JP2019521704A - Baff−r標的化キメラ抗原受容体修飾t細胞及びその使用 - Google Patents
Baff−r標的化キメラ抗原受容体修飾t細胞及びその使用 Download PDFInfo
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- 238000012447 xenograft mouse model Methods 0.000 description 1
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Abstract
Description
本出願は、2016年6月6日に出願された米国仮出願第62/346,324号及び2016年9月19日に出願された米国仮出願第62/396,767号の優先権を主張し、それらの全体は参照により本明細書に援用される。
C90 CDR L1:ESVDNYGISF(配列番号1)
C90 CDR L2:AAS(配列番号2)
C90 CDR L3:QQSKEVPWT(配列番号3)
C90 CDR H1:GDSITSGY(配列番号4)
C90 CDR H2:ISYSGST(配列番号5)
C90 CDR H3:ASPNYPFYAMDY(配列番号6)
C55 CDR L1:QDISNY(配列番号7)
C55 CDR L2:YTS(配列番号8)
C55 CDR L3:FSELPWT(配列番号9)
C55 CDR H1:GFSLSTSGMG(配列番号10)
C55 CDR H2:IWWDDDK(配列番号11)
C55 CDR H3:ARSFGYGLDY(配列番号12)
MYRMQLLSCIALSLALVTNSEVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYISYSGSTYYNPSLKSRISITRDTSKNQYYLQLNSVTPEDTATYYCASPNYPFYAMDYWGQGTSVTVSSDI(配列番号16)
MDPKGSLSWRILLFLSLAFELSYGQVQLQESGPGLVKPSQTLSLTCTVSGDSITSGYWNWIRQHPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCASPNYPFYAMDYWGQGTLVTVSS(配列番号24)
MDPKGSLSWRILLFLSLAFELSYGEVQLQESGPGLVKPSQTLSLTCTVSGDSITSGYWNWIRQHPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCASPNYPFYAMDYWGQGTLVTVSS(配列番号26)
MDPKGSLSWRILLFLSLAFELSYGEVQLQESGPGLVKPSETLSLTCSVSGDSITSGYWNWIRQPPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQYSLRLSSVTAADTALYYCASPNYPFYAMDYWGQGTRVTVSS(配列番号28)
MYRMQLLSCIALSLALVTNSDIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYAASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKTMEIKR(配列番号14)
METDTLLLWVLLLWVPGSTGEIVLTQSPATLSLSPGERATLSCRASESVDNYGISFLNWFQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKVEIKRTV(配列番号18)
METDTLLLWVLLLWVPGSTGDIVLTQSPATLSLSPGERATLSCRASESVDNYGISFMNWFQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKVEIKRTV(配列番号20)
METDTLLLWVLLLWVPGSTGDIVMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKLLIYAASNLGSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSKEVPWTFGQGTKVEIKRTV(配列番号22)
MYRMQLLSCIALSLALVTNSQVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNSSLKSHLTISKDTSRNQVFLKITSVDTADTATYYCARSFGYGLDYWGQGTTLTVSSAS(配列番号23)
MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS(配列番号33)
MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNSSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS(配列番号34)
MDPKGSLSWRILLFLSLAFELSYGQVTLKESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNTSLKSRLTITKDTSKNQVVLKMTNMDPVDTATYYCARSFGYGLDYWGQGTLVTVSS(配列番号35)
MYRMQLLSCIALSLALVTNSDIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYSLTISSLEPEDIATYYCHQFSELPWTFGGGTKLEIKRT(配列番号30)
METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSSLHTGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV(配列番号36)
METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSSLHTGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV(配列番号37)
METDTLLLWVLLLWVPGSTGDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKTPKLLIYYTSSLHTGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCHQFSELPWTFGGGTKVEIKRTV(配列番号38)
1)アラニン(A)、グリシン(G);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7)セリン(S)、スレオニン(T);及び
8)システイン(C)、メチオニン(M)
は各々、互いについて保存的置換であるアミノ酸を含有する(例えばCreighton,Proteins(1984)を参照)。
mAbの開発のために細菌において産生された従来の組み換え免疫原タンパク質は翻訳後修飾を欠如し、原核生物は真核生物と比較してシャペロンタンパク質及び酸化環境を欠如するので、単純化して折り畳まれる。結果として、かかるタンパク質は、対応する原形質膜にアンカーされた天然タンパク質とは立体配座的構造で異なり得る。さらに、抗体は、標的外のドメイン(標的タンパク質の膜貫通ドメインまたは細胞内ドメイン等)に対して作製され得る。本明細書において記載されるように、真核生物細胞上で発現されるネイティブに折り畳まれ糖鎖付加された免疫原に対するmAbを生成するストラテジーが適用された。特に、ヒトBAFF−Rはマウス線維芽細胞上でネイティブタンパク質としてあり、マウスにおける免疫原として操作された細胞クローンを使用した。ヒト悪性B細胞株及び原発性リンパ腫をインビトロで特異的に結合及び溶解し、異種の腫瘍モデルにおいて薬剤耐性リンパ腫細胞株の増殖をインビボで阻害する、新規のmAbの生成が本明細書において記載される。
動物、細胞株及び原発性ヒト腫瘍サンプル。抗体開発のためにBALB/cマウス及びNOD scidγ(NSG)繁殖ペアを、Jackson Laboratory(Bar Harbor、ME)から購入した。NSG繁殖コロニーはCity of HopeのAnimal Resource Centerによって維持された。マウスは、施設のガイドラインに従って病原体除去動物施設中で飼育した。すべての動物研究は、Institutional Animal Care and Use Committee(IACUC:15020)によって承認された。JeKo−1、SU−DHL−6、Raji、U266及びRLは、ATCC(Manassas(VA))から購入した。Z−138株は、Dr.Michael Wang(MD Anderson Cancer Center)によって提供された。イブルチニブ耐性SP49−IR株は、Dr.Jianguo Tao(University of South Florida)によって開発され提供された。イブルチニブ耐性SP49細胞株(SP49−IR)は、漸増用量のイブルチニブにより細胞を処理することによって確立した。IC50は、SP49−IRについての>100nMに比較して、親SP49では5nMであった。100nMのイブルチニブで、SP49−IR細胞の>90%と比較して、SP49細胞の約5%が生存可能であった。ヒトNK−92 176V細胞は、Conkwest Inc.(San Diego、CA)から得た。ヒト血液及び腫瘍のサンプルのために、培養していない原発性ヒトリンパ腫を、10%のDMSO中で冷凍保存された生存可能な単一細胞懸濁液として、施設内審査委員会に認可されたプロトコール(IRB:2005−0656)下で、MD Anderson Cancer CenterのLymphoma Satellite Tissue Bankから得た。原発性患者サンプルは、マントル細胞リンパ腫(MCL)または慢性リンパ球性白血病(CLL)に罹患する患者からの白血球除去血輸血または血液、ならびにびまん性大細胞型B細胞リンパ腫(DLBCL)または濾胞性リンパ腫(FL)に罹患する患者から切除されたリンパ節を含んでいた。各々のサンプル中の腫瘍細胞は、白血球除去血輸血または血液について80%〜98%及びリンパ節生検について50%〜60の範囲であった。末梢血単核細胞(PBMC)は、City of HopeのMichael Amini Transfusion Medicine Centerによって提供された(IRB:15283)。
ヒトBAFF−Rに対するモノクローナル抗体の生成。BAFF−Rの生物学的に意義のあるエピトープへの治療抗体を生成するために、真核生物細胞表面発現系が使用され、そこで、内在性細胞表面タンパク質は、適切な翻訳後修飾によりそれらのネイティブな立体配座で提供される。マウス線維芽細胞(L)細胞クローンを、細胞表面GFPタグ付加されたヒトBAFF−Rを発現するように操作した。BAFF−R発現L細胞クローンを生成し、GFP発現について特徴づけた(図1A)。クローンD2Cを増やし、これを使用して、方法及び図7A中で免疫付与スケジュールに従ってBALB/cマウスに成功裡に免疫付与した。
提供されたBAFF−R mAbは、NHL、CLL及びALLを含む複数のB細胞腫瘍タイプに対する単一剤として着実なインビボの抗腫瘍効果を誘発した。さらに、抗体は確立された腫瘍を根絶し、それはインビボで長期の無腫瘍生存を導いた。
キメラ抗体(クローン90)は、その結合特異性及び細胞毒性効果を保持しながらヒト化された。CDRのコンピューター分析及び予測された構造を介して、重鎖の3つのバリアント及び軽鎖の3つのバリアントを、変動するヒト抗体への類似度により産生した。合計9つの組み合わせのバリアントを、ヒト化された重鎖及び軽鎖から構築した。これらのバリアントはすべて、2.6〜5.0nMの範囲のKD値であり、結合親和性において親キメラ抗体に匹敵することが証明された(表1)。
高い結合親和性及び生物活性を備えた抗体を使用して、インビボの研究のためのキメラ抗原受容体(CAR)T細胞を構築した。重鎖可変ドメイン及び軽鎖可変ドメインのためのDNA配列を一本鎖(sFv)フォーマットへとアレンジし、4−1BBモチーフと一緒にT細胞シグナル伝達ドメイン(δ鎖)へ操作した。操作されたCAR遺伝子を共発現GFPと一緒に、精製された健康なドナー由来のCD8+ T細胞の中へレンチウイルス経由で導入した。CAR−T細胞をGFPの発現について細胞選別し、動物研究のためにCD3及びCD28のビーズによりインビトロで増やした。NSGマウスに、ルシフェラーゼを発現するJeKo−1 MCL株(JeKo−1−luci)を攻撃投与した。腫瘍を発達させ、腫瘍細胞の目視可能な集団が観察されるまで、生物発光画像化によってモニタリングし、それはおよそ腫瘍攻撃投与の9日後であった。マウスに、腫瘍攻撃投与の9及び15日後に、5×106のCAR−T細胞(抗BAFF−R及び抗CD19)の2回の用量を投与した。対照群に、無処理のT細胞または食塩水(PBS)を投与した。CAR−T療法の治療的抗腫瘍効果を評価するために、マウスを3日ごとに厳密にモニタリング及び画像化して腫瘍発達を追跡した。
以下のT細胞集団:CD4+ナイーブT細胞(CD4+ TN)、CD8+ナイーブT細胞(CD8+ TN)、CD8+セントラルメモリーT細胞(CD8+ TCM)、CD8+メモリー幹細胞(CD8+ MSC)、及び汎T細胞(汎T)を、BAFF−R CARの発現のために調製した。簡潔には、5mLの血液サンプルを5mLのhistopaque−1077(Sigma Aldrich)へ添加した。混合物を2500RPMで20分間遠心分離した(室温(RT)、ブレーキ無し)。中間の末梢血単核細胞(PBMC)層を収集し、50mLのPBS(Corning)により洗浄し、1500RPMで5分間遠心分離した(RT)。収集した細胞を、10mLのRBC溶解バッファー(Qiagen)と組み合わせて、7分間インキュベーションした。次いで細胞をPBSにより洗浄し、5分間遠心分離した(1500RPM、RT)。
2つの異なるBAFF−R CARを構築した。各々は、CD3シグナル配列、後続して、BAFF−R scFv、CD8a膜貫通ドメイン(追加の細胞外アミノ酸及び細胞質アミノ酸を有する)、4−1BB共刺激ドメイン、及びCD3ζシグナル伝達ドメインを含んでいた。様々な領域は、以下のアミノ酸配列:
CD3シグナル:MLLLVTSLLLCELPHPAFLLIP(配列番号39)
追加の細胞外アミノ酸配列及び細胞質アミノ酸配列を含む、CD8a膜貫通(下線):
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC(配列番号40)
共刺激4−1BB:KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号41)
CD3ζシグナリング:RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号42)
を有する。
VQLQESGPGLVKPSQTLSLTCTVSGDSITSGYWNWIRQHPGKGLEYIGYISYSGSTYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCASPNYPFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASESVDNYGISFMNWFQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSKEVPWTFGGGTKVEIKR(配列番号43)
を有する。
EVQLVESGGGLVQPGGSLRLSCAASGFSLSTSGMGVGWVRQSPGKGLEWVAHIWWDDDKYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAIYYCSRSFGYGLDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPILLSASVGDRVTITCRASKSVSTSGYSYMHWYQQRTNGSPRLLIYLVSNLESGVPSRFSGSRSGTDFTLTISSLQPEDEADYYCHQFSELPWTFGAGTKVEIKR(配列番号44)
を有する。
BAFF−R CARを発現するレンチウイルスベクターによる形質導入のための調製において、1:1のビーズ対細胞の比でCD3/CD28磁気ビーズ(Thermo Fisher、Waltham、MA)と細胞を組み合わせ、一晩インキュベーションすること(加湿、5%のCO2、37℃)によって、細胞を活性化した。インキュベーション後に、細胞をカウントし、48ウェルプレート中に1×106細胞/ウェルで播種した。細胞は1のMOIで感染させた。各々の事例において、全体の培養培地を250μLまで補足し、30分間遠心分離した(800g、RT)。細胞を一晩インキュベーションし(加湿、5%のCO2、37℃)、次いで表1中で示される培地中で10日間培養した。CD4+ TN、CD8+ TN、CD8+ TCM、及び汎T細胞の培養は、1:1の細胞対ビーズの比でCD3/CD28磁気ビーズを含んでいた。CD8+ T MSCの培養はCD3/CD28磁気ビーズを含まなかった。BAFF−R CARの発現は、フローサイトメトリーを使用して、GFP陽性細胞のパーセンテージによって査定した。
H90 BAFF−R CARを発現する様々なT細胞集団を使用するインビトロのアッセイを使用して、マントル細胞リンパ腫細胞のJeKo−1細胞(Jeon et al.1998 British Journal of Haematology 102:1323)に対する細胞毒性を査定する。この4時間の51Cr放出アッセイにおいて、H90 BAFF−R CAR T細胞を、様々なエフェクター対標的の比で51Cr標識BAFF−R陽性標的細胞(JeKo−1細胞)と、またはPBMCの陰性対照と共培養した。H90 BAFF−R CARを、汎T細胞、CD4+ TN細胞、CD8+ TCM細胞、またはCD4+ TN細胞及びCD8+ TCM細胞の混合物において発現させた。この分析の結果を図26中で提示する。各々のエフェクター対標的の比(E/T)にわたるT細胞サブセットは、用量依存的細胞毒性を示した。単離されたCD4+ナイーブCAR T細胞(TN)は最も低い細胞毒性をもたらした。インビトロの細胞毒性効果は、汎T細胞からTN+TCM(1:1の混合物)へそして最終的にTCMのみへと、CD8+セントラルメモリーCAR−T細胞(TCM)の濃度を増加させると、より大きかった。
マントル細胞リンパ腫のJeKo−1異種移植マウスモデル(Klanova et al.2014 Laboratory Investigation 94:806;Verner et al.2015 Leukemia & lymphoma 56:3198)を使用して、H90 BAFF−R CARのインビボの活性を査定した。
ルシフェラーゼ発現JeKo−1による0日目の静脈内の(IV)腫瘍攻撃投与(1×106細胞/マウス)に後続する、NSGマウスの群(n=5)の生物発光画像。活性化CAR T細胞治療をIVで点滴した。治療を、10及び17日目(図32A)ならびに10日目のみ(図32B及び32C)に与えた。CD8+ TCM、TN、またはTSCM CAR−T細胞のいずれかと組み合わせた、CD4+ TN CAR−T細胞の出発材料及び治療用量について、治療を至適化した。示された治療は、指摘されたT細胞サブセットに由来する、(図32A)2.5×106のCD4+ TN+2.5×106のCD8+ T細胞、(図32B)2.5×106のCD4+ TN+1×106のCD8+ T細胞、(図32C)1×106のCD4+ TN+1×106のCD8+ T細胞、からなるCAR−T細胞である。同じドナーサンプルからの形質導入されていないCD4+/CD8+ T細胞を同種異系対照として使用し、PBSを腫瘍対照として使用した。非腫瘍関連死が、炎症を示すマウスにおいて観察され;特に、(図32A)CD4 TN+CD8 TN群(4/5の死)及び(図32B)CD4 TN+CD8 TSCM群(2/4の死)において観察された。図32B及び32C中の画像については、100日の経過にわたる全生存のカプラン−マイヤープロットも示す。
CD8+ TN及びCD8+ TCMの実験群中の図32Bからの生存する無腫瘍マウス(1群あたりn=4)に、追加の治療無しで、初回攻撃投与の100日後に1×106のJeKo−1細胞を再攻撃投与した。以前に無治療であるNSGマウス(n=5)に、腫瘍対照として同数のJeKo−1細胞を攻撃投与した。生物発光画像を図33A中で示す。各々の実験マウスからの血液を、腫瘍の再攻撃投与の0及び5日目でサンプリングした。白血球をRBC溶解によって血液から単離し、フローサイトメトリーによって検査した。図33Bは、GFP+ BAFF−R CAR−T細胞についてゲートし、後続してCD4及びCD8 T細胞についてゲートした、白血球の各々の実験群及び日からの代表的なFACSプロットを示す。図33Cは、各々のマウスについて計算及びプロットした、全白血球中のBAFF−R+ CAR−T細胞のパーセンテージを示す、グラフである。CD4 T細胞集団及びCD8 T細胞集団のパーセンテージを各々の積層バー内に示す。
ルシフェラーゼ発現Raji−1による0日目の静脈内の(IV)腫瘍攻撃投与(0.5×106細胞/マウス)に後続する、NSGマウスの群(n=5)の生物発光画像。単回の活性化CAR T細胞治療を、7日目にIVで点滴した。標準的な作業治療用量は、CD4+ TN 2.5×106+CD8+ TN 1×106 BAFF−R CAR T細胞またはCD19 CAR−T細胞からなっていた。scFv(抗BAFF−Rまたは抗CD19)でのみ異なる、等価なCARプラットフォームを使用した。同じドナーサンプルからの形質導入されていないCD4+/CD8+ T細胞を同種異系対照として使用し、PBSを腫瘍対照として使用した。画像を、80日の経過にわたる全生存のカプラン−マイヤープロットの隣りで、図34中で示す。
Claims (27)
- キメラ抗原受容体をコードする核酸分子であって、前記キメラ抗原受容体が、BAFF−Rを標的とするscFv;CD4膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、CD8膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、CD28膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、及びCD3ζ膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアントから選択される、膜貫通ドメイン;共刺激ドメイン;及びCD3ζシグナル伝達ドメインまたは1〜5のアミノ酸修飾を有するそのバリアントを含む、前記核酸分子。
- 前記共刺激ドメインが、CD28の共刺激ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、4−1BBの共刺激ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、及びOX40の共刺激ドメインまたは1〜5のアミノ酸修飾を有するそのバリアントからなる群から選択される、請求項1に記載の核酸分子。
- 前記scFvが軽鎖可変領域及び重鎖可変領域を含み、前記軽鎖可変領域がCDR L1(配列番号1)、CDR L2(配列番号2)及びCDR L3(配列番号3)を含み;前記重鎖可変領域がCDR H1(配列番号4)、CDR H2(配列番号5)及びCDR H3(配列番号6)を含む、請求項1に記載の核酸分子。
- 前記scFvが軽鎖可変領域及び重鎖可変領域を含み、前記軽鎖可変領域がCDR L1(配列番号7)、CDR L2(配列番号8)及びCDR L3(配列番号9)を含み;前記重鎖可変領域がCDR H1(配列番号10)、CDR H2(配列番号11)及びCDR H3(配列番号12)を含む、請求項1に記載の核酸分子。
- 前記scFvが、Chi90 HC、Hu90 HC−1、Hu90 HC−2、Hu90 HC−3、Chi55 HC、Hu55 HC−1、Hu55 HC−2及びHu55 HC−3から選択される重鎖可変ドメイン、ならびにChi90 LC、Hu90 LC−1、Hu90 LC−2、Hu90 LC−3、Chi55 LC、Hu55 LC−1、Hu55 LC−2及びHu55 LC−3から選択される軽鎖可変ドメインを含む、請求項1に記載の核酸分子。
- 前記scFvが前記重鎖可変ドメインと前記軽鎖可変ドメインとの間にスペーサーを含む、請求項3または4のいずれか一項に記載の核酸分子。
- 前記scFvまたはそのバリアントと前記膜貫通ドメインとの間に所在するスペーサー領域を含む、請求項1に記載の核酸分子。
- 前記4−1BBシグナル伝達ドメインが配列番号41のアミノ酸配列を含む、請求項2に記載の核酸分子。
- 前記CD3ζシグナル伝達ドメインが配列番号42のアミノ酸配列を含む、請求項1に記載の核酸分子。
- 3〜15のアミノ酸のリンカーが、前記共刺激ドメインと前記CD3ζシグナル伝達ドメインまたはそのバリアントとの間に所在する、請求項1に記載の核酸分子。
- 前記scFvが、配列番号14、18、20、22、30、36、37または38から選択されるアミノ酸配列を有する軽鎖可変ドメインを含む、請求項1に記載の核酸分子。
- 前記scFvが、配列番号16、24、26、28、23、33、34及び35から選択されるアミノ酸配列を有する重鎖可変ドメインを含む、請求項1に記載の核酸分子。
- 前記scFvが、配列番号43及び44から選択されるアミノ酸配列を含む、請求項1に記載の核酸分子。
- 請求項1〜13のいずれか一項に記載の核酸分子を含む発現カセットを含むベクターによって形質導入された、ヒトT細胞の集団。
- キメラ抗原受容体をコードする発現カセットを含むベクターによって形質導入された、ヒトT細胞の集団であって、キメラ抗原受容体が、BAFF−Rを標的とするscFv;CD4膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、CD8膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、CD28膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアント、及びCD3ζ膜貫通ドメインまたは1〜5のアミノ酸修飾を有するそのバリアントから選択される、膜貫通ドメイン;共刺激ドメイン;及びCD3ζシグナル伝達ドメインまたは1〜5のアミノ酸修飾を有するそのバリアントを含む、前記ヒトT細胞の集団。
- 前記scFvが、Chi90 HC、Hu90 HC−1、Hu90 HC−2、Hu90 HC−3、Chi55 HC、Hu55 HC−1、Hu55 HC−2及びHu55 HC−3から選択される重鎖可変ドメイン、ならびにChi90 LC、Hu90 LC−1、Hu90 LC−2、Hu90 LC−3、Chi55 LC、Hu55 LC−1、Hu55 LC−2及びHu55 LC−3から選択される軽鎖可変ドメインを含む、請求項11に記載のヒトT細胞の集団。
- 前記T細胞が、CD4+ TN細胞及びCD8+ TN細胞を含む、請求項11に記載のヒトT細胞の集団。
- 治療有効量の請求項14〜17のいずれか一項に記載のヒトT細胞の集団を含む組成物を対象へ投与し、それによって前記対象におけるがんを治療することを含む、それを必要とする対象におけるがんを治療する方法。
- 前記がんが、リンパ腫、白血病、または骨髄腫である、請求項18に記載の方法。
- 前記リンパ腫が、マントル細胞リンパ腫、濾胞性リンパ腫、びまん性大細胞型B細胞リンパ腫、辺縁帯リンパ腫、またはバーキットリンパ腫である、請求項19に記載の方法。
- 前記白血病が、リンパ芽球性白血病、慢性リンパ球性白血病、または有毛細胞白血病である、請求項19に記載の方法。
- 前記骨髄腫が多発性骨髄腫である、請求項19に記載の方法。
- 前記対象へ第2の治療剤を投与することをさらに含む、請求項18〜22のいずれか一項に記載の方法。
- 前記T細胞の集団が、自己由来であるか、または前記患者へ同種異系である、請求項18〜23のいずれか一項に記載の方法。
- 前記ヒトT細胞の集団が、CD4+ TN細胞及びCD8 TN細胞を含む細胞を含む、請求項18〜24のいずれか一項に記載の方法。
- 治療有効量の請求項14〜17のいずれか一項に記載のヒトT細胞の集団を含む組成物を対象へ投与し、それによって前記対象におけるがんを治療することを含む、それを必要とする対象における自己免疫疾患を治療する方法。
- 前記自己免疫疾患が、関節リウマチ、全身性紅斑性狼瘡、多発性硬化症、糸球体腎炎、シェーグレン症候群、または自己免疫性溶血性貧血である、請求項27に記載の方法。
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US11779602B2 (en) | 2018-01-22 | 2023-10-10 | Endocyte, Inc. | Methods of use for CAR T cells |
US20220056132A1 (en) * | 2018-12-19 | 2022-02-24 | City Of Hope | Baff-r bispecific t-cell engager antibody |
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US12023354B2 (en) | 2019-05-31 | 2024-07-02 | Case Western Reserve University | Targeting B cell activating factor receptor (BAFF-R) using ligand-based chimeric antigen receptor (CAR)-T cells |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
ES2087997T3 (es) | 1990-01-12 | 1996-08-01 | Cell Genesys Inc | Generacion de anticuerpos xenogenicos. |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
JPH06508511A (ja) | 1990-07-10 | 1994-09-29 | ケンブリッジ アンティボディー テクノロジー リミティド | 特異的な結合ペアーの構成員の製造方法 |
AU3328493A (en) | 1991-12-17 | 1993-07-19 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US6066718A (en) | 1992-09-25 | 2000-05-23 | Novartis Corporation | Reshaped monoclonal antibodies against an immunoglobulin isotype |
US6881557B2 (en) | 2001-07-12 | 2005-04-19 | Arrowsmith Technologies Llp | Super humanized antibodies |
KR20160145802A (ko) * | 2014-04-23 | 2016-12-20 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 요법에 사용하기 위한 키메라 항원 수용체 (car) 및 이의 제조 방법 |
GB201412658D0 (en) | 2014-07-16 | 2014-08-27 | Ucb Biopharma Sprl | Molecules |
KR20160016725A (ko) * | 2014-08-05 | 2016-02-15 | 주식회사 유영제약 | 암 세포에 과발현되는 IL13Rα2에 특이적으로 결합하는 키메라 항원 수용체로 변형된 T 세포 |
SG11201810887UA (en) | 2016-06-06 | 2019-01-30 | Hope City | Baff-r targeted chimeric antigen receptor-modified t-cells and uses thereof |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008526205A (ja) * | 2004-12-31 | 2008-07-24 | ジェネンテック・インコーポレーテッド | Br3に結合するポリペプチド及びその使用 |
Non-Patent Citations (4)
Title |
---|
ADAM D COHEN: "B-CELL MATURATION ANTIGEN (BCMA)-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELLS (CART-BCMA) 以下備考", BLOOD, JPN5019005122, 2016, pages 1 - 6, ISSN: 0004689481 * |
EISENBERG R: "COMBINATION BIOLOGICS: 1 STONE, 2 BIRDS", BLOOD, vol. VOL:110, NR:12, JPN5019005123, December 2007 (2007-12-01), pages 3817, ISSN: 0004689482 * |
PARAMESWARAN R: "EFFECTOR-MEDIATED ERADICATION OF PRECURSOR B ACUTE LYMPHOBLASTIC LEUKEMIA WITH A NOVEL 以下備考", MOLECULAR CANCER THERAPEUTICS, vol. VOL:13, NR:6, JPN5019005126, 13 May 2014 (2014-05-13), US, pages 1567 - 1577, ISSN: 0004689483 * |
SYED ABBAS ALI: "REMISSIONS OF MULTIPLE MYELOMA DURING A FIRST-IN-HUMANS CLINICAL TRIAL OF T CELLS 以下備考", BLOOD, JPN5019005120, 2015, pages 1 - 5, ISSN: 0004689480 * |
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