JP2020519232A - 抗メソセリン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
抗メソセリン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
本出願は、米国特許法第119条(e)の下で、その全内容が参照により本明細書に組み込まれる、2017年1月9日出願の米国仮特許出願第62/444,201号に対する優先権の利益を主張する。
本出願は、ASCII形式で電子的に提出された、その全体にわたって参照により本明細書に組み込まれる配列表を含む。2018年1月8日に作成された前記ASCIIコピーはSequence_Listing.txtと名付けられ、48.0キロバイトのサイズである。
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、メソセリン抗原結合性ドメイン、およびこのようなメソセリン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。
新規の抗メソセリン抗体またはその抗原結合性ドメイン、およびこのようなメソセリン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、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、メソセリンに結合することが可能な少なくとも1つのメソセリン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の細胞外メソセリン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、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、CAR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。
メソセリン抗原結合性ドメインの同定
ファージディスプレイした完全ヒトscFvライブラリーからのメソセリン特異的抗体の単離
材料および方法:
a)ファージディスプレイしたヒトscFvメソセリン特異的抗体の産生
50人の健康なドナーの末梢血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単鎖断片可変)ファージディスプレイライブラリー(およその多様性、1010種の独自の特異性)(Z.Y.ZhuおよびD.S.Dimitrov、未公開データ)を、組換えヒトメソセリンに特異的なscFvの選択に使用した。ファージディスプレイしたscFv1012種の増幅されたライブラリーを、体積5×100μlのコーティングされたメソセリン5、3、および1μgとともにインキュベートし、第1、第2および第3のラウンドそれぞれのバイオパニング中に96ウェルプレートのウェル5つに等しく分配し室温で2時間置いた。各ラウンドのインキュベーション後に、0.05%Tween20を含むリン酸緩衝生理食塩水(PBST)で、第1のラウンドでは5回、その後のラウンドでは10回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、結合したファージをTG1コンピテント細胞と37℃で1時間混合し、感染させた細胞からファージを増幅させて次のラウンドのバイオパニングに使用した。第3のラウンドのバイオパニング後、感染させたTG1細胞から380のクローンをランダムに選び、それぞれを、自動BioRobotics BioPickコロニーピッキングシステム(Genomic Solutions、Ann Arbor、MI)を使用することにより、96ウェルプレート中の、100μg/mlカルベニシリンおよび0.2%グルコースを含む2YT培地150μlに接種した。細菌培養物が600nmでの光学密度(OD600)0.5に到達した後、感染多重度(MOI)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、プレートを振とう機において250rpmで、30℃で一晩さらにインキュベートした。ファージ上清を体積比4:1で、PBS中3%脱脂乳溶液と混合し、酵素結合免疫吸着アッセイ(ELISA)に使用して、高メソセリン結合親和性を有するscFvを提示するファージのクローンを同定した。上清を、96ウェルプレート中で1ウェルあたり50ngのコーティングされた組換えヒトメソセリンとともに室温で2時間インキュベートし、PBSTで5回洗浄し、(4℃で一晩インキュベートした後、PBS中3%脱脂乳溶液でブロッキングし、0.05%Tween20を含むPBSで3回洗浄した。)メソセリンに結合したファージを、西洋ワサビペルオキシダーゼとコンジュゲートされたヤギ抗M13抗体を使用して検出した。抗体とともにインキュベートした後、ウェルを洗浄することにより、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、450nmでの溶液吸光度(A450)を測定した。A450が1.0を超える、メソセリンに結合したクローンをさらなる特徴決定のために選択した。
選択されたクローンのVHおよびVLをDNA配列決定し、独自の配列を有するクローンによりコードされるscFvを下記のように発現させ、精製した。これらのクローンから抽出されたプラスミドを、HB2151細胞の形質転換に使用した。新しく形質転換された細胞を含むプレートから単一コロニーを選び、100μg/mlアンピシリンおよび0.2%グルコースを含む2YT培地200mlに接種し、250rpmで振とうしながら37℃でインキュベートした。600nmでの培養物ODが0.90に到達すると、最終濃度0.5mMでイソプロピル−β−d−チオガラクトピラノシドを添加し、培養物を30℃で一晩さらにインキュベートした。8,000×gで20分間遠心分離した後、細菌ペレットを収集し、0.5mUポリミキシンB(Sigma−Aldrich、St.Louis、MO)を含むPBS緩衝液に再懸濁した。50rpmで回転させながら室温で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25分間、4℃で遠心分離し、上清を、Ni−NTA樹脂を使用して供給業者のプロトコール(Qiagen)に従ってscFv精製に使用した。
PBSで2μg/mlに希釈された組換えヒトメソセリン50μlを、96ウェルプレートに4℃で一晩コーティングした。HisおよびFlagタグを有する精製されたscFv(上記より)を段階希釈し、標的タンパク質でコーティングされたウェルに添加した。洗浄後、1:3000に希釈された、HRPとコンジュゲートされた抗Flag抗体をRTで1時間添加した。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、室温で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、O.D.を450nmで読み取って、scFvの、メソセリンに結合する相対的能力を定量化した。
ELISA結合アッセイの結果に基づき、組換えヒトメソセリンに特異的な別々のscFsクローン4種を同定し、それぞれヒト抗メソセリンScFvバインダーMH1P、MH2P、MH6PおよびM1−4Sと標識した。MH1P、MH2P、MH6PおよびM1−4Sヒト抗メソセリンScFvバインダーを発現するキメラ抗原受容体の生成について、以下の実施例2で概説する。
抗メソセリン完全ヒトScFv結合性配列を発現するCAR
この実施例では、4種の新規の完全ヒトScFvバインダー配列由来の抗メソセリンCAR T細胞について記載する。新規の抗メソセリンCART構築物は、初代ヒトT細胞における高レベルの発現、およびメソセリン陽性腫瘍細胞に対する特異的かつ強力な細胞溶解活性を実証した。
(a)細胞株
A431ヒト扁平上皮癌細胞株を、American Tissue Culture Collection(ATCC、Manassas、VA)から購入した。親A431株およびそのサブクローンを、10%熱不活化ウシ胎児血清を添加したダルベッコ改変イーグル培地(ATCC)で培養した。
CARの抗原結合性ドメイン、scFv、配列は、ヒト抗メソセリンScFvバインダーMH1P、MH2P、MH6PおよびM1−4Sに由来していた。バインダーscFvをインフレームで、CD8a連結および膜貫通ドメイン(UniProt配列ID P01732、aa 138−206)、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。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。
正常なドナー由来のヒト初代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+細胞を免疫磁性ビーズで選択した後にバフィーコートから精製し、密度0.3〜2×106細胞/mlで、40IU/ml IL−2を添加したTexMACS培地で培養し、CD3/CD28MACS(登録商標)GMP TransAct試薬(Miltenyi Biotec)で活性化し、3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、4日目に培地を交換した。5日目に、200IU/ml IL−2を添加したTexMACS培地に培養物を移し、10〜13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。
細胞染色では、CAR T形質導入細胞50万個を培養物から採取し、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、1:200希釈のF(ab’)2断片−PEヤギ抗ヒトIgG試薬(Jackson ImmunoResearch Laboratories、West Grove、PA)で染色し、4℃で30分間インキュベートすることによりCAR表面発現を検出した。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、MACSQuantifyソフトウェア(Miltenyi Biotec)を使用してデータプロットを生成した。
新規の抗メソセリン完全ヒトScFv結合性配列を評価するため、配列MH1P、MH2P、MH6PまたはM1−4Sのうち各1つを腫瘍抗原結合性ドメインとして組み込むCAR構築物を設計した。各CAR設計では、腫瘍標的化ドメインの後に、ヒトCD8タンパク質由来のリンカーおよび膜貫通ドメイン、4−1BB共刺激ドメインならびにCD3ゼータシグナル伝達ドメインが続いた(表1)。
4種の新規の抗メソセリンCARを評価するため、ヒトEf1aプロモーターの制御下で、CAR構築物MH1P、MH2P、MH6PおよびM1−4Sをコードするレンチウイルスベクター(LV)を、材料および方法に記載されるように生成した。次いで、2人の別々の健康なドナー由来のヒト初代T細胞に、CARをコードする4種のレンチウイルスベクターを形質導入した。同じドナー由来の非形質導入細胞(モック)または同じドナー由来のGFP形質導入細胞は、陰性対照として機能した。
生成されたCAR T細胞の細胞溶解機能を実証するため、ヒトメソセリンを安定に発現するA431−MSLN株を使用して、ルシフェラーゼベースの死滅アッセイを実施した。メソセリン陰性であるA431親株を、死滅特異性対照として使用した。CART細胞および標的細胞をエフェクター対標的(E:T)比20、10および5で組み合わせ、一晩コインキュベートして、次いで材料および方法に記載されるように、発光により細胞死滅を評価した(図3)。CAR T構築物pLTG1902、pLTG1903およびpLTG1904は、A431−MSLN株に対して強い、比に依存的な細胞毒性を示したが、陰性対照GFP構築物pLTG1398、およびモック(同じドナー由来の非形質導入T細胞)は細胞溶解性ではなかった。また、メソセリン陰性A431株でも細胞溶解が観察されず、観察された死滅効果がメソセリン特異的であることが示された。特に、CAR pLTG1901はT細胞表面で検出されず(図2)、A431−MSLN細胞に対して細胞溶解活性を示さなかった。一方、こちらもフローサイトメトリーでT細胞表面において検出されなかったCAR pLTG1903はA431−MSLN株に対する強い細胞毒性を実証し、この構築物がT細胞内でも発現されることが示唆された。CAR pLTG1903で得られた結果は、細胞表面発現と、in vitroでの腫瘍細胞死滅能力との相関関係が予測不可能であることを実証した。
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は、メソセリン抗原ScFv結合性ドメインMH1Pのヌクレオチド配列である。
caggtacagctgcagcagtcaggtccaggactggtgaagccctcgcggaccctc
tcactcacctgtgccatctccggggacagtgtctctagcaacagtgctgcttggaactgg
atcaggcagtccccatcgagaggccttgagtggctgggaaggacatactacaggtccaag
tggtataatgattatgcagtatctgtgaaaagtcgaataaccatcaacccagacacatcc
aagaaccagttctccctgcagctgaactctgtgactcccgaggacacggctgtgtattac
tgtgcaagagggaagggtggtaagaagggtggtgcttttgatatctggggccaagggaca
atggtcaccgtctcttcaggaggtggcgggtctggtggaggcggtagcggcggtggcgga
tcctcttctgagctgactcaggaccctgctgtgtctgtggccttgggacagacagtcagg
atcacatgccaaggagacagcctcagaagctattatgcaagctggtaccagcagaagcca
ggacaggctcctgtacttgtcatctatggtaaaaacaaccggccctcagggatcccagac
cgattctctggctcctcctcaggcaacacagcttccttgaccatcactggggctcaggcg
gaagatgaggctgaatattactgtagctccagcactcgtaatcatgtgttcttcggcaga
Gggaccaaggtcaccgtcctaggt
配列番号2は、メソセリン抗原ScFv結合性ドメインMH1Pのアミノ酸配列である。
Q V Q L Q S G P G L V K P S R T L
S L T C A I S G D S V S S N S A A W N W
I R Q S P S R G L E W L G R T Y Y R S K
W Y N D Y A V S V K S R I T I N P D T S
K N Q F S L Q L N S V T P E D T A V Y Y
C A R G K G G K K G G A F D I W G Q G T
M V T V S S G G G G S G G G G S G G G G
S S S E L T Q D P A V S V A L G Q T V R
I T C Q G D S L R S Y Y A S W Y Q Q K P
G Q A P V L V I Y G K N N R P S G I P D
R F S G S S S G N T A S L T I T G A Q A
E D E A E Y Y C S S S T R N H V F F G R
G T K V T V L G
配列番号3は、メソセリン抗原ScFv結合性ドメインMH2Pのヌクレオチド配列である。
gaggtgcagctggtgcagtctgggggaggcttggtacagcctggcaggtcccag
agactctcctgtgcagcctctggattcacctttgatgattatgccatgcactgggtccgg
caagctccagggaagggcctggagtgggtctcaggtattagttggaatagtggtagcata
ggctatgcggactctgtgaagggccgattcaccatctccagagacaacgccaagaactcc
ctgtatctgcaaatgaacagtctgagagctgaggacacggccttgtattactgtgcaaaa
gatatttcgtcgtcagctggtaacgcttttgatatctggggccaagggacaatggtcacc
gtctcttcaggaggtggcgggtctggtggaggcggtagcggcggtggcggatcctcttct
gagctgactcaggaccctgctgtgtctgtggccttgggacagacagtcaggatcacatgc
caaggagacagactcagaagctattatgcaagctggtaccagcagaagccaggacaggcc
cctgtacttgtcatctatggtaaaaacaaccggccctcagggatcccagaccgcttctct
ggctccgactcaggagacacagcttccttgaccatcactggggctcaggcggaagatgag
gctgactattactgtcactcccgtgacagtggtggtaaccatgtggtattcggcggaggc
Acccagctgaccgtcctcggt
配列番号4は、メソセリン抗原ScFv結合性ドメインMH2Pのアミノ酸配列である。
E V Q L V Q S G G G L V Q P G R S Q
R L S C A A S G F T F D D Y A M H W V R
Q A P G K G L E W V S G I S W N S G S I
G Y A D S V K G R F T I S R D N A K N S
L Y L Q M N S L R A E D T A L Y Y C A K
D I S S S A G N A F D I W G Q G T M V T
V S S G G G G S G G G G S G G G G S S S
E L T Q D P A V S V A L G Q T V R I T C
Q G D R L R S Y Y A S W Y Q Q K P G Q A
P V L V I Y G K N N R P S G I P D R F S
G S D S G D T A S L T I T G A Q A E D E
A D Y Y C H S R D S G G N H V V F G G G
T Q L T V L G
配列番号5は、メソセリン抗原ScFv結合性ドメインM1−4Sのヌクレオチド配列である。
gaggtccagctggtacagtctgggggaggcttggtacagcctggggggtccctg
agactctcctgtgcagcctctggattcacctttgatgattatgccatgcactgggtccgg
caagctccagggaagggcctggagtgggtctcaggtattagttggaatagtggtagcata
ggctatgcggactctgtgaagggccgattcaccatctccagagacaacgccaagaactcc
ctgtatctgcaaatgaacagtctgagagctgaggacacggccttgtattactgtgcaaaa
gatttatcgtcagtggctggaccctttaactactggggccagggcaccctggtcaccgtc
tcctcaggaggtggcgggtctggtggaggcggtagcggcggtggcggatcctcttctgag
ctgactcaggaccctgctgtgtctgtggccttgggacagacagtcaggatcacatgccaa
ggagacagcctcagaagctattatgcaagctggtaccagcagaagccaggacaggcccct
gtacttgtcatctatggtaaaaacaaccggccctcagggatcccagaccgattctctggc
tccagctcaggaaacacagcttccttgaccatcactggggctcaggcggaggatgaggct
gactattactgtaactcccgggacagcagtggtaaccatctggtattcggcggaggcacc
Cagctgaccgtcctcggt
配列番号6は、メソセリン抗原ScFv結合性ドメインM1−4Sのアミノ酸配列である。
E V Q L V Q S G G G L V Q P G G S L
R L S C A A S G F T F D D Y A M H W V R
Q A P G K G L E W V S G I S W N S G S I
G Y A D S V K G R F T I S R D N A K N S
L Y L Q M N S L R A E D T A L Y Y C A K
D L S S V A G P F N Y W G Q G T L V T V
S S G G G G S G G G G S G G G G S S S E
L T Q D P A V S V A L G Q T V R I T C Q
G D S L R S Y Y A S W Y Q Q K P G Q A P
V L V I Y G K N N R P S G I P D R F S G
S S S G N T A S L T I T G A Q A E D E A
D Y Y C N S R D S S G N H L V F G G G T
Q L T V L G
配列番号7は、メソセリン抗原ScFv結合性ドメインMH6Pのヌクレオチド配列である。
caggtccagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtg
aaggtctcctgcaaggcttctggatacaccttcaccggctactatatgcactgggtgcga
caggcccctggacaagggcttgagtggatgggacggatcaaccctaacagtggtggcaca
aactatgcacagaagtttcagggcagggtcaccatgaccaggaacacgtccatcagcaca
gcctacatggagctgagcaggctgagatctgacgacacggccgtgtattactgtgcgaga
tccggctactactacggtttggacgtctggggccaagggaccacggtcaccgtctcctca
ggaggtggcgggtctggtggaggcggtagcggcggtggcggatcccagtctgtgttgacg
cagccgccctcagcgtctgggacccccgggcagcgggtcaccatctcttgttctggaagt
cgctccaacatcggaagaaacactgtcaactggtatcaacaactcccaggactggccccc
aaactcatcatccagaggagtgatcagcggccctcaggggtccctgaccgattctctggc
tccaagtctgtcacctcagcctccctggccatcagtgggctccggtccgaggatgaggct
gattattactgcggaacatgggataacagcctgagtgcttatgtcttcggaactgggacc
aagctgaccgtcctaggt
配列番号8は、メソセリン抗原ScFv結合性ドメインMH6Pのアミノ酸配列である。
Q V Q L V Q S G A E V K K P G A S V
K V S C K A S G Y T F T G Y Y M H W V R
Q A P G Q G L E W M G R I N P N S G G T
N Y A Q K F Q G R V T M T R N T S I S T
A Y M E L S R L R S D D T A V Y Y C A R
S G Y Y Y G L D V W G Q G T T V T V S S
G G G G S G S G G S G G G G S Q S V L T
Q P P S A S G T P G Q R V T I S C S G S
R S N I G R N T V N W Y Q Q L P G L A P
K L I I Q R S D Q R P S G V P D R F S G
S K S V T S A S L A I S G L R S E D E A
D Y Y C G T W D N S L S A Y V F G T G T
K L T V L G
配列番号9は、リーダー/シグナルペプチド配列のヌクレオチド配列である。
atgctgctgctggtgaccagcctgctgctgtgcgaactgccgcatccggcgtttctgctgattccg
配列番号10は、リーダー/シグナルペプチド配列のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIP
配列番号11は、pLTG1901 EF1a MH1P−−CD8TM−4−1BB−CD3ゼータ核酸配列のヌクレオチド配列である。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTG
ATTCCGCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCGGACCCTC
TCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGG
ATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAG
TGGTATAATGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCC
AAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTAC
TGTGCAAGAGGGAAGGGTGGTAAGAAGGGTGGTGCTTTTGATATCTGGGGCCAAGGGACA
ATGGTCACCGTCTCTTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGG
ATCACATGCCAAGGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCA
GGACAGGCTCCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGAC
CGATTCTCTGGCTCCTCCTCAGGCAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCG
GAAGATGAGGCTGAATATTACTGTAGCTCCAGCACTCGTAATCATGTGTTCTTCGGCAGA
GGGACCAAGGTCACCGTCCTCGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCG
ACTCCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCG
GCCGCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGG
GCCCCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGC
AAGAGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAG
ACGACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGC
GAACTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAAT
CAGCTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGA
CGCGGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGA
GAGCGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号12は、pLTG1901 EF1a MH1P−−CD8TM−4−1BB−CD3ゼータアミノ酸配列のアミノ酸配列である。
MLLLVTSLLLCELPHPAFLLIPQVQLQQSGPGLVKPSRTLSLTCAISGDSVSSNSAAWNW
IRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYY
CARGKGGKKGGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVR
ITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQA
EDEAEYYCSSSTRNHVFFGRGTKVTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRP
AAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQ
TTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKR
RGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK
DTYDALHMQALPPR
配列番号13は、pLTG1902 Ef1a MH2P CD8TM−4−1BB−CD3ゼータ核酸配列のヌクレオチド配列である(図2B)。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTG
ATTCCGGAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCAG
AGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGG
CAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATA
GGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCC
CTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAA
GATATTTCGTCGTCAGCTGGTAACGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACC
GTCTCTTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCT
GAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGC
CAAGGAGACAGACTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCC
CCTGTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGCTTCTCT
GGCTCCGACTCAGGAGACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAG
GCTGACTATTACTGTCACTCCCGTGACAGTGGTGGTAACCATGTGGTATTCGGCGGAGGC
ACCCAGCTGACCGTCCTCGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACT
CCGGCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCC
GCGGGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCC
CCGCTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAG
AGGGGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACG
ACTCAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAA
CTGCGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAG
CTCTACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGC
GGACGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTAC
AACGAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAG
CGGAGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGAT
ACCTACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号14は、pLTG1902 Ef1a MH2P CD8TM−4−1BB−CD3ゼータアミノ酸配列のアミノ酸配列である(図2B)。
MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVQPGRSQRLSCAASGFTFDDYAMHWVR
QAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAK
DISSSAGNAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVRITC
QGDRLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSDSGDTASLTITGAQAEDE
ADYYCHSRDSGGNHVVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPA
AGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT
TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR
GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD
TYDALHMQALPPR
配列番号15は、pLTG1903 Ef1a MH6P CD8TM−4−1BB−CD3ゼータ核酸配列のヌクレオチド配列である(図2C)。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTG
ATTCCGCAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTG
AAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGA
CAGGCCCCTGGACAAGGGCTTGAGTGGATGGGACGGATCAACCCTAACAGTGGTGGCACA
AACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGAACACGTCCATCAGCACA
GCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGA
TCCGGCTACTACTACGGTTTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
GGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCCAGTCTGTGTTGACGCAGCCGCCCTCAGCGTCTGGGACCCCCGGGCAGCGGGTCACCATCTCTTGTTCTGGAAGTCGCTCCAACATCGGAAGAAACACTGTCAACTGGTATCAACAACTCCCAGGACTGGCCCCC
AAACTCATCATCCAGAGGAGTGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGC
TCCAAGTCTGTCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCT
GATTATTACTGCGGAACATGGGATAACAGCCTGAGTGCTTATGTCTTCGGAACTGGGACC
AAGCTGACCGTCCTCGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCG
GCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCG
GGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG
CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGG
GGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACT
CAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTG
CGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTC
TACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGA
CGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAAC
GAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGG
AGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACC
TACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号16は、pLTG1903 Ef1a MH6P CD8TM−4−1BB−CD3ゼータアミノ酸配列のアミノ酸配列である(図2C)。
MLLLVTSLLLCELPHPAFLLIPQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVR
QAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRNTSISTAYMELSRLRSDDTAVYYCAR
SGYYYGLDVWGQGTTVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGS
RSNIGRNTVNWYQQLPGLAPKLIIQRSDQRPSGVPDRFSGSKSVTSASLAISGLRSEDEA
DYYCGTWDNSLSAYVFGTGTKLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAA
GGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT
QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRG
RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT
YDALHMQALPPR
配列番号17は、pLTG1904 Ef1a M1−4S CD8TM−4−1BB−CD3ゼータ核酸配列のヌクレオチド配列である(図2D)。
ATGCTGCTGCTGGTGACCAGCCTGCTGCTGTGCGAACTGCCGCATCCGGCGTTTCTGCTG
ATTCCGGAGGTCCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTG
AGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGG
CAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATA
GGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCC
CTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAA
GATTTATCGTCAGTGGCTGGACCCTTTAACTACTGGGGCCAGGGCACCCTGGTCACCGTC
TCCTCAGGAGGTGGCGGGTCTGGTGGAGGCGGTAGCGGCGGTGGCGGATCCTCTTCTGAG
CTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAA
GGAGACAGCCTCAGAAGCTATTATGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCT
GTACTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGC
TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAGGATGAGGCT
GACTATTACTGTAACTCCCGGGACAGCAGTGGTAACCATCTGGTATTCGGCGGAGGCACC
CAGCTGACCGTCCTCGGTGCGGCCGCAACTACCACCCCTGCCCCTCGGCCGCCGACTCCG
GCCCCAACCATCGCAAGCCAACCCCTCTCCTTGCGCCCCGAAGCTTGCCGCCCGGCCGCG
GGTGGAGCCGTGCATACCCGGGGGCTGGACTTTGCCTGCGATATCTACATTTGGGCCCCG
CTGGCCGGCACTTGCGGCGTGCTCCTGCTGTCGCTGGTCATCACCCTTTACTGCAAGAGG
GGCCGGAAGAAGCTGCTTTACATCTTCAAGCAGCCGTTCATGCGGCCCGTGCAGACGACT
CAGGAAGAGGACGGATGCTCGTGCAGATTCCCTGAGGAGGAAGAGGGGGGATGCGAACTG
CGCGTCAAGTTCTCACGGTCCGCCGACGCCCCCGCATATCAACAGGGCCAGAATCAGCTC
TACAACGAGCTGAACCTGGGAAGGAGAGAGGAGTACGACGTGCTGGACAAGCGACGCGGA
CGCGACCCGGAGATGGGGGGGAAACCACGGCGGAAAAACCCTCAGGAAGGACTGTACAAC
GAACTCCAGAAAGACAAGATGGCGGAAGCCTACTCAGAAATCGGGATGAAGGGAGAGCGG
AGGAGGGGAAAGGGTCACGACGGGCTGTACCAGGGACTGAGCACCGCCACTAAGGATACC
TACGATGCCTTGCATATGCAAGCACTCCCACCCCGG
配列番号18は、pLTG1904 Ef1a M1−4S CD8TM−4−1BB−CD3ゼータアミノ酸配列のアミノ酸配列である(図2D)。
MLLLVTSLLLCELPHPAFLLIPEVQLVQSGGGLVQPGGSLRLSCAASGFTFDDYAMHWVR
QAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAK
DLSSVAGPFNYWGQGTLVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSVALGQTVRITCQ
GDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEA
DYYCNSRDSSGNHLVFGGGTQLTVLGAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAA
GGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT
QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRG
RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT
YDALHMQALPPR
配列番号19は、DNA CD8膜貫通ドメインのヌクレオチド配列である。
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc accctttact gc
配列番号20は、CD8膜貫通ドメインのアミノ酸配列である。
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21は、DNA CD8ヒンジドメインのヌクレオチド配列である。
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg
gacttcgcct gtgat
配列番号22は、CD8ヒンジドメインのアミノ酸配列である。
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23は、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である。
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24は、ヒトIgG CL配列のアミノ酸配列である。
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25は、4−1BBのDNAシグナル伝達ドメインのヌクレオチド配列である。
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt
gaactg
配列番号26は、4−1BBのシグナル伝達ドメインのアミノ酸配列である。
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27は、CD3−ゼータのDNAシグナル伝達ドメインのヌクレオチド配列である。
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28は、CD3ゼータのアミノ酸配列である。
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29は、Scvf cd19のヌクレオチド配列である。
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30は、Scvf cd19のアミノ酸配列である。
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
Claims (48)
- 配列番号1、3、5、または7を含むヌクレオチド配列によりコードされるメソセリン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つのメソセリン抗原結合性ドメインが、メソセリン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つのメソセリン抗原結合性ドメインが、メソセリン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つのメソセリン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メソセリン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10のリーダーアミノ酸配列をコードする配列番号9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、CD86、CD134、CD137、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1に記載の単離された核酸分子。
- 前記細胞外メソセリン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、もしくは7、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、または8のアミノ酸配列を含むメソセリン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。
- 前記メソセリン抗原結合性ドメインが、メソセリン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。
- 前記メソセリン抗原結合性ドメインが、メソセリン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15に記載のCAR。
- 前記CD8膜貫通ドメインが、配列番号19のアミノ酸配列、または配列番号19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、もしくは8のアミノ酸配列を含むメソセリン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のアミノ酸配列を含むメソセリン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、慢性リンパ性白血病(CLL)、急性リンパ性白血病(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、または8のアミノ酸配列を含むメソセリン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、または8のアミノ酸配列を含むメソセリン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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