCGGAGACTTCGACTACTGGGGACAGGGAACCCTGGTCACTGTGTCCAGCGGGGGGGGGGGATCCGGCGGCGGCGGTTCCGGTGGCGGAGGGTCCCAGTCAGTGCTGACTCAGCCACCTTCCGTGTCTGTGTCGCCCGGACAAACCGCCAGCATCACGTGCTCCGGCGACAACCTCGGTGATCACTATGTGTGCTGGTACCAACAGCGGCCGGGGCAGTCACCGGTGCTGATTATGTACGAGGATACTAAGCGCCCTTCCGGAATCCCTGACCGGTTCTCGGGAAGCAACTCCGGAAACACCGCCACCCTGACCATCTCCGGAACCCAGACAATGGATGAAGCGGACTACTATTGCGTGGCGTGGGACGATTCGCTGTCCGGCTGGGTGTTCGGCGGGGGAACTCAGCTGACTGTGCTCGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号100 LTG2096(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPKVQLQESGPGLVKPSQTLSLTCAVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGVMGGDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSVSPGQTASITCSGDNLGDHYVCWYQQRPGQSPVLIMYEDTKRPSGIPDRFSGSNSGNTATLTISGTQTMDEADYYCVAWDDSLSGWVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号101 LTG2097(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAACTCCAACTCCAAGAATCTGGACCAGGCCTCGTGAAGCCCTCCCAAACTCTGTCCCTGACCTGTACCGTGTCGGGTGGAAGCATTTCGAGCGGTGGATACTACTGGTCCTGGATCAGGCAGCATCCTGGAAAGGGACTGGAGTGGATTGGGTACATCTACTACTCCGGCTCAACCTACTACAACCCGTCCTTGAAATCGCGCGTGACGATCTCCGTGGACACTTCAAAGAACCAGTTCAGCCTGAAGCTTTCCTCCGTGACCGCGGCCGATACAGCGGTGTACTACTGCGCTCGGGATCAGAGCGTGGCCGACCCTGGTGGCGGCTACTACTACTACGGAATGGATGTCTGGGGACAGGGAACCACCGTGACTGTGTCCAGCGGGGGCGGCGGATCCGGGGGGGGGGGATCGGGCGGCGGCGGTTCGCAGTCCGTGCTGACCCAGCCACCTAGCGTGTCAGTGGCACCGGGACAGACCGCCTCCATTTCCTGCGGGGGAAATGACTTCGGTAGCCGCTCCGTGTCATGGTATCACCAGAAGCCGGGACAGGCCCCGGTGCTGGTCATCTATGACGACAACGACAGACCCTCGGGCATCCCCGAACGGTTTTCGGGAAGCACCTCCGGAGACACTGCCACCCTGACCATCTCCCGGGTCGAGGTCGGCGATGAAGCCGATTACTACTGCCAAGTCTGGGACGACGACTCCGACCACTGGGTGTTCGGCGGCGGAACTAAGCTGACTGTGCTGGGGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号102 LTG2097(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDQSVADPGGGYYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSVAPGQTASISCGGNDFGSRSVSWYHQKPGQAPVLVIYDDNDRPSGIPERFSGSTSGDTATLTISRVEVGDEADYYCQVWDDDSDHWVFGGGTKLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号103 LTG2098(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTGCAACTCCAACAATCGGGCCCCGGACTCGTGAAACCGTCCCAGACTCTGTCCCTTACTTGCGTGATTTCCGGGGACTCCGTGAGCTCAAACTCGGCGGCCTGGAACTGGATTAGACAGTCCCCTTCCCGGGGTCTGGAATGGCTGGGCCGGACTTACTACCGGTCGAAGTGGCACAACGATTACGCAGTCAGCGTCGAGAGCCGCATCATCGTGAACCCGGACACCTCAAAGAACCAGTTCAGCCTGCAACTGAATTCCGTGACCCCCGAGGACACCGCTGTGTACTACTGCGCCCGCGACCCCGGATACTTCTATGGACTGGACGTCTGGGGACAGGGGACCATGGTCACCGTGTCGAGCGGCGGCGGCGGATCCGGTGGCGGGGGATCCGGCGGTGGCGGATCCAACTTCATGTTGACTCAGCCGCATTCGGTGTCGGAGTCCCCTGGAAAGACAGTCACCATCCCATGTACCCGGAGCAGCGGAACTATCGCCGACTACTACGTGCAGTGGTACCAGCAGCGCCCTGATTCCTCACCGATCATTGTGATCTATGACGACAACCAGAGGCCCTCCGGGGTGCCGGATAGATTCAGCGGATCCATTGACTCCTCGTCCAACTCTGCCTCACTGACGATCTCCGGGCTCAAGACCGAAGATGAAGCGGCCTACTACTGCCAGTCATACGACTCCACCAACCACTGGGTGTTTGGTGGCGGAACTAAGCTGACCGTGCTGGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号104 LTG2098(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSQTLSLTCVISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWHNDYAVSVESRIIVNPDTSKNQFSLQLNSVTPEDTAVYYCARDPGYFYGLDVWGQGTMVTVSSGGGGSGGGGSGGGGSNFMLTQPHSVSESPGKTVTIPCTRSSGTIADYYVQWYQQRPDSSPIIVIYDDNQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEAAYYCQSYDSTNHWVFGGGTKLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号105 LTG2099(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTCACACTCAAAGAATCCGGACCGGTGCTCGTGAAGCCTACTGAAACCTTGACCCTGACATGCACCTTTTCCGGGTTCTCCCTGAGCACCTCGGGAGTCGGAGTGGCGTGGATTAGGCAGCCGCCAGGAAAAGACCTCGAGTGGCTCGCCCTTATCTACTGGGACGATGACAAGCGCTACTCACCCTCACTGGAGAGCAGACTGACGATCACCAAGGATACCTCGAAGAACCAAGTGGCCCTGACTATGTCCGACATGGACCCTGTGGACACCGCGACTTACTACTGCGCCCGGGGCGATTACTGGGGACGGCTGGACTACTGGGGACAGGGAACTCTGGTCACCGTGTCCAGCGGCGGCGGTGGTTCAGGGGGTGGCGGCAGCGGGGGGGGCGGATCGGATATCCAGCTTACCCAGTCGCCGTCCTCCCTCTCTGCATCGATTGGCGACCGCGTGACTATTACGTGTCAGGCCTCCGAGGACATCAACAACTACCTGAACTGGTACCAGCAGAAGCCCGGAAAGGCCCCAAAGCTGCTGATCTACGACGCTAGCAACTTGGAAACCGGAGTGCCGTCCCGGTTCTCCGGATCCGGGAGCGGTACCGACTTCACCTTCACCATCAACTCCCTGCAACCCGAGGATATTGCCACCTATTACTGCCAACAGTTCGACAATATGCCTCTGACTTTCGGGGGCGGCACTAAGCTCGAAATCAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号106 LTG2099(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVTLKESGPVLVKPTETLTLTCTFSGFSLSTSGVGVAWIRQPPGKDLEWLALIYWDDDKRYSPSLESRLTITKDTSKNQVALTMSDMDPVDTATYYCARGDYWGRLDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASIGDRVTITCQASEDINNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTINSLQPEDIATYYCQQFDNMPLTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号107 LTG2501(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTCACTCTGAAAGAATCCGGTCCCGTGCTCGTCAAACCCACCGAAACCCTGACCCTGACCTGTACTTTCTCCGGATTTTCCCTCTCAACCTCCGGCGTGGGCGTGGCCTGGATTCGGCAGCCTCCCGGAAAGGATTTGGAGTGGCTGGCCCTGATCTACTGGGATGACGATAAGCGCTACTCCCCATCCCTCGAGTCCCGGCTGACTATCACTAAGGACACCTCCAAGAATCAAGTCGCCCTTACTATGTCGGACATGGACCCTGTGGACACCGCTACGTACTACTGCGCTCGGGGAGACTATTGGGGGCGCCTGGACTACTGGGGACAGGGAACCCTCGTGACCGTGTCGTCTGGGGGCGGCGGACCGGGTGGCGGAGCGTCCGGGGGCGGTGGATCGGACATCCAGCTGACACAGAGCCCCAGCAGCCTGAGCGCCTCGATTGGCGACAGAGTGACCATTACGTGCCAGGCATCCGAGGACATCAACAACTACCTGAACTGGTACCAGCAGAAGCCTGGGAAGGCCCCAAAGCTGCTGATCTACGACGCCTCCAACCTGGAAACCGGAGTGCCGTCAAGGTTCAGCGGCTCGGGATCAGGAACCGATTTCACTTTCACCATCAACAGCTTGCAGCCGGAAGATATCGCGACCTACTACTGCCAACAGTTCGACAACATGCCGCTGACTTTCGGTGGCGGGACCAAGCTTGAGATTAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号108 LTG2501(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVTLKESGPVLVKPTETLTLTCTFSGFSLSTSGVGVAWIRQPPGKDLEWLALIYWDDDKRYSPSLESRLTITKDTSKNQVALTMSDMDPVDTATYYCARGDYWGRLDYWGQGTLVTVSSGGGGPGGGASGGGGSDIQLTQSPSSLSASIGDRVTITCQASEDINNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTINSLQPEDIATYYCQQFDNMPLTFGGGTKLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号109 LTG2502(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTGCAACTCCAAGAATCCGGTCCTGGCCTCGTCAAACCTTCCGAAACACTGTCCCTGACCTGTACCGTGTCCGGAGGGTCGATTAGCTCGTCGTCATACTACTGGGGATGGATCAGACAGCCGCCGGGAAAGGGACTCGAGTGGATCGGGTCCATCTACTACTCGGGTAGCACTTACTACAACCCGTCGCTGAAGTCCCGCGTGACTATTTCCGTGGACACCTCCAAGAACCAGTTCAGCCTGAAGCTGAGCTCCGTGACCGCTGCCGATACCGCAGTGTACTACTGCGCGCGCCGGGGAAGCATCCGCGCCTTTGACATCTGGGGACAGGGAACTATGGTCACGGTGTCCAGCGGCGGTGGCGGATCTGGCGGCGGCGGATCCGGGGGGGGGGGAAGCCAGTCAGTGCTGACTCAGCCGCCTTCGGTGTCCGAGGCGCCCGGCCAGAGGGTCACCATTTCCTGCTCTGGATCGTCCAGCAACATTGGCAACAACGCCGTCAACTGGTACCAGCAGCTGCCCGGGGAAGCCCCCAAGCTGTTGATCTACTACGACGAGTATCTGCCAAGCGGAGTGTCAGACAGATTCTCCGCGTCGAAGTCCGGCACCTCCGCCTCACTTGCAATCTCCGGCCTGCGGTCCGAGGACGAAGCCGATTACTATTGCGCCGCCTGGGACGATAATCTGTCCGGTTGGGTGTTCGGCGGTGGAACCCAGCTTACCGTGCTCGGAGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号110 LTG2502(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARRGSIRAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSVLTQPPSVSEAPGQRVTISCSGSSSNIGNNAVNWYQQLPGEAPKLLIYYDEYLPSGVSDRFSASKSGTSASLAISGLRSEDEADYYCAAWDDNLSGWVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号111 LTG2503(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGCAAGTGCAACTCCAAGAATCCGGTCCTGGTCTGGTCAAACCCTCCGAAACTCTGTCCCTGACGTGCACCGTGTCGGGATACTCCATTTCCTCCGGATACTACTGGGGTTGGATCCGCCAGCCTCCGGGAAAAGGCCTGGAATGGGTCGGAACCATCGGGAAGGACGGATCCACTTTCTATTCCCCGTCGCTGAAGTCACGGATCACCATTAGCCAGGACACCTCCAAGAACCAGTTCAGCCTGAAGCTGAACTCCGTGAACGCCGCGGACACTGCCGTCTACTACTGTGCGAAGCACAAGTGGTCCTTCGACTCCGGGAACGATTACTTCGACCACTGGGGCCAGGGGACCCTCGTGACCGTGTCGTCCGGCGGCGGGGGATCCGGTGGCGGGGGAAGCGGCGGCGGCGGATCAGACATTCAGCTGACCCAGTCTCCCTCATCCCTGTCGGCTAGCGTGGGCGATAGAGTGACCATCACATGCCAGGCATCGCAGGACATTTCGAACTATCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCGAAGCTTTTGATCTACGACGCCAGCAACCTGGAGACTGGAGTGCCCAGCCGGTTCAGCGGATCGGGATCCGGTACCGATTTCACCTTTACCATCTCCTCACTGCAACCAGAGGATATCGCCACCTACTACTGCCAGCAGTACCAGAATCTCCCGCTCACTTTCGGACAAGGGACTAGGCTTGAGATCAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号112 LTG2503(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPQVQLQESGPGLVKPSETLSLTCTVSGYSISSGYYWGWIRQPPGKGLEWVGTIGKDGSTFYSPSLKSRITISQDTSKNQFSLKLNSVNAADTAVYYCAKHKWSFDSGNDYFDHWGQGTLVTVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYQNLPLTFGQGTRLEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号113 LTG2525(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAGGTACAGTTGCTGGAGAGTGGAGGTGGTCTGGTACAGCCGGGAGGGTCCTTGCGGCTGTCATGCGCAGTTAGCGGATTTACTTTCAACTCCTTCGCCATGTCCTGGGTTAGGCAGGCCCCTGGAAAGGGTCTCGAATGGGTCTCTGCCATCAGTGGGAGTGGAGGTGGCACTTACTATGCTGACAGCGTCAAAGGGCGCTTCACTATTAGTCGAGACAACTCAAAGAATACTCTGTACCTTCAAATGAACTCCCTCCGAGCCGAAGACACTGCCGTATACTTTTGTGCTAAAGACAAAATCCTCTGGTTCGGCGAGCCTGTGTTCGACTACTGGGGACAGGGTACGCTCGTGACCGTGTCATCTGCTAGCGGTGGTGGCGGCTCAGGTGGTGGTGGCTCTGGTGGAGGTGGTAGTGAGATAGTACTGACACAGAGCCCGGCAACTCTTTCTCTCTCACCTGGTGAAAGAGCAACCCTCAGTTGCAGGGCTTCCCAGTCCGTATCTTCTTATCTCGCCTGGTACCAACAGAAACCGGGGCAAGCACCACGACTCTTGATCTATGATGCCTCTAACCGCGCAACAGGGATTCCGGCCCGATTTAGCGGCAGCGGTAGCGGCACGGACTTTACACTGACGATTTCTTCCCTTGAGCCGGAAGACTTTGCTGTGTATTATTGTCAACAACGGTCTAATTGGCCGCCGACGTTTGGACAGGGCACAAAGGTTGAAATAAAGGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号114 LTG2525(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
配列番号115 LTG2526(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のヌクレオチド配列
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTGATTCCGGAAATTGTTTTGACTCAGAGTCCTGCGACATTGAGCTTGAGTCCGGGTGAACGGGCTACTCTTAGTTGCCGCGCCTCACAGTCCGTATCTTCATACCTCGCCTGGTATCAACAGAAGCCGGGGCAGGCCCCTCGCCTGCTTATATATGATGCCAGCAATAGAGCTACTGGAATACCTGCCCGATTTTCTGGGTCTGGAAGTGGGACGGATTTCACACTGACAATATCTTCTCTTGAGCCGGAAGACTTTGCCGTCTATTACTGCCAACAGCGCTCTAACTGGCCGCCCACGTTTGGTCAGGGAACAAAGGTAGAGATAAAGGGGGGCGGTGGCTCCGGTGGGGGAGGGAGCGGAGGAGGTGGTTCTGAAGTCCAGCTTCTCGAATCCGGTGGGGGTCTGGTTCAACCTGGAGGTAGTCTCCGCTTGTCCTGTGCTGTCTCAGGGTTCACATTTAACTCTTTTGCTATGTCTTGGGTTCGGCAAGCTCCTGGCAAGGGCCTGGAGTGGGTGTCCGCTATTAGTGGCTCCGGAGGCGGCACGTACTATGCAGATAGTGTGAAGGGCAGGTTTACTATTTCCCGGGATAACTCTAAGAACACCCTGTACTTGCAGATGAATAGTTTGCGAGCCGAAGACACTGCAGTGTATTTTTGCGCCAAGGATAAAATACTCTGGTTTGGCGAGCCGGTATTTGACTATTGGGGGCAAGGCACACTTGTCACAGTATCCAGCGCCTCCGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号116 LTG2526(hScFv aCD38 CD8 TM 4-1BB CD3ゼータ)のアミノ酸配列
MLLLVTSLLLCELPHPAFLLIPEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Claims (48)
- 配列番号1、3、5、7、9、11、15、17、19、21、23、25、69、または71を含むヌクレオチド配列によりコードされるCD38抗原結合性ドメインを含む少なくとも1つの細胞外抗原結合性ドメイン、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ドメイン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CD38抗原結合性ドメインが、CD38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CD38抗原結合性ドメインが、CD38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CD38抗原結合性ドメイン、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ードメインが、CD8、TNFRSF19、またはCD28の細胞外ドメインに由来し、膜貫通ドメイン連結されている、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CD38抗原結合性ドメインに、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が先行する、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が、配列番号14のリーダーアミノ酸配列をコードする配列番号13、または配列番号40のリーダーアミノ酸配列をコードする配列番号39、または配列番号42のリーダーアミノ酸配列をコードする配列番号41、または配列番号44のリーダーアミノ酸配列をコードする配列番号43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が、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またはそれらの任意の組合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CD38抗原結合性ドメインをコードする核酸配列が、配列番号1、3、5、7、9、11、15、17、19、21、23、25、69、もしくは71、または85%、90%、95%、96%、97%、98%もしくは99%の同一性を有するその配列を含む核酸配列を含む、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が、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、4、6、8、10、12、16、18、20、22、24、26、70、または72のアミノ酸配列を含むCD38抗原結合性ドメインを含む少なくとも1つの細胞外抗原結合性ドメイン、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ドメインを含む、請求項14に記載のCAR。
- 前記CD38抗原結合性ドメインが、CD38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15に記載のCAR。
- 前記CD38抗原結合性ドメインが、CD38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が、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またはそれらの任意の組合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膜貫通ドメインが、配列番号27のアミノ酸配列、または配列番号28のアミノ酸配列に対し85%、90%、95%、96%、97%、98%もしくは99%の同一性を有するアミノ酸配列を含む、請求項18に記載のCAR。
- 配列番号2、4、6、8、10、12、16、18、20、22、24、26、70、もしくは72のアミノ酸配列を含むCD38抗原結合性ドメインを含む前記少なくとも1つの細胞外抗原結合性ドメイン、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、またはその両方が、リンカーまたはスペーサードメインによって前記膜貫通ドメインに接続されている、請求項15に記載のCAR。
- 前記リンカーまたはスペーサードメインが、CD8、TNFRSF19、IgG4、またはCD28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が、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17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が、OX40、CD70、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、DAP10、DAP12、および4-1BB(CD137)、またはそれらの組合せからなる群から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。
- 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、またはそれらの組合せからなる群から選択される、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。
- 前記プロモーターが、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、またはそれらの任意の組合せである、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。
- T細胞である、請求項28に記載の細胞。
- 前記T細胞がCD8+T細胞である、請求項28に記載の細胞。
- 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ステップを含む、細胞を作製する方法。
- RNA操作された細胞の集団を生成する方法であって、in vitro転写されたRNAまたは合成RNAを細胞中に導入するステップを含み、前記RNAが請求項1に記載の核酸分子を含む、方法。
- 哺乳動物における抗腫瘍免疫をもたらす方法であって、有効量の請求項28に記載の細胞を前記哺乳動物に投与するステップを含む、方法。
- 哺乳動物においてがんを処置または予防する方法であって、請求項15に記載のCARを、前記哺乳動物におけるがんを処置または予防するのに有効な量で前記哺乳動物に投与するステップを含む、方法。
- 抗腫瘍有効量のヒトT細胞集団を含む医薬組成物であって、前記T細胞がキメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARが配列番号2、4、6、8、10、12、16、18、20、22、24、26、70、または72のアミノ酸配列を含むCD38抗原結合性ドメインを含む少なくとも1つの細胞外抗原結合性ドメイン、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、前記T細胞が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が、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、またはそれらの任意の組合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細胞が、血液学的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。
- 前記血液学的がんが、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。
- 前記白血病が、急性骨髄性白血病(AML)、芽球性形質細胞様樹状細胞新生物(BPDCN)、慢性骨髄性白血病(CML)、慢性リンパ性白血病(CLL)、急性リンパ芽球性T細胞白血病(T-ALL)、または急性リンパ芽球性B細胞白血病(B-ALL)である、請求項39に記載の医薬組成物。
- 前記リンパ腫が、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39に記載の医薬組成物。
- 前記血液学的がんが多発性骨髄腫である、請求項38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36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、抗腫瘍有効量のT細胞集団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T細胞がキメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARが、配列番号2、4、6、8、10、12、16、18、20、22、24、26、70、または72のアミノ酸配列を含むCD38抗原結合性ドメインを含む少なくとも1つの細胞外抗原結合性ドメイン、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細胞ががんを有する対象のT細胞である、方法。
- それを必要とする対象におけるがんを処置する方法であって、抗腫瘍有効量のT細胞集団を含む医薬組成物を前記対象に投与するステップを含み、前記T細胞がキメラ抗原受容体(CAR)をコードする核酸配列を含み、前記CARが、配列番号2、4、6、8、10、12、16、18、20、22、24、26、70、または72のアミノ酸配列を含むCD38抗原結合性ドメインを含む少なくとも1つの細胞外抗原結合性ドメイン、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細胞ががんを有する対象の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が、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、またはそれらの任意の組合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を産生する方法であって、請求項1に記載の単離された核酸を細胞に導入するステップを含む、方法。
- 請求項47に記載のキメラ抗原受容体発現細胞を産生する方法であって、前記細胞がT細胞またはT細胞を含む細胞集団である、方法。
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US11103533B2 (en) | 2021-08-31 |
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