JP6975841B2 - Cd19に対するヒト化抗原結合ドメイン及び使用方法 - Google Patents
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Description
本出願は、2017年4月24日付で出願された米国仮特許出願第62/489,258号の利益を主張し、その開示全体が引用することにより本明細書の一部をなす。
本出願は、ASCIIフォーマットで電子的に提出された配列表を含み、その全体が引用することにより本明細書の一部をなす。2017年4月24日付けで作製された上記ASCIIコピーの名前はK−1046_01SL_ST25.txtであり、43305バイトのサイズである。
本発明がより容易に理解されるように、まず特定の用語を以下に定義する。以下の用語及び他の用語に対する更なる定義は、本明細書を通して記載される。
キメラ抗原受容体(CAR又はCAR−T)及びT細胞受容体(TCR)は、遺伝子操作された受容体である。これらの操作された受容体は、当該技術分野で知られている技術によりT細胞を含む免疫細胞に容易に挿入され得て、その細胞によって発現され得る。CARにより、単一の受容体は、特異抗原を認識するとともに、その抗原に結合した場合に免疫細胞を活性化させてその抗原を持っている細胞を攻撃して破壊するよう、プログラム化され得る。これらの抗原が腫瘍細胞上に存在する場合、CARを発現する免疫細胞は、腫瘍細胞を標的とし、死滅させることができる。
CARは、抗原(例えば、細胞表面抗原)に結合するように、特異的な標的となる抗原と相互作用する抗原結合分子を導入することによって操作され得る。幾つかの実施形態では、抗原結合分子は、その抗体フラグメント、例えば1種以上の単鎖抗体フラグメント(「scFv」)である。scFvは、互いに連結された抗体の重鎖及び軽鎖の可変領域を有する単鎖抗体フラグメントである。米国特許第7,741,465号及び同第6,319,494号、並びにEshhar et al., Cancer Immunol Immunotherapy (1997) 45: 131-136を参照のこと。scFvは、親抗体が標的抗原と特異的に相互作用する能力を維持している。scFvは、キメラ抗原受容体において有用である。それというのも、scFvは、その他のCAR成分と一緒に単一の鎖の一部として発現されるように操作され得るからである。同上。Krause et al., J. Exp. Med., Volume 188, No. 4, 1998 (619-626)、Finney et al., Journal of Immunology, 1998, 161: 2791-2797も参照のこと。抗原結合分子は、典型的には、対象となる抗原を認識して結合することができるようにCARの細胞外部分の範囲内に含まれることを理解されたい。対象となる2つ以上の標的に特異性を有する二重特異性及び多重特異性のCARが、本発明の範囲内で考慮される。
以下のポリペプチド配列は、「リーダー配列−VL−リンカー−VH−Hisタグ」の形式で示されており、すなわち「リーダー配列」は太字体であり、「リンカー」はイタリック体であり、かつ「Hisタグ」は太字イタリック体である。
キメラ抗原受容体が共刺激(シグナル伝達)ドメインを含むことで、それらの効力は高められる。米国特許第7,741,465号及び同第6,319,494号、並びにKrause et al.及びFinney et al.(上記参照)、Song et al., Blood 119:696-706 (2012)、Kalos et al., Sci. Transl. Med. 3:95 (2011)、Porter et al., N. Engl. J. Med. 365:725-33 (2011)、及びGross et al., Annu. Rev. Pharmacol. Toxicol. 56:59-83 (2016)を参照のこと。例示的な共刺激タンパク質は、T細胞上に天然に見られる共刺激タンパク質のアミノ酸配列を有する。この共刺激タンパク質の完全な天然アミノ酸配列は、NCBI参照配列:NP_006130.1に記載されている。
1つの実施形態では、本開示のCAR又はTCRは、「細胞外」又は「ヒンジ」又は「スペーサー」ドメイン又は領域を含み、それらの用語は本明細書では区別なく使用される。別の実施形態では、前記細胞外ドメインは、CD2、CD3デルタ、CD3イプシロン、CD3ガンマ、CD4、CD7、CD8α、CD8β、CD11a(ITGAL)、CD11b(ITGAM)、CD11c(ITGAX)、CD11d(ITGAD)、CD18(ITGB2)、CD19(B4)、CD27(TNFRSF7)、CD28、CD28T、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B細胞抗原受容体複合体関連α鎖)、CD79B(B細胞抗原受容体複合体関連β鎖)、CD84(SLAMF5)、CD96(Tactile)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4−1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3ゼータ)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7−H3)、CD279(PD−1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK−p46)、CD336(NK−p44)、CD337(NK−p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、誘導性T細胞共刺激分子(ICOS)、LFA−1(CD11a/CD18)、NKG2C、DAP−10、ICAM−1、NKp80(KLRF1)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、LFA−1、SLAMF9、LAT、GADS(GrpL)、SLP−76(LCP2)、PAG1/CBP、CD83リガンド、Fcガンマ受容体、MHCクラス1分子、MHCクラス2分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、活性化NK細胞受容体、Tollリガンド受容体、及びそれらの断片又は組み合わせに由来する、又はそれらに基づく(例えばそれらの全て又は断片を含む)。「細胞外」又は「ヒンジ」又は「スペーサー」ドメイン又は領域は、天然起源又は合成起源のいずれかに由来し得る。これらのヒンジドメインのポリヌクレオチド配列及びポリペプチド配列は、当該技術分野において知られている。
本発明のCAR又はTCRのための共刺激ドメインは、膜貫通ドメイン及び/又は細胞内シグナル伝達ドメインを更に含み得る。膜貫通ドメインは、CARの細胞外ドメインに融合されるように設計され得る。膜貫通ドメインは、同様にCARの細胞内ドメインに融合され得る。1つの実施形態では、CAR中のドメインの1つと本来会合される膜貫通ドメインが使用される。幾つかの場合においては、膜貫通ドメインは、そのようなドメインが同じ又は異なる表面膜タンパク質の膜貫通ドメインに結合することを避け、受容体複合体のその他のメンバーとの相互作用を最小限にするように選択される、又はアミノ酸置換により改変され得る。膜貫通ドメインは、天然起源又は合成起源のいずれかに基づき得る。その起源が天然である場合に、上記ドメインは、任意の膜結合タンパク質又は膜貫通タンパク質に基づき得る。本発明における具体的な用途の膜貫通領域は、4−1BB/CD137、活性化NK細胞受容体、免疫グロブリンタンパク質、B7−H3、BAFFR、BLAME(SLAMF8)、BTLA、CD100(SEMA4D)、CD103、CD160(BY55)、CD18、CD19、CD19a、CD2、CD247、CD27、CD276(B7−H3)、CD28、CD29、CD3デルタ、CD3イプシロン、CD3ガンマ、CD30、CD4、CD40、CD49a、CD49D、CD49f、CD69、CD7、CD84、CD8アルファ、CD8ベータ、CD96(Tactile)、CD11a、CD11b、CD11c、CD11d、CDS、CEACAM1、CRT AM、サイトカイン受容体、DAP−10、DNAM1(CD226)、Fcガンマ受容体、GADS、GITR、HVEM(LIGHTR)、IA4、ICAM−1、ICAM−1、Igアルファ(CD79a)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、誘導性T細胞共刺激分子(ICOS)、インテグリン、ITGA4、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB2、ITGB7、ITGB1、KIRDS2、LAT、LFA−1、LFA−1、CD83と特異的に結合するリガンド、LIGHT、LIGHT、LTBR、Ly9(CD229)、リンパ球機能関連抗原−1(LFA−1;CD11a/CD18)、MHCクラス1分子、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、OX−40、PAG/Cbp、プログラム細胞死−1(PD−1)、PSGL1、SELPLG(CD162)、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、SLAM(SLAMF1;CD150;IPO−3)、SLAMF4(CD244;2B4)、SLAMF6(NTB−A;Ly108)、SLAMF7、SLP−76、TNF受容体タンパク質、TNFR2、TNFSF14、Tollリガンド受容体、TRANCE/RANKL、VLA1若しくはVLA−6、又はそれらの断片、短縮物若しくは組み合わせに基づき(すなわち含み)得る。これらの膜貫通ドメインのポリヌクレオチド配列及びポリペプチド配列は、当該技術分野において知られている。
本発明の操作されたT細胞の細胞内(シグナル伝達)ドメインは、活性化ドメインへのシグナル伝達をもたらし得て、次いでそれは免疫細胞の通常のエフェクター機能の少なくとも1つを活性化する。T細胞のエフェクター機能は、例えば、サイトカインの分泌を含む細胞溶解活性又はヘルパー活性であり得る。
CD3は、天然T細胞上のT細胞受容体の1つの要素であり、CAR中の重要な細胞内活性化要素であることが示されている。幾つかの実施形態では、CD3は、CD3ゼータ又はCD3イプシロンであり、その各々のポリヌクレオチド配列及びポリペプチド配列は、当該技術分野において知られている。
有害事象は、自殺遺伝子で免疫細胞(1以上のCAR又はTCRを含む)を形質導入することにより最小化され得ることが理解される。また、免疫細胞への誘導性の「オン」又は「アクセラレーター(accelerator)」スイッチを組み込むことが望ましい場合がある。好適な技術として、細胞が本発明のCARコンストラクトで形質導入される前、その後、又はそれと同時の誘導性カスパーゼ−9(米国特許出願公開第2011/0286980号)又はチミジンキナーゼの使用が挙げられる。自殺遺伝子及び/又は「オン」スイッチを導入する追加の方法として、TALENS、ジンクフィンガー、RNAi、siRNA、shRNA、アンチセンス技術、及び当該技術分野で知られている他の技術が挙げられる。
幾つかの実施形態では、本発明のポリヌクレオチドは、リーダーペプチド(本明細書では「シグナルペプチド」又は「リーダー配列」とも呼ばれる)を更に含み得るCAR又はTCRをコードする。或る特定の実施形態では、リーダーペプチドは、アミノ酸配列MEWTWVFLFLLSVTAGVHS(配列番号6)又はMALPVTALLLPLALLLHAARP(配列番号35)と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約96%、少なくとも約97%、少なくとも約98%、少なくとも約99%又は100%同一であるアミノ酸配列を含む。幾つかの実施形態では、リーダーペプチドは、配列番号6又は配列番号35のアミノ酸配列を含む。
或る特定の態様においては、本明細書において本発明のポリヌクレオチドを含むベクターが提供される。幾つかの実施形態では、本発明は、本明細書に記載される抗原結合ドメインを含むCAR又はTCRをコードするポリヌクレオチドを含むベクター又は一式のベクターに関する。
本発明の別の態様は、適切な条件下で、本明細書に開示されるポリヌクレオチドで細胞に形質導入することを含む、CAR又はTCRを発現する細胞を作製する方法に関する。幾つかの実施形態では、上記方法は、本明細書に開示されるように、CAR又はTCRをコードするポリヌクレオチドで細胞に形質導入することを含む。幾つかの実施形態では、上記方法は、CAR又はTCRをコードするポリヌクレオチドを含むベクターで細胞に形質導入することを含む。
本発明の方法は、被験体において癌を治療し、腫瘍のサイズを縮小させ、腫瘍細胞を死滅させ、腫瘍細胞増殖を予防し、腫瘍の成長を予防し、患者から腫瘍を排除し、腫瘍の再発を予防し、腫瘍転移を予防し、患者において寛解を誘導するために、又はそれらの任意の組み合わせに使用され得る。或る特定の実施形態では、上記方法は完全奏功を誘導する。他の実施形態では、上記方法は部分奏功を誘導する。
本発明の抗原結合ドメイン(例えば、抗ヒトCD19 scFv)は、本明細書に記載されるように治療剤(例えば、化学療法剤及び放射性原子)にコンジュゲート(例えば連結)され得る。
抗体のヒト化は、非ヒト抗体、例えばscFvのフレームワークをヒトのものと置き換えるプロセスである。好結果の抗体のヒト化は、残部の置き換え後に親和性が維持されることに依存する。幾つかの実施形態では、ヒト化抗体は、軽鎖及び重鎖の両方の配列の少なくとも一部がヒト遺伝子に起因する抗体分子である。そのような抗体は、本明細書では「ヒト化抗体」、「ヒト抗体」又は「完全ヒト抗体」と呼ばれる。ヒトモノクローナル抗体は、トリオーマ技術、ヒトB細胞ハイブリドーマ技術(Kozbor, et al., 1983 Immunol Today 4: 72を参照)及びヒトモノクローナル抗体の生産のためのEBVハイブリドーマ技術(Cole, et al., 1985 In: Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96を参照)を使用することによって製造され得る。ヒトモノクローナル抗体は、ヒトハイブリドーマ(Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030を参照)又はヒトB細胞をin vitroにてエプスタインバールウイルスで形質転換させる(Cole, et al., 1985 In: Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96を参照)ことによって生産され得る。
この実施例の目的は、CDRグラフティング及び復帰突然変異を使用して親(野生型)抗体の結合親和性を犠牲にすることなく抗CD19マウスモノクローナル抗体(mAb)クローンFMC63をヒト化することであった。
Raji(ヒトバーキットリンパ腫)細胞を培養し、遠心分離により採取した。1ウェル当たり約3×105個の細胞を、PBSで2回洗浄し、参照抗体(FMC63:マウス抗ヒトB細胞(CD19)IgG抗体)の200μlの連続希釈物中にて4℃で30分間インキュベートした。PBSで洗浄した後に、二次抗体(5μg/mlのヤギ抗マウスIgG[FITC])を上記細胞に加え、4℃で30分間インキュベートした。PBSで洗浄した後に、FACSCalibur(商標)(BD Bioscience社、カリフォルニア州、サンノゼ)及びFlowJoソフトウェア(オレゴン州、アシュランド)を使用することにより細胞をEC50結合について分析した。
FMC63についての重鎖及び軽鎖に関するコンビナトリアルヒト化復帰突然変異(BM)スクリーニングライブラリーをデザインした。ライブラリーの構築は、GenScriptの標準的な操作手順に従って実施した。
上述のヒト化ライブラリーから得られたヒト化scFvファージディスプレイライブラリーを、Raji(ヒトバーキットリンパ腫)細胞に対してパンニングした。インプットファージ粒子を、Eol−1(ヒト急性骨髄性(好酸球性)白血病)細胞と一緒に及びEol−1細胞無しにプレインキュベートし、結合されたファージを、多様な高親和性結合体を得るために、野生型抗体による事前の競合溶出と共にTEAによって溶出させた。
選択されたアウトプットファージを使用して、対数増殖期TG1(ファージディスプレイ用コンピテント)細胞に感染させた。トランスフェクションした細胞を増殖させ、そこからdsDNAを抽出した。ヒト化scFv断片を、2本鎖ファージミドから消化し、最良のヒト化抗体クローンのスクリーニングのためにpFASEBAベクターに挿入した。
FMC63(マウス抗ヒトB細胞(CD19)IgG抗体)についてのヒト化重鎖及び軽鎖をコードするDNA配列を合成し、pTT5発現ベクター中に挿入することで、scFv(単鎖可変フラグメント)発現プラスミドを構築した。ヒト化抗体の発現を100mlのHEK293細胞培養物において行い、Niキレート化親和性カラムを用いて上清を精製した。精製された抗体を、PD−10脱塩カラムを使用してPBSへとバッファー交換した。精製されたタンパク質の濃度及び純度を、それぞれOD280及びSDS−PAGEによって測定した。
ヒト化FMC63抗体のRaji細胞への親和性のランク付けのために、精製した抗体を、フローサイトメトリー抗体価測定にかけた。簡潔には、Raji細胞を培養し、遠心分離により採取した。1ウェル当たり約3×105個の細胞を、PBSで2回洗浄し、scFvの200μlの連続希釈物中にて4℃で30分間インキュベートした。PBSで洗浄した後に、二次抗体(5μg/mlのHisタグ抗体[FITC])を細胞に加え、4℃で30分間インキュベートした。PBSで洗浄した後に、FACSCalibur(商標)及びFlowJoソフトウェアを使用することにより細胞をEC50結合について分析した。
Eol−1細胞と一緒に及びEol−1細胞無しにプレインキュベートされたヒト化scFvファージライブラリーのパンニングを実施した(表4)。
第2のアウトプットファージのscFvフラグメントをコードするDNAを増幅させ、pFASEBAベクター中に挿入して、リード抗体をスクリーニングした。個々のFASEBAライブラリーのクローンを、96深ウェルプレートにおいて接種し、発現のために誘導した。FACSスクリーニングを実施して、Raji細胞を特異的に認識するscFvを単離した。
上述の7種のヒト化scFv及び野生型scFvを、100mlのHEK293細胞中で発現させ、NTA−Ni樹脂により精製した。各scFvの純度は、SDS−PAGEによる評価で90%を上回っていた。
ヒト化scFvとRaji細胞との結合をまず、使用に際して3μMの精製抗体から開始するFACSにより調査した。陽性の結合シグナルが、7種の上述のヒト化scFvクローンについてフローサイトメトリーの2ラウンドの間に一貫して観察された。
野生型scFv及び7種の選択されたヒト化scFvのうちの4種をコードするヌクレオチドは、詳細な説明で先に記載されている。同様に、野生型scFv及び7種の選択されたヒト化scFvのうちの4種についてのアミノ酸配列は、詳細な説明で先に記載されている。
この実施例において、抗CD19マウスモノクローナル抗体(mAb)クローンFMC63のヒト化に成功した。7種のヒト化scFvが、FASEBAハイスループットスクリーニング及びファージディスプレイ技術から得られた。4種のヒト化scFv(SS、JS、AS、及びNSと呼ばれるクローン)は、野生型FMC63 scFvと同等の結合(EC50値)を示した。
4種の選択されたscFv(SS、JS、AS、及びNS)のうちの1種をその抗原結合分子として発現するキメラ抗原受容体(CAR)を設計した。
増強された安定性は、所望のタンパク質特性である。これはしばしば、様々な条件下でのタンパク質の融解温度の測定により評価される。より高い融解温度を有するタンパク質は、一般的により長い時間にわたって安定である。CARがより熱安定性である場合に、そのCARは、細胞表面上でより長期にわたり機能的に活性であり得る。
SSのscFv、JSのscFv、ASのscFv及びNSのscFvを含むCARを、2種のT細胞ドナー細胞:5244(図6A)及び5273(図6B)中で発現させた。モックのCARを発現するドナー細胞試料及びFMC63(親)scFvを含むCARを発現するドナー細胞も準備した。
CAR又はモックが形質導入されたドナー由来のT細胞5244(図7A〜図7D)又は5273(図8A〜図8D)を、1:1又は4:1のエフェクター対標的比で標的細胞系統に添加した。4種の標的細胞型を使用した:Raji(CD19+ヒトバーキットリンパ腫細胞;図7A及び図8A)、Namalawa(CD19+ヒトバーキットリンパ腫細胞;図7B及び図8B)、Eol−1(CD19−ヒト急性骨髄性(好酸球性)白血病細胞;図7C及び図8C)及びMv411(CD19−ヒト二重表現型B骨髄単球性白血病細胞;図7D及び図8D)。スタウロスポリン(「Stauro」)を、腫瘍細胞死滅のためのポジティブコントロールとして使用した。
Claims (82)
- 軽鎖可変(VL)領域及び重鎖可変(VH)領域を含むヒト化抗CD19抗体又はその抗原結合フラグメントであって、前記VL領域は、VL相補性決定領域(CDR)1(VL CDR1)、VL CDR2及びVL CDR3を含み、かつ前記VH領域は、VH CDR1、VH CDR2及びVH CDR3を含み、
前記VL領域は、配列番号11に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VH領域は、配列番号12に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VL CDR1は配列番号27を含み、前記VL CDR2は配列番号28を含み、前記VL CDR3は配列番号29を含み、
前記VH CDR1は配列番号30又は配列番号33を含み、前記VH CDR2は配列番号31又は配列番号34を含み、前記VH CDR3は配列番号32を含む、
ヒト化抗CD19抗体又はその抗原結合フラグメント。 - 軽鎖可変(VL)領域及び重鎖可変(VH)領域を含むヒト化抗CD19抗体又はその抗原結合フラグメントであって、前記VL領域は、VL相補性決定領域(CDR)1(VL CDR1)、VL CDR2及びVL CDR3を含み、かつ前記VH領域は、VH CDR1、VH CDR2及びVH CDR3を含み、
前記VL領域は、配列番号14に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VH領域は、配列番号15に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VL CDR1は配列番号27を含み、前記VL CDR2は配列番号28を含み、前記VL CDR3は配列番号29を含み、
前記VH CDR1は配列番号30又は配列番号33を含み、前記VH CDR2は配列番号31又は配列番号34を含み、前記VH CDR3は配列番号32を含む、
ヒト化抗CD19抗体又はその抗原結合フラグメント。 - 軽鎖可変(VL)領域及び重鎖可変(VH)領域を含むヒト化抗CD19抗体又はその抗原結合フラグメントであって、前記VL領域は、VL相補性決定領域(CDR)1(VL CDR1)、VL CDR2及びVL CDR3を含み、かつ前記VH領域は、VH CDR1、VH CDR2及びVH CDR3を含み、
前記VL領域は、配列番号17に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VH領域は、配列番号18に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VL CDR1は配列番号27を含み、前記VL CDR2は配列番号28を含み、前記VL CDR3は配列番号29を含み、
前記VH CDR1は配列番号30又は配列番号33を含み、前記VH CDR2は配列番号31又は配列番号34を含み、前記VH CDR3は配列番号32を含む、
ヒト化抗CD19抗体又はその抗原結合フラグメント。 - 軽鎖可変(VL)領域及び重鎖可変(VH)領域を含むヒト化抗CD19抗体又はその抗原結合フラグメントであって、前記VL領域は、VL相補性決定領域(CDR)1(VL CDR1)、VL CDR2及びVL CDR3を含み、かつ前記VH領域は、VH CDR1、VH CDR2及びVH CDR3を含み、
前記VL領域は、配列番号20に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VH領域は、配列番号21に対して少なくとも95%の同一性を有するアミノ酸配列を有し、
前記VL CDR1は配列番号27を含み、前記VL CDR2は配列番号28を含み、前記VL CDR3は配列番号29を含み、
前記VH CDR1は配列番号30又は配列番号33を含み、前記VH CDR2は配列番号31又は配列番号34を含み、前記VH CDR3は配列番号32を含む、
ヒト化抗CD19抗体又はその抗原結合フラグメント。 - 前記VL領域は、
配列番号36の7位、8位、10位、15位、22位、41位、42位、43位、44位、49位、71位、72位、77位、79位、80位、83位、87位、100位、及び/又は107位に相当する位置における1つ以上のアミノ酸置換を含む、請求項1〜4のいずれかに記載のヒト化抗CD19抗体又はその抗原結合フラグメント。 - 前記VL領域における前記1つ以上のアミノ酸置換は、配列番号36の7位のSerへの置換、8位のProへの置換、15位のValへの置換、22位のThrへの置換、41位のGlnへの置換、42位のLysへの置換、43位のAlaへの置換、72位のThrへの置換、77位のSerへの置換、79位のGlnへの置換、80位のProへの置換、及び/又は107位のLysへの置換から選択される、請求項5に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VH領域は、
配列番号37の1位、3位、5位、9位、13位、15位、16位、17位、19位、20位、21位、23位、24位、37位、42位、48位、67位、69位、70位、71位、73位、76位、77位、78位、79位、81位、83位、86位、87位、88位、92位、及び/又は115位に相当する位置における1つ以上のアミノ酸置換を含む、請求項1〜6のいずれか一項に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。 - 前記VH領域における前記1つ以上のアミノ酸置換は、配列番号37の1位のGlnへの置換、3位のGlnへの置換、5位のValへの置換、9位のGlyへの置換、13位のLysへの置換、13位のGlnへの置換、15位のGlyへの置換、16位のArgへの置換、16位のThrへの置換、17位のThrへの置換、19位のArgへの置換、20位のLeuへの置換、21位のSerへの置換、24位のAlaへの置換、42位のGlyへの置換、48位のIleへの置換、67位のPheへの置換、70位のSerへの置換、71位のArgへの置換、73位のThrへの置換、76位のAsnへの置換、77位のThrへの置換、78位のLeuへの置換、79位のTyrへの置換、81位のGlnへの置換、83位のSerへの置換、86位のThrへの置換、86位のArgへの置換、87位のAlaへの置換、88位のGluへの置換、88位のAlaへの置換、92位のValへの置換、及び/又は115位のLeuへの置換から選択される、請求項7に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記抗体又はその抗原結合フラグメントは、IgG、Fab、Fab’、F(ab’)2、Fv、scFv、及びシングルドメイン抗体(dAB)からなる群から選択される、請求項1〜8のいずれか一項に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記抗体又はその抗原結合フラグメントは、scFvである、請求項9に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VL CDR1は、配列番号27を含み、前記VL CDR2は、配列番号28を含み、前記VL CDR3は、配列番号29を含み、前記VH CDR1は、配列番号30を含み、前記VH CDR2は、配列番号31を含み、かつ前記VH CDR3は、配列番号32を含む、請求項1〜10のいずれかに記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VL CDR1は、配列番号27を含み、前記VL CDR2は、配列番号28を含み、前記VL CDR3は、配列番号29を含み、前記VH CDR1は、配列番号33を含み、前記VH CDR2は、配列番号34を含み、かつ前記VH CDR3は、配列番号32を含む、請求項1〜10のいずれかに記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VL CDR1は、配列番号27を含み、前記VL CDR2は、配列番号28を含み、前記VL CDR3は、配列番号29を含み、前記VH CDR1は、配列番号30を含み、前記VH CDR2は、配列番号34を含み、かつ前記VH CDR3は、配列番号32を含む、請求項1〜10のいずれかに記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号14と少なくとも99%同一であり、かつ前記VHは、配列番号15と少なくとも99%同一である、請求項2に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号14を含み、かつ前記VHは、配列番号15を含む、請求項2に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 配列番号24のアミノ酸配列を含む、請求項15に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号20と少なくとも99%同一であり、かつ前記VHは、配列番号21と少なくとも99%同一である、請求項4に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号20を含み、かつ前記VHは、配列番号21を含む、請求項4に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 配列番号26のアミノ酸配列を含む、請求項18に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号11と少なくとも99%同一であり、かつ前記VHは、配列番号12と少なくとも99%同一である、請求項1に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号11を含み、かつ前記VHは、配列番号12を含む、請求項1に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 配列番号23のアミノ酸配列を含む、請求項21に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号17と少なくとも99%同一であり、かつ前記VHは、配列番号18と少なくとも99%同一である、請求項3に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 前記VLは、配列番号17を含み、かつ前記VHは、配列番号18を含む、請求項3に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 配列番号25のアミノ酸配列を含む、請求項24に記載のヒト化抗CD19抗体又はその抗原結合フラグメント。
- 請求項1〜25のいずれか一項に記載のヒト化抗CD19抗体又はその抗原結合フラグメントを含むポリペプチド。
- 配列番号8のアミノ酸配列を含むHisタグを更に含む、請求項26に記載のポリペプチド。
- 前記ポリペプチドは、配列番号10と少なくとも95%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号13と少なくとも95%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号16と少なくとも95%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号19と少なくとも95%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号10と少なくとも99%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号13と少なくとも99%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号16と少なくとも99%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号19と少なくとも99%同一である、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、配列番号10、配列番号13、配列番号16、又は配列番号19を含む、請求項26又は27に記載のポリペプチド。
- 前記ポリペプチドは、治療剤と連結されている、請求項26〜36のいずれか一項に記載のポリペプチド。
- 前記治療剤は、化学療法剤、サイトカイン、放射性原子、siRNA、又はトキシンである、請求項37に記載のポリペプチド。
- 前記治療剤は、化学療法剤である、請求項38に記載のポリペプチド。
- 前記治療剤は、放射性原子である、請求項38に記載のポリペプチド。
- (i)抗原結合ドメインと、(ii)共刺激ドメインと、(iii)活性化ドメインとを含むキメラ抗原受容体(CAR)又はT細胞受容体(TCR)であって、
前記共刺激ドメインは、細胞外ドメインと、膜貫通ドメインと、細胞内ドメインとを含み、
前記抗原結合ドメインは、請求項26に記載のポリペプチドを少なくとも含む、キメラ抗原受容体(CAR)又はT細胞受容体(TCR)。 - 前記共刺激ドメインは、CD2、CD3デルタ、CD3イプシロン、CD3ガンマ、CD4、CD7、CD8α、CD8β、CD11a(ITGAL)、CD11b(ITGAM)、CD11c(ITGAX)、CD11d(ITGAD)、CD18(ITGB2)、CD19(B4)、CD27(TNFRSF7)、CD28、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B細胞抗原受容体複合体関連α鎖)、CD79B(B細胞抗原受容体複合体関連β鎖)、CD84(SLAMF5)、CD96(Tactile)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4−1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3ゼータ)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7−H3)、CD279(PD−1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK−p46)、CD336(NK−p44)、CD337(NK−p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、誘導性T細胞共刺激分子(ICOS)、LFA−1(CD11a/CD18)、NKG2C、DAP−10、ICAM−1、NKp80(KLRF1)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、LFA−1、SLAMF9、LAT、GADS(GrpL)、SLP−76(LCP2)、PAG1/CBP、CD83リガンド、Fcガンマ受容体、MHCクラス1分子、MHCクラス2分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、活性化NK細胞受容体、Tollリガンド受容体、及びそれらの断片又は組み合わせである、請求項41に記載のCAR又はTCR。
- 前記膜貫通ドメインは、4−1BB/CD137、T細胞受容体のα鎖、T細胞受容体のβ鎖、CD2、CD3デルタ、CD3イプシロン、CD3ガンマ、CD4、CD7、CD8α、CD8β、CD11a(ITGAL)、CD11b(ITGAM)、CD11c(ITGAX)、CD11d(ITGAD)、CD18(ITGB2)、CD19(B4)、CD27(TNFRSF7)、CD28、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B細胞抗原受容体複合体関連α鎖)、CD79B(B細胞抗原受容体複合体関連β鎖)、CD84(SLAMF5)、CD96(Tactile)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4−1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3ゼータ)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7−H3)、CD279(PD−1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK−p46)、CD336(NK−p44)、CD337(NK−p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、誘導性T細胞共刺激分子(ICOS)、LFA−1(CD11a/CD18)、NKG2C、DAP−10、ICAM−1、NKp80(KLRF1)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、LFA−1、SLAMF9、LAT、GADS(GrpL)、SLP−76(LCP2)、PAG1/CBP、CD83リガンド、Fcガンマ受容体、MHCクラス1分子、MHCクラス2分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、活性化NK細胞受容体、Tollリガンド受容体、及びそれらの組み合わせである、請求項41又は42に記載のCAR又はTCR。
- 前記細胞内ドメインは、4−1BB/CD137、活性化NK細胞受容体、B7−H3、BAFFR、BLAME(SLAMF8)、BTLA、CD100(SEMA4D)、CD103、CD160(BY55)、CD18、CD19、CD19a、CD2、CD247、CD27、CD276(B7−H3)、CD28、CD29、CD3デルタ、CD3イプシロン、CD3ガンマ、CD30、CD4、CD40、CD49a、CD49D、CD49f、CD69、CD7、CD84、CD8アルファ、CD8ベータ、CD96(Tactile)、CD11a、CD11b、CD11c、CD11d、CDS、CEACAM1、CRT AM、サイトカイン受容体、DAP−10、DNAM1(CD226)、Fcガンマ受容体、GADS、GITR、HVEM(LIGHTR)、IA4、ICAM−1、Igアルファ(CD79a)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、免疫グロブリン様タンパク質、誘導性T細胞共刺激分子(ICOS)、インテグリン、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB2、ITGB7、ITGB1、KIRDS2、LAT、LFA−1、CD83と特異的に結合するリガンド、LIGHT、LIGHT(腫瘍壊死因子スーパーファミリーメンバー14、TNFSF14)、LTBR、Ly9(CD229)、リンパ球機能関連抗原−1(LFA−1(CD11a/CD18))、MHCクラスI分子、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、OX−40、PAG/Cbp、プログラム細胞死−1(PD−1)、PSGL1、SELPLG(CD162)、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、SLAM(SLAMF1、CD150、IPO−3)、SLAMF4(CD244、2B4)、SLAMF6(NTB−A、Ly108)、SLAMF7、SLP−76、TNF受容体タンパク質、TNFR2、Tollリガンド受容体、TRANCE/RANKL、VLA1若しくはVLA−6、又はそれらの組み合わせである、請求項41〜43のいずれか一項に記載のCAR又はTCR。
- 前記細胞外ドメインは、CD2、CD3デルタ、CD3イプシロン、CD3ガンマ、CD4、CD7、CD8α、CD8β、CD11a(ITGAL)、CD11b(ITGAM)、CD11c(ITGAX)、CD11d(ITGAD)、CD18(ITGB2)、CD19(B4)、CD27(TNFRSF7)、CD28、CD29(ITGB1)、CD30(TNFRSF8)、CD40(TNFRSF5)、CD48(SLAMF2)、CD49a(ITGA1)、CD49d(ITGA4)、CD49f(ITGA6)、CD66a(CEACAM1)、CD66b(CEACAM8)、CD66c(CEACAM6)、CD66d(CEACAM3)、CD66e(CEACAM5)、CD69(CLEC2)、CD79A(B細胞抗原受容体複合体関連α鎖)、CD79B(B細胞抗原受容体複合体関連β鎖)、CD84(SLAMF5)、CD96(Tactile)、CD100(SEMA4D)、CD103(ITGAE)、CD134(OX40)、CD137(4−1BB)、CD150(SLAMF1)、CD158A(KIR2DL1)、CD158B1(KIR2DL2)、CD158B2(KIR2DL3)、CD158C(KIR3DP1)、CD158D(KIRDL4)、CD158F1(KIR2DL5A)、CD158F2(KIR2DL5B)、CD158K(KIR3DL2)、CD160(BY55)、CD162(SELPLG)、CD226(DNAM1)、CD229(SLAMF3)、CD244(SLAMF4)、CD247(CD3ゼータ)、CD258(LIGHT)、CD268(BAFFR)、CD270(TNFSF14)、CD272(BTLA)、CD276(B7−H3)、CD279(PD−1)、CD314(NKG2D)、CD319(SLAMF7)、CD335(NK−p46)、CD336(NK−p44)、CD337(NK−p30)、CD352(SLAMF6)、CD353(SLAMF8)、CD355(CRTAM)、CD357(TNFRSF18)、誘導性T細胞共刺激分子(ICOS)、LFA−1(CD11a/CD18)、NKG2C、DAP−10、ICAM−1、NKp80(KLRF1)、IL−2Rベータ、IL−2Rガンマ、IL−7Rアルファ、LFA−1、SLAMF9、LAT、GADS(GrpL)、SLP−76(LCP2)、PAG1/CBP、CD83リガンド、Fcガンマ受容体、MHCクラス1分子、MHCクラス2分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、活性化NK細胞受容体、Tollリガンド受容体、及びそれらの断片又は組み合わせである、請求項41〜44のいずれか一項に記載のCAR又はTCR。
- 前記活性化ドメインは、CD3ゼータ又はCD3イプシロンである、請求項41〜45のいずれか一項に記載のCAR又はTCR。
- 請求項1〜25のいずれかに記載のヒト化抗CD19抗体又はその抗原結合フラグメント、或いは、請求項41〜46のいずれかに記載のCAR又はTCRをコードするポリヌクレオチドを含むベクター。
- 前記ベクターは、アデノウイルスベクター、アデノウイルス随伴ベクター、DNAベクター、レンチウイルスベクター、プラスミド、レトロウイルスベクター、又はRNAベクターである、請求項47に記載のベクター。
- 前記ベクターは、レトロウイルスベクターである、請求項48に記載のベクター。
- 前記レトロウイルスベクターは、レンチウイルスベクターである、請求項49に記載のベクター。
- 請求項1〜25のいずれかに記載のヒト化抗CD19抗体若しくはその抗原結合フラグメント、請求項47〜50のいずれか一項に記載のベクター、又は請求項41〜46のいずれか一項に記載のキメラ抗原受容体(CAR)若しくはT細胞受容体(TCR)を含む細胞。
- 前記細胞は、T細胞である、請求項51に記載の細胞。
- 前記T細胞は、同種異系T細胞、自己T細胞、操作された自己T細胞(eACT)、又は腫瘍浸潤リンパ球(TIL)である、請求項52に記載の細胞。
- 前記T細胞は、CD4+T細胞である、請求項53に記載の細胞。
- 前記T細胞は、CD8+T細胞である、請求項53に記載の細胞。
- 前記細胞は、in vitro細胞である、請求項51〜55のいずれか一項に記載の細胞。
- 前記T細胞は、自己T細胞である、請求項52〜56のいずれか一項に記載の細胞。
- 前記細胞は、ヒトCD19への結合時に少なくともインターフェロンγ(IFNγ)を産生する、請求項51〜57のいずれか一項に記載の細胞。
- 請求項51〜58のいずれか一項に記載の細胞を複数含む組成物。
- 前記組成物は、CD4+細胞又はCD8+細胞を含む、請求項59に記載の組成物。
- 前記組成物は、CD4+細胞及びCD8+細胞を含む、請求項60に記載の組成物。
- 前記T細胞の20%以上80%以下はCD4+細胞であり、残りのT細胞はCD8+細胞である、請求項61に記載の組成物。
- 前記T細胞の30%以上70%以下はCD4+細胞であり、残りのT細胞はCD8+細胞である、請求項62に記載の組成物。
- 前記T細胞の40%以上60%以下はCD4+細胞であり、残りのT細胞はCD8+細胞である、請求項63に記載の組成物。
- 前記T細胞の50%はCD4+細胞であり、かつ前記T細胞の50%はCD8+細胞である、請求項64に記載の組成物。
- 前記T細胞の20%以上80%以下はCD8+細胞であり、残りのT細胞はCD4+細胞である、請求項61に記載の組成物。
- 前記T細胞の30%以上70%以下はCD8+細胞であり、残りのT細胞はCD4+細胞である、請求項66に記載の組成物。
- 前記T細胞の40%以上60%以下はCD8+細胞であり、残りのT細胞はCD4+細胞である、請求項67に記載の組成物。
- 前記複数の細胞における各細胞は、自己T細胞である、請求項59〜68のいずれか一項に記載の組成物。
- 前記組成物は、少なくとも1種の薬学的に許容可能な賦形剤を含む、請求項59〜69のいずれか一項に記載の組成物。
- 請求項1〜25のいずれかに記載のヒト化抗CD19抗体若しくはその抗原結合フラグメント、請求項47〜50のいずれか一項に記載のベクター、又は請求項41〜46のいずれか一項に記載のキメラ抗原受容体(CAR)若しくはT細胞受容体(TCR)を含む組成物。
- キメラ抗原受容体(CAR)又はT細胞受容体(TCR)を発現する細胞を製造する方法であって、単離された細胞に、請求項69に記載のヒト化抗CD19抗体若しくはその抗原結合フラグメント、又は請求項47〜50のいずれか一項に記載のベクターを形質導入する工程含む、方法。
- 前記細胞は、治療を必要とする患者から単離されたリンパ球である、請求項72に記載の方法。
- 前記リンパ球は、ナチュラルキラー細胞、T細胞、又はB細胞である、請求項73に記載の方法。
- 前記細胞を、細胞増殖及び/又はT細胞活性化を促進する条件下で培養する工程を更に含む、請求項72〜74のいずれか一項に記載の方法。
- 所望のT細胞を単離する工程を更に含む、請求項72〜75のいずれか一項に記載の方法。
- 前記所望のT細胞を単離する工程は、培養の6日後に行われる、請求項76に記載の方法。
- 前記所望のT細胞は、CD4及び/又はCD8を発現する、請求項77に記載の方法。
- B細胞リンパ腫を治療するための、請求項59〜71のいずれか一項に記載の組成物。
- 前記B細胞リンパ腫は、急性リンパ芽球性白血病(ALL)、AIDS関連リンパ腫、ALK陽性大B細胞リンパ腫、バーキットリンパ腫、慢性リンパ性白血病(CLL)、古典的ホジキンリンパ腫、びまん性大B細胞リンパ腫(DLBCL)、濾胞性リンパ腫、血管内大B細胞リンパ腫、HHV8関連多中心キャッスルマン病において生ずる大B細胞リンパ腫、リンパ腫様肉芽腫症、リンパ形質細胞性リンパ腫、マントル細胞リンパ腫(MCL)、辺縁帯B細胞リンパ腫(MZL)、粘膜関連リンパ組織リンパ腫(MALT)、結節性辺縁帯B細胞リンパ腫(NMZL)、結節性リンパ球優勢ホジキンリンパ腫、非ホジキンリンパ腫、形質芽細胞性リンパ腫、原発性中枢神経系リンパ腫、原発性滲出性リンパ腫、脾臓辺縁帯リンパ腫(SMZL)及びワルデンシュトレームのマクログロブリン血症からなる群から選択される、請求項79に記載の組成物。
- 前記B細胞リンパ腫は、急性リンパ芽球性白血病(ALL)、慢性リンパ性白血病(CLL)、びまん性大B細胞リンパ腫(DLBCL)、濾胞性リンパ腫、マントル細胞リンパ腫(MCL)、辺縁帯B細胞リンパ腫(MZL)、粘膜関連リンパ組織リンパ腫(MALT)及び非ホジキンリンパ腫からなる群から選択される、請求項80に記載の組成物。
- 前記B細胞リンパ腫は、非ホジキンリンパ腫である、請求項81に記載の組成物。
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