JP2021503952A - Il−1rapを標的とするcar−t細胞及びその使用 - Google Patents
Il−1rapを標的とするcar−t細胞及びその使用 Download PDFInfo
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Abstract
Description
・TKI中止後に再発する患者
・同種移植(移植片対白血病、同種幹細胞移植、ドナーリンパ球輸注(DLI))後に再発した患者
・TKI下で最適以下の奏効を示す非適格患者
・再発のリスクが大きい移行期/急性転化期CML患者
・若年又は小児CML患者
(i)アミノ酸配列番号6との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する重鎖と
を有している、単離核酸分子に関する。
(i)アミノ酸配列番号6との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する重鎖とを有している、単離CAR分子も検討される。
(i)アミノ酸配列番号6との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%、85%、90%、95%、96%、97%、98%、99%、又は100%である相補性決定領域3(CDR3)を有する重鎖とを有する。
診断時及びTKI治療後の経過観察時に、患者からCML試料コレクションを確立した。末梢血単核細胞は、Ficoll−Paque(Velizy−Villacoublay、フランス)を用いたフィコール密度勾配遠心分離により、フランス血液センター(仏国ブザンソン)で収集した健常ドナーの匿名血液試料から単離した。ヒト腫瘍細胞株KU812(CRL−2099)、K562(CCL−243)、又は上皮細胞株239T(CRL−3216)、HT1080(CCL−121)は、ATCC(登録商標)コレクション(LGC Standards、仏国モルスアイム)由来である。
標準的なハイブリドーマ法により、マウス抗hIL−1RAPモノクローナル抗体を作製した。
Wang.Z.,et al(J.Immunol.Methods,2000;233,pp167−77)のプロトコルに従い、FR1並びに重鎖及び軽鎖の定常領域に特異的な縮重プライマーで得られたクローン化PCR増幅産物のサンガーシークエンシングによって、分子キャラクタリゼーションを実施した。Brochet X.,et al.(Nucleic Acids Res.,2008,36,pp503−8)に従い、V−QUESTオンラインツールを用いて、IMGT(登録商標)データベースに対して共通ヌクレオチド配列をアライメントすることにより、V−D−J−C遺伝子再構成及びCDR3領域を同定できた。分子サンガーシークエンシングにより、5つのモノクローナル抗体は全て同一であり、同じCDR3ヌクレオチド配列を有していることが分かった。サイトメトリーによる相対蛍光強度(RFI)が最も高かったことから、モノクローナル抗体サブクローン(#E3C3)を選択した。
超音波処理により、実施例1で列挙した細胞の全細胞画分、細胞成分画分、又は分泌タンパク質画分を得、プロテアーゼインヒビターカクテル(complete Mini EDTA−free、Roche、スイス)を添加したRIPA溶解・抽出緩衝液(ThermoFisher Scientific)に懸濁させた。IL−1RAP cDNA変異体1(NM_002182.2、NCBI)でトランスフェクトしたHT1080細胞株をコントロールとして使用した。アクチンはタンパク質ローディングコントロールとして検出した。IL−1RAP、CAR、又はβ−アクチン発現に対して、それぞれ一次IL−1RAP#E3C3(1:103に希釈)、CD3ζ(BD Pharmigen、クローン#8D3)、又はβ−アクチン(1:103、クローンAC15、(#A5441、Sigma−Aldrich)のいずれかを用いて、PDVF膜に移したタンパク質を1晩プローブした。二次ポリクローナル抗体ヒツジ抗マウスIgG(#515−035−062、Jackson、米国)を用いて免疫検出染色を実施した。カメラ及びBio−1Dソフトウェア(Vilber−Lourmat、仏国コレジアン)を用いて検出した。ウェスタンブロットにおいて#E3C3モノクローナル抗体を使用すると、KU812が示される(図1)。
抗ヒトFc抗体をプラスチック製ELISAプレートの底に被覆した。ヒト抗体にロードしたIL−1RAPタンパク質をマウス及びヒトIL−1RAP(#E3C3)抗体でプローブした後、西洋ワサビペルオキシダーゼ(HRP)で被覆した抗マウスFC抗体により検出した。
マウスAlexa Fluor488標識IL−1RAP抗体クローン#E3C3を含むCD45、CD34、CD38、CD33、CD133、CD117のパネルを用いて、CML患者の造血幹細胞をトラッキングした。CD3、CD4、CD8、及びCD19を含む抗体パネルを用いて、形質導入細胞を染色して、ヘルパー又は細胞傷害性GMTCを識別した。CD45RA、CD62L、CD95、CCR7モノクローナル抗体のパネルを用いて、ナイーブ、セントラル、又はメモリーT細胞サブセットを分析した。CANTO IIサイトメーター(BD Biosciences、仏国ルポンドクレ)を用いて細胞を採取し、DIVA6.1ソフトウェア(BD Biosciences、仏国ルポンドクレ)を用いて分析した。
サイトスピンでスライドグラス(SuperfrostTM Plus、4951PLUS4、ThermoFisher Scientific)上に集めたKU812細胞株及びRaji細胞株に対して、共焦点顕微鏡観察で評価した。簡潔に言うと、上記細胞を蛍光モノクローナル抗体である抗マウスFc−IgG;IL−1RAP(#E3C3)で染色し、QImaging製Retiga2000Rカメラを取り付けたOlympus製BХ51顕微鏡で分析した。40倍の対物レンズを使用し、Image−Pro Plus(version 6.0、Media Cybernetics)でデジタル化したデジタル画像を取得した。核染色DAPI(2−(4−アミジノフェニル)−6−インドールカルバミジン二塩酸塩、Sigma−Aldrich、フランス)により対比染色を実施し、蛍光染色と重ね合わせた。
特異的又は非標的組織結合を検討するために、1器官あたり3名の個々のドナーから得た90個の組織コア(30器官)を含むFDA標準凍結組織アレイ(US Biomax、米国ロックビル)を上述した通りインキュベートした。UltraView Universal DAB Detection Kit(Ventana、米国)を用いて免疫染色を検出した。NDP.view2ソフトウェアで画像を取得し、分析した。IL−1RAP高発現(KU812)又はネガティブ発現(Raji)細胞株をそれぞれポジティブ又はネガティブコントロールとして使用した。染色強度は以下の通り等級を付けた:ネガティブ(0)、弱染色(1+)、中染色(2+)、又は強染色(3+)。IL−1RAP高発現(KU812)又はネガティブ発現(Raji)細胞株をそれぞれポジティブ又はネガティブコントロールとして使用した。
VDJ又はVJ再構成の分子シークエンシング及びCDR3ヌクレオチド配列決定に基づき、実施例1の#E3C3 IL−1RAPハイブリドーマ由来の合成的に作製された一本鎖可変領域断片(scFv)をSIN−pSDYバックボーンにクローニングして、CARレンチウイルスコンストラクト(pSDY−iC9−IL−1RAPCAR−dCD19)を調製した(Rossolillo P,Winter F,Simon−Loriere E,Gallois−Montbrun S,Negroni M.,Retrovolution:HIV−driven evolution of cellular genes and improvement of anticancer drug activation.,PLoS Genet.,2012;8(8):e1002904)。
製造業者の指示書に従い、抗CD3/CD28ビーズ(Life Technologies、フランス)を用いて、健常ドナーの末梢血単核細胞から得たCD3+Tリンパ球を活性化した後、磁気カラム(MACS、Miltenyi Biotec、仏国パリ)で単離した。2日目に、活性化したT細胞を上清(SN)と接触させて2000g、10℃で90分間スピノキュレーション(spinoculation)して形質導入した。フローサイトメトリー分析によって形質導入効率を測定して、ΔCD19細胞表面マーカー発現を同定した。形質導入から4日後、CD19マイクロビーズ(Miltenyi Biotec、仏国パリ)で標識したCD19ポジティブ細胞をMACSカラムで磁気的に分離した。単離したCD19発現細胞を、8%ヒト血清を添加した500UI/mLのrhIL−2(プロロイキン、Novartis)を含むX−vivo完全培地(Lonza、スイス国バーゼル)で増殖させ、凍結保存した。実験的には、T Cell TransAct試薬と、ヒトIL−2、IL−7、IL−15、又はIL−7+IL−15を添加したTexMACS培地(Miltenyi Biotec、仏国パリ)とを使用した。
水疱性口内炎ウイルス(VSV)エンベロープ(pMDG)をコードするヘルパープラスミドと、GAG/POL(psPAX2)パッケージングプラスミド(Addgene、それぞれ#12259及び#12260、Trono et al、スイス国ローザンヌ)とを用いたCaCl2法でサブコンフルエントな293T細胞の一過性同時導入を行うことによって、レンチウイルスベクター上清ストックを作製した。48時間及び72時間後にウイルス上清を回収し、PEG及び低速遠心分離(3000g、一晩)により濃縮してから、使用するまで−80℃で保管した。IL−1RAP scFvを含まない同レンチウイルスコンストラクト(Mock)をコントロールとして使用した。SNの段階希釈液を用いた293T許容細胞の形質導入により、レンチウイルス上清の力価測定を確立した。
IL−1RAP形質導入T細胞の膜又は細胞質細胞亜画分(超遠心後に得られたもの)から抽出したタンパク質又は全タンパク質ライセートを、マウス抗ヒトCD3z抗体でプローブした。細胞成分画分へのウェスタンブロッティングにより、IL−1RAP CARがCD3zシグナル伝達(予測される内在性CD3zシグナルが16KDaであるのに対して、55KDaのシグナル)と関連することが分かった(図7)。
T細胞表面でのCAR発現について、組換えIL−1RAPビオチン化タンパク質を用いて分析し、二次抗ビオチン抗体(Miltenyi Biotec、クローン#Bio3−18E7)を用いたフローサイトメトリーにより検出した。Mock又はCAR IL−1RAPのいずれかでCEM細胞株又は初代T細胞を形質導入した。次いで、ビオチンで標識した組換えIL−1RAPの量を増やしながら、各量の存在下で細胞をインキュベートした。抗ビオチン蛍光抗体を用いて染色し、フローサイトメトリーで分析した。ビオチン+/CD19+CEM又はT細胞のパーセンテージを標識ビオチン組換えタンパク質の量に対してプロットした。サイトメトリー分析のドットプロットは、最大値を含む代表的な染色に対して示したす。非形質導入細胞(C0)又はMock T細胞をコントロールとして使用する。
形質導入細胞(IL−1RAP CAR293T)又は非形質導入細胞(293T)を、培地のみ(−化学誘導二量体形成物質(CID))又は20nMのCID AP1903を含む培地で24時間培養した。光学顕微鏡観察によって、培養液中の生細胞又は死細胞の存在及び構造を画像化できる(×40)。
IL−1RAP CART細胞の増殖性、ひいては機能性を分析するために、天然IL−1RAP発現細胞株KU812に加えて、変異体1(v1)又は5(v5)転写物からそれぞれ翻訳された膜型(アイソフォーム1)又は可溶型(アイソフォーム3)IL−1RAPのいずれかを発現する欠損MHCクラスI細胞株K562を作製した。膜型(mb)又は可溶型(s)IL−1RAP発現細胞株を得るために、K562細胞をそれぞれ変異体1(アイソフォーム1、NM_002182.2)又は変異体5(アイソフォーム2、NM_001167930)ORFクローン(pCMV6−AC−GFPベクター、Origen、又はpEZ−M61、Gene Copoeia)でトランスフェクトした。次いで、安定したmb−又はs−IL−1RAP発現K562細胞をpLenti CMV V5−LUC Blast(Addgene、プラスミド#21474)で形質導入した。
IL−1RAP標的発現細胞に誘発されるIL−1RAP CART細胞の増殖能を測定するために、K562、K562−v1、K562−v5、又はKU812細胞株の存在下、CFSE染色したC0、Mock、又はIL−1RAP CART細胞を共培養した(エフェクター/標的比E:T=1:1)。
CART細胞により産生されたサイトカインのプロファイルを決定するために、ヒトIL−2、IL−4、IL−6、IL−10、TNF−a、IFN−y、及びIL−17Aの分泌を定量化できるヒトTh1/Th2/Th17Cytokines Bead Array(CBA)Kit(BD Biosciences)を製造業者の指示書に従って使用した。簡潔に言うと、標的細胞の存在下(比1:1)又は非存在下(コントロール)、ビーズ及びPE結合抗サイトカイン抗体を用いて、1×105個のCART細胞の一晩培養液の上清を3時間インキュベートした。ビーズを洗浄し、標準化フローサイトメトリーアッセイにより取得した。FCAP ArrayaソフトウェアVersion3.0(BD Biosciences)を用いてデータを分析した。標的細胞から回収した上清のみをコントロールとして使用した。IL−1RAPを発現する標的(K562−IL−1RAP+v1、KU812)又は発現しない標的(K562)の存在下又は非存在下(培地、PMA/Iono)、非形質導入、Mock−、又はCAR IL−1RAP T細胞の培養上清の代表的なキャプチャービーズ蛍光分析。IL−1RAPポジティブ細胞培養上清をエフェクターと共培養するために、上清を1/3に希釈した。培地及びPMA/Ionoは、それぞれネガティブ及びポジティブコントロールとして使用する。
CD107脱顆粒アッセイでT細胞介在性細胞傷害活性を分析した。各種E:T細胞比で20〜24時間インキュベートすることにより、生腫瘍細胞に対するCAR−T細胞の細胞傷害性を評価した。IL−1RAP+(K532−V1、KU812)発現標的細胞に対してE:T比=1:5で共培養したIL−1RAP CART細胞に実施したCD107a&b脱顆粒アッセイから、IL−1RAP特異的T細胞のCD8−(主にCD4+)及びCD8+区画の両方においてCD107a&bの顕著な細胞表面動員が見られたが、細胞表面IL−1RAP−(K562、K562−v5)発現細胞では見られず、また、細胞ドナーのMock又は非形質導入(C0)細胞では、認識可能な脱顆粒は見られなかった(p<0.001、n=4)(図14)。
エフェクターCAR T細胞を注射して又はしないで、NSG(NOD.Cg−Prkdcscid Il2rgtm1WjI/SzJ)マウス(Charles River、フランス)にLuc+、IL−1RAP+腫瘍細胞株を移植した。マウス生存率に加え、循環CART細胞及び腫瘍量をサイトメトリー又は生物発光分析のいずれかで毎週分析した。
4年にわたる4種のTKIを用いた5つの治療ライン(図17上)に対する初代TKI耐性CML患者(常にBCR−ABL(IS)比>10%)から、形質導入効率95.5%でCART細胞を作製できた(図17下)。IL−1RAP CART細胞は、E:T比=3:1で95%の効率でIL−1RAP+KU812細胞に対して用量依存的細胞傷害活性を示したのに対して、C0又はMock T細胞ではそれぞれ18%及び21%のアロ反応性細胞傷害性が示された(図18)。これは、健常ドナーから得られたIL1−RAP CART細胞と同等であった。また、CML患者PBMCに対する自己IL−1RAP CART細胞の共培養では、24時間後にIL−1RAP+/CD34+細胞の特異的な溶解(IL−1RAP CART細胞では76.65±9.2%であるのに対して、C0又はMock T細胞ではそれぞれ4.16±4.3%及び2.78±1.72%)が示された(図19)。
オフターゲット毒性を予測するために、#A3C3mAbを使用して、30個の正常ヒト組織の組織マクロアッセイ(TMA)によりIL−1RAP発現を検討した。染色は、リンパ節、前立腺、骨格筋、胃、結腸及び小腸、並びに膵臓という6組織のみにおいて、炎症性又は壊死性要素を除いて様々な強度レベルで検出された(図22A及び表2)。興味深いことに、微小血管HMEC−1内皮細胞株は、我々の#A3C3 IL−1RAP mAbでは認識されず(図22B)、R&D IL−1RAP mAb(R&D Systems、Ref#89412)では細胞表面発現が明確に検出されるため、異なるエピトープが認識されたものと思われる。
Claims (16)
- キメラ抗原受容体(CAR)をコードする単離核酸分子であって、上記CARは、抗IL−1RAP結合領域と、膜貫通領域と、少なくとも刺激領域を有する細胞内シグナル伝達領域とを有する抗体又は抗体断片を有しており、上記抗IL−1RAP結合領域は、
(i)アミノ酸配列番号6との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する重鎖と
を有している、単離核酸分子。 - 上記IL−1RAP結合領域は、抗体、Fv、scFv、Fab、又は他の抗体断片からなる群より選択され、好ましくはscFvである、請求項1に記載の単離核酸分子。
- 上記膜貫通領域は、T細胞受容体のα、β、又はζ鎖、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、及びCD154からなる群より選択されるタンパク質の膜貫通領域であり、好ましくはCD28の膜貫通領域である、請求項1又は2に記載の単離核酸分子。
- 上記抗IL−1RAP結合領域は、ヒンジ領域によって上記膜貫通領域と接続しており、好ましくは、上記ヒンジ領域は、IgG1のヒンジ配列又はその同一性が95〜99%である配列を有する、請求項1〜3のいずれか1項に記載の単離核酸分子。
- 上記細胞内シグナル伝達領域は少なくとも1つの共刺激領域を有し、好ましくは、上記機能的細胞内シグナル伝達領域の上記少なくとも1つの共刺激領域は、OX40、CD2、CD27、CD28、CDS、CD3ζ、ICAM−1、LFA−1(CD11a/CD18)、ICOS(CD278)、及び4−1BB(CD137)からなる群より選択される1種以上のタンパク質から得られ、好ましくは4−1BB(CD137)及び/又はCD3ζから得られる、請求項1〜4のいずれか1項に記載の単離核酸分子。
- 請求項1〜5のいずれか1項に記載の核酸分子でコードされる単離ポリペプチド分子。
- 抗IL−1RAP結合領域と、膜貫通領域と、細胞内シグナル伝達領域とを有する抗体又は抗体断片を有する単離キメラ抗原受容体(CAR)分子であって、上記抗IL−1RAP結合領域は、
(i)アミノ酸配列番号6との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する重鎖と
を有している、単離キメラ抗原受容体(CAR)分子。 - 上記CARは、請求項2〜5のいずれか1項で定義されたCARである、請求項7に記載の単離CAR分子。
- 請求項1〜5のいずれか1項で定義された核酸分子を有するベクターであって、該ベクターは、DNA、RNA、プラスミド、レンチウイルスベクター、アデノウイルスベクター、又はレトロウイルスベクターからなる群より選択され、好ましくはレンチウイルスベクターである、ベクター。
- 請求項1〜5のいずれか1項に記載の核酸分子又は請求項9に記載のベクターを有する細胞であって、該細胞はT細胞であり、好ましくはCD8+T細胞である、細胞。
- 請求項6〜8のいずれか1項に記載のCARを膜で発現する請求項10に記載の細胞。
- 薬剤として使用される請求項10又は11に記載の細胞。
- 哺乳類、好ましくはヒトにおける増殖性疾患の治療に使用される請求項10又は11に記載の細胞。
- 上記増殖性疾患は、IL−1RAP発現に関連する疾患であり、好ましくは、脊髄形成異常症、骨髄異形成症候群、又は前白血病等のがん、悪性腫瘍、又は前がん状態から選択される疾患であり、より好ましくは、B細胞急性リンパ性白血病(「BALL」)、T細胞急性リンパ性白血病(「TALL」)、急性リンパ性白血病(ALL)等の1種以上の急性白血病;慢性骨髄性白血病(CML)及び慢性リンパ性白血病(CLL)等の1種以上の慢性白血病からなる群より選択される血液がんである、請求項13に記載の細胞。
- 上記CARは、抗原結合領域と、CD28タンパク質の膜貫通領域と、共刺激4−1BBシグナル伝達領域と、CD3ζシグナル伝達領域とを有しており、上記抗原結合領域は、
(i)アミノ酸配列番号6との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号7との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号8との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する軽鎖可変領域を有する軽鎖と、
(ii)アミノ酸配列番号12との同一性が少なくとも80%である相補性決定領域1(CDR1)、アミノ酸配列番号13との同一性が少なくとも80%である相補性決定領域2(CDR2)、及びアミノ酸配列番号14との同一性が少なくとも80%である相補性決定領域3(CDR3)を有する重鎖可変領域を有する重鎖と
を有する抗IL−1RAP scFvである、請求項13又は14に記載の細胞。 - 少なくとも1種のチロシンキナーゼ阻害剤(TKI)、好ましくはイマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、及びポナチニブから選択される少なくとも1種のTKIと組み合わせて使用される請求項13〜15のいずれか1項に記載の細胞。
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US20210008108A1 (en) * | 2017-11-23 | 2021-01-14 | Etablissement Francais Du Sang | Car-t cells targeting il-1rap and their use |
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US11248054B2 (en) | 2017-06-12 | 2022-02-15 | Bluefin Biomedicine, Inc. | Anti-IL1RAP antibodies and antibody drug conjugates |
EP3744400A1 (en) * | 2019-05-28 | 2020-12-02 | Etablissement Français du Sang | Car-t cells targeting il-1rap and their use in acute myeloid leukemia (aml) |
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JP2017513478A (ja) * | 2014-04-14 | 2017-06-01 | セレクティスCellectis | 癌免疫療法のためのbcma(cd269)特異的キメラ抗原受容体 |
CN106831998A (zh) * | 2016-06-22 | 2017-06-13 | 徐州医科大学 | 一种人il1rap特异性car及其应用 |
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EP3489259A1 (en) * | 2017-11-23 | 2019-05-29 | Etablissement Français du Sang | Anti-il-1rap-car-t cells and their use |
EP3744400A1 (en) * | 2019-05-28 | 2020-12-02 | Etablissement Français du Sang | Car-t cells targeting il-1rap and their use in acute myeloid leukemia (aml) |
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Cited By (2)
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US20210008108A1 (en) * | 2017-11-23 | 2021-01-14 | Etablissement Francais Du Sang | Car-t cells targeting il-1rap and their use |
US11839630B2 (en) * | 2017-11-23 | 2023-12-12 | Etablissement Francais Du Sang | CAR-T cells targeting IL-1RAP and their use |
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US20210008108A1 (en) | 2021-01-14 |
EP3713960A1 (en) | 2020-09-30 |
CN111712517A (zh) | 2020-09-25 |
WO2019101604A1 (en) | 2019-05-31 |
CN111712517B (zh) | 2024-05-14 |
JP7307083B2 (ja) | 2023-07-11 |
KR20200121783A (ko) | 2020-10-26 |
US11839630B2 (en) | 2023-12-12 |
EP3489259A1 (en) | 2019-05-29 |
JP2023115299A (ja) | 2023-08-18 |
CA3080451A1 (en) | 2019-05-31 |
US20240139249A1 (en) | 2024-05-02 |
AU2018371071A1 (en) | 2020-05-14 |
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