JP7382829B2 - キメラ抗原受容体を発現するt細胞 - Google Patents
キメラ抗原受容体を発現するt細胞 Download PDFInfo
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Description
本出願は、米国特許法第119(e)条の下、2017年1月10日に出願された米国仮出願第62/444622号、2017年6月7日に出願された第62/516279号、及び2017年11月1日に出願された第62/580258号に基づく優先権を主張し、それらの内容は、それらの全体が出典明示により本明細書に援用される。
便宜上、明細書、実施例、及び添付の請求の範囲において使用されるいくつかの用語並びに語句の意味が、以下で提供される。別段示されないか、又は文脈から暗に示されていない限り、次の用語及び語句は、以下で提供される意味を含む。定義は、特定の実施態様を記載するのに役立つよう提供され、テクノロジーの範囲は、請求項によってのみ制限されるので、請求されたテクノロジーを制限することは意図されない。別段定義されない限り、本明細書において使用される全ての技術用語及び科学用語は、本テクノロジーが属する当該技術分野における当業者により一般に理解されるのと同じ意味を有する。当該技術分野における用語の使用と本明細書におけるその定義の間に明らかな食い違いが存在するなら、明細書内で提供される定義が優先する。
本明細書に記載されるテクノロジーは、免疫療法における使用のための改善されたCARを提供する。以下は、CAR及び様々な改善を考察する。
様々な実施態様において、本明細書に記載されるCARは、抗体試薬又は細胞外標的結合ドメインとしてのその抗原結合ドメインを含む。
VLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFV(配列番号37)
任意の細胞表面部分は、CARにより標的にされ得る。最も頻繁には、標的は、人が、T細胞応答について標的化することを望む細胞上で異なって又は優先的に発現される細胞表面ポリペプチドである。これに関して、腫瘍抗原又は腫瘍関連抗原は、魅力的な標的をもたらし、これが、非腫瘍細胞若しくは組織への二次的な損傷を回避するか、又は少なくとも制限しながら、腫瘍細胞を標的にする手段をもたらす。腫瘍抗原又は腫瘍関連抗原の非限定的な例は、CEA、未成熟ラミニン受容体、TAG-72、HPV E6及びE7、BING-4、カルシウムにより活性化されたクロライドチャネル2、サイクリンB1、9D7、Ep-CAM、EphA3、Her2/neu、テロメラーゼ、メソセリウン、SAP-1、サバイビン、BAGEファミリー、CAGEファミリー、GAGEファミリー、MAGEファミリー、SAGEファミリー、XAGEファミリー、NY-ESO-1/LAGE-1、PRAME、SSX-2、メランA/MART-1、Gp100/pmel17、チロシナーゼ、TRP-1/-2、MC1R、BRCA1/2、CDK4、MART-2、p53、Ras、MUC1、並びにTGF-βRIIを含む。
本明細書に記載されるそれぞれのCARは、必ず、細胞外標的結合ドメインを細胞内シグナル伝達ドメインに結び付ける膜貫通型ドメインを含む。
本明細書に記載されるそれぞれのCARは、共刺激分子の細胞内ドメイン、又は共刺激ドメインを含む。本明細書において使用される、用語「共刺激ドメイン」は、共刺激分子の細胞内シグナル伝達ドメインを指す。共刺激分子は、抗原への結合の際にTリンパ球の効率的な活性化及び機能に要求される第2のシグナルをもたらす抗原受容体又はFc受容体以外の細胞表面分子である。かかる共刺激分子の実例は、CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKD2C SLP76、TRIM、及びZAP70を含む。1つの実施態様において、細胞内ドメインは、4-1BBの細胞内ドメインである。
本明細書に記載されるCARは、細胞内シグナル伝達ドメインを含む。「細胞内シグナル伝達ドメイン」は、標的抗原への有効なCAR結合のメッセージを免疫エフェクター細胞の内部に移動して、エフェクター細胞機能、例えば、CARが結合した標的細胞への細胞傷害性因子の放出を含む、活性化、サイトカイン産生、増殖及び細胞傷害性活性、又は抗原の細胞外CARドメインへの結合後に誘発された他の細胞応答を誘発する際に関与するCARポリペプチドの一部を指す。
いくつかの実施態様において、本明細書に記載される方法は、がん、形質細胞疾患若しくは障害、又は自己免疫疾患若しくは障害を有するか、或いは有すると診断された対象を、本明細書に記載されるCARポリペプチドの何れか、又は本明細書に記載されるCARポリペプチドの何れかをコードする核酸を含む哺乳類細胞で処置することに関する。本明細書において使用される、「本明細書に記載されるCAR T細胞」は、本明細書に記載されるCARポリペプチドの何れか、又は本明細書に記載されるCARポリペプチドの何れかをコードする核酸を含む哺乳類細胞を指す。本明細書において使用される、「状態」は、がん、形質細胞疾患若しくは障害、又は自己免疫疾患若しくは障害を指す。状態を有する対象は、状態を診断する現在の方法を使用して医師により同定され得る。これらの状態を特徴付け、診断に役立つ、状態の症状及び/又は合併症は、当該技術分野において周知であり、疲労、持続感染、及び持続性出血を含むが、これらに限定されない。例えば、状態の診断に役立ち得る試験は、非限定的に、血液スクリーニング及び骨髄試験であり、規定の状態について当該技術分野において知られている。状態の家族歴、又は状態のリスク因子への曝露もまた、対象が状態を有しそうであるかどうかの決定、又は状態の診断をなすのに役立ち得る。
本明細書において使用される用語としての「単位投薬形態」は、適当な1回の投与のための投薬量を指す。例示の目的で、単位投薬形態は、デリバリー装置、例えば、シリンジ又は静脈内ドリップバックに配置した治療剤の量であり得る。1つの実施態様において、単位投薬形態は、単一の投与において投与される。別の実施態様において、1回より多い単位投薬形態は、同時に投与することができる。
本明細書に記載される活性化されたCAR T細胞は、他の公知の薬剤及び療法と組合されて使用され得る。1つの実施態様において、対象は、抗BCMA療法をさらに投与される。1つの実施態様において、対象は、抗BCMA療法に抵抗性である。本明細書において使用される「組み合わせて」投与されるは、2種(又はそれ以上の)異なる処置が、障害に伴う対象の苦痛の経過中対象にデリバリーされること、例えば、2種以上の処置が、対象が、障害と診断された後、かつ障害が、治癒していないか、若しくは除去されていないか、又は処置が、他の理由のため中止される前に、デリバリーされることを意味する。いくつかの実施態様において、投与に関して重複が存在するように、1種の処置のデリバリーは、第2のデリバリーが始まるときに依然として生じている。これは、時に、本明細書において「同時」又は「並行デリバリー」として言及される。他の実施態様において、他方の処置のデリバリーが始まる前に、一方の処置のデリバリーが終わる。何れかの場合のいくつかの実施態様において、処置は、併用された投与のため、より有効である。例えば、第2の処置は、第1の処置の非存在下で投与されたなら観察されるものより、より有効である、例えば、同等の効果が、第2の処置を少なくして観察されるか、若しくは第2の処置は、第2の処置が、より高い程度に症状を低減するか、又は類似の状況が、第1の処置に関しても観察される。いくつかの実施態様において、デリバリーは、症状における低減、又は障害と関連する他のパラメーターが、他方の非存在下でデリバリーされた一方の処置で観察されるものより大きくなるようなデリバリーである。2種の処置の効果は、部分的に相加、全体的に相加、又は相加より大きくあり得る。デリバリーは、デリバリーされる第1の処置の効果が、第2がデリバリーされるとき、依然として検出可能であるようなデリバリーであり得る。本明細書に記載される活性化されたCAR T細胞及び少なくとも1種の追加の治療剤は、同じ組成物において、又は別々の組成物において、同時に、又は連続して投与され得る。連続投与について、本明細書に記載されるCARを発現する細胞が、最初に投与され、追加の薬剤が、2番目に投与され得るか、又は投与の順が、逆であることもできる。CAR T療法及び/又は他の治療剤、手法若しくはモダリティは、活発な障害の期間中、又は寛解若しくはあまり活発でない疾患の期間中に、投与され得る。CAR T療法は、別の処置前、処置と同時、処置後、又は障害の寛解中に、投与され得る。
Idamycin PFS(登録商標));マイトマイシンC(Mutamycin(登録商標));ゲルダナマイシン;ハービマイシン;ラビドマイシン;並びにデスアセチルラビドマイシンを含む。典型的なビンカアルカロイドは、例えば、ビノレルビン酒石酸塩(Navelbine(登録商標))、ビンクリスチン(Oncovin(登録商標))、及びビンデシン(Eldisine(登録商標)));ビンブラスチン(ビンブラスチン硫酸塩、ビンカロイコブラスチン及びVLBとしても知られる、Alkaban-AQ(登録商標)及びVelban(登録商標));並びにビノレルビン(Navelbine(登録商標))を含む。典型的なプロテオソーム阻害剤は、ボルテゾミブ(Velcade(登録商標));カルフィルゾミブ(PX-171-007、(5)-4-メチル-N-((5)-l-(((5)-4-メチル-l-((R)-2-メチルオキシラン-2-イル)-l-オキソペンタン-2-イル)アミノ)-l-オキソ-3-フェニルプロパン-2-イル)-2-((5,)-2-(2-モルホリノアセタミド)-4-フェニルブタンアミド)-ペンタンアミド);マリゾミブ(NPT0052);イキサゾミブクエン酸エステル(MLN-9708);デランゾミブ(CEP-18770);並びにO-メチル-N-[(2-メチル-5-チアゾリル)カルボニル]-L-セリル-O-メチル-N-[(llS’)-2-[(2R)-2-メチル-2-オキシラニル]-2-オキソ-l-(フェニルメチル)エチル]-L-セリンアミド(ONX-0912)を含む。
例えば、本明細書に記載される状態の処置における、又は本明細書に記載される応答(例えば、がん細胞における低減)を誘導するための活性化されたCAR T細胞の有効性は、熟練した臨床医により決定され得る。しかしながら、本明細書に記載される状態の徴候若しくは症状の一又は複数が、有益な様式で変更されるか、他の臨床上許容される症状が、改善されるか、若しくは向上されるか、又は所望の応答が、本明細書に記載される方法による処置後、例えば、少なくとも10%誘導されるなら、処置は、本明細書において使用される用語「有効な処置」であるとみなされる。有効性は、例えば、本明細書に記載される方法に従い処置される状態のマーカー、指標、症状、及び/若しくは発生率、又は任意の他の適当な測定可能なパラメーターを測定することにより、評価され得る。本明細書に記載される方法は、マーカーのレベル若しくは状態の症状を、例えば、少なくとも10%、少なくとも15%、少なくとも20%、少なくとも25%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%又は少なくとも90%以上減少し得る。
1.
a)腫瘍壊死因子(TNF)スーパーファミリー受容体リガンドの部分を含む一又は複数の細胞外ドメイン;
b)ヒンジ及び膜貫通型ドメイン;
c)共刺激ドメイン;及び
d)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)ポリペプチド。
2.TNFスーパーファミリー受容体リガンドが、A増殖誘導リガンド(APRIL)である、パラグラフ1のCARポリペプチド。
3.TNFスーパーファミリー受容体リガンドが、TNF-アルファ、リンホトキシンベータ、OX40L、CD154、FasL、LIGHT、TL1A、CD70、Siva、CD153、4-1BBリガンド、TRAIL、RANKL、TWEAK、BAFF、CAMLG、LIGHT、NGF、BDNF、NT-3、NT-4、GITRリガンド、TL1A、又はEDA-A2である、パラグラフ1のCARポリペプチド。
4.CD8リーダー配列をさらに含む、パラグラフ1から3の何れか1つのCARポリペプチド。
5.CD8リーダー配列が、配列番号20、26、又は32から選択される配列を含む、パラグラフ4のCARポリペプチド。
6.APRILの部分が、APRILのリジンリッチな領域を含まない、パラグラフ2、4、又は5の何れかのCARポリペプチド。
7.APRILの部分が、配列番号21、27、又は33から選択される配列を含む、パラグラフ2又は4から6の何れかのCARポリペプチド。
8.ヒンジ及び膜貫通型ドメインが、CD8又は4-1BBのヒンジ及び膜貫通型ドメインを含む、パラグラフ1から7の何れかのCARポリペプチド。
9.CD8ヒンジ及び膜貫通型ドメイン配列が、配列番号22の配列を含む、パラグラフ1から8の何れかのCARポリペプチド。
10.4-1BBヒンジ及び膜貫通型ドメイン配列が、配列番号28又は34から選択される配列を含む、パラグラフ1から9の何れかのCARポリペプチド。
11.細胞内シグナル伝達ドメインが、CD3ζ、CD3ε、又はCD3θのシグナル伝達ドメインを含む、パラグラフ1から10の何れかのCARポリペプチド。
12.CD3ζ細胞内シグナル伝達ドメイン配列が、配列番号24又は30から選択される配列を含む、パラグラフ1から11の何れかのCARポリペプチド。
13.CD3θ細胞内シグナル伝達ドメイン配列が、配列番号36の配列を含む、パラグラフ1から12の何れかのCARポリペプチド。
14.共刺激ドメインが、4-1BB ICD、CD28 ICD、CD27 ICD、ICOS ICD、及びOX40 ICDからなる群から選択される細胞内ドメインである、パラグラフ1から13の何れかのCAR。
15.共刺激ドメインが、4-1BBの細胞内ドメインである、パラグラフ1から14の何れかのCARポリペプチド。
16.4-1BB配列の細胞内ドメインが、配列番号23、29、又は35から選択される配列を含む、パラグラフ15のCARポリペプチド。
17.CARポリペプチドが、TNFスーパーファミリー受容体リガンドの部分を含む2個以上の細胞外ドメインを含む、パラグラフ1から16の何れか1つのCARポリペプチド。
18.CARポリペプチドが、TNFスーパーファミリー受容体リガンドの部分を含む3個の細胞外ドメインを含む、パラグラフ17のCARポリペプチド。
19.配列番号19、25、若しくは31から選択される配列と少なくとも95%の同一性を含むか、又は配列番号1、7、若しくは13から選択される配列と少なくとも95%の同一性を含む配列によりコードされるCARポリペプチド。
20.配列番号19、25、若しくは31から選択される配列を含むか、又は配列番号1、7、若しくは13から選択される配列によりコードされるCARポリペプチド。
21.配列番号19、25、若しくは31から選択される配列に対応する配列を含むか、又は配列番号1、7、若しくは13から選択される配列によりコードされるCARポリペプチド。
22.パラグラフ1から21の何れか1つのCARポリペプチドの2種以上を含むポリペプチド複合体。
23.ポリペプチド複合体が、パラグラフ1から21の何れか1つの3種のCARポリペプチドを含む、パラグラフ22のポリペプチド複合体。
24.
a)パラグラフ1から21の何れかのCARポリペプチド;
b)パラグラフ1から21の何れかのCARポリペプチドをコードする核酸;又は
c)パラグラフ22若しくは23のポリペプチド複合体
を含む哺乳類細胞。
25.細胞がT細胞である、パラグラフ24の細胞。
26.細胞がヒト細胞である、パラグラフ24又は25の細胞。
27.細胞が、がん、形質細胞障害、若しくは自己免疫疾患を有するか、又は有すると診断された個体から得られる、パラグラフ24から26の何れかの細胞。
28.対象においてがん、形質細胞障害、アミロイドーシス、又は自己免疫疾患を処置する方法であって、
a)T細胞表面上にパラグラフ1から21の何れかのCARを含むようにT細胞を操作すること;
b)操作されたT細胞を対象に投与すること
を含む方法。
29.対象においてがん、形質細胞障害、又は自己免疫疾患を処置する方法であって、パラグラフ24から27の何れかの細胞を対象に投与することを含む方法。
30.がんが、BAFF+、BCMA+及び/又はTACI+である、パラグラフ28又は29の方法。
31.対象が、抗BCMA療法をさらに投与される、パラグラフ28から30の何れかの方法。
32.対象が、抗BCMA療法に抵抗性である、パラグラフ28から31の何れかの方法。
33.がんが、多発性骨髄腫又はくすぶり型多発性骨髄腫である、パラグラフ28から32の何れかの方法。
34.自己免疫疾患が、凝固因子に対する抗体を有する血友病、重症筋無力症、多発性硬化症、及び慢性移植片対宿主病からなる群から選択される、パラグラフ28から32の何れかの方法。
35.がんの処置のため製剤された、パラグラフ1から21の何れか1つのCARポリペプチド、パラグラフ22若しくは23のポリペプチド複合体、又はパラグラフ24から27の何れか1つの細胞を含む組成物。
36.薬学的に許容される担体をさらに含む、パラグラフ35の組成物。
CD8又は4-1BBの膜貫通型ドメインに融合したAPRIL(A増殖誘導リガンド)の細胞外ドメイン及びT細胞活性化受容体CD3ゼータ、CD3エータ、又はCD3シータのシグナル伝達ドメインに基づくキメラ抗原受容体を、本明細書に記載する。これらのCARは、抗BCMA標的化療法に対する抵抗性を克服し、最適な機能のため膜貫通型ドメインのダイマー形成及びトリマー形成を利用する。これらのCARは、がん、例えば、多発性骨髄腫、形質細胞障害、及び/又は重篤な自己免疫疾患の処置のために企図される。
本発明者らのCAR骨格の文脈におけるマウス及びファージディスプレイ由来抗BCMA コンストラクトの公開された配列に基づくBCMAに特異的なscFv配列の小さなパネルの試験を、本明細書に記載する。加えて、BCMA及びTACIに結合するAPRILドメインの大部分の細胞外部分のみを利用する、APRILベースのCARを、特徴付ける。ヘパラン硫酸鎖に結合するリジンリッチな領域を除去するためのAPRILのN末端の切断バージョンも記載する。次に、2つのscFv及び2つのAPRILベースのCARを有するレンチウイルスベクターを使用して、ビオチン化可溶性BCMA-Ig及びTACI-Ig(市販されている)での染色後、フローサイトメトリーを介してCARの発現について初代T細胞を試験する。最終的に、APRILベースのCARが、T細胞培養物から上清を回収し、ELISAを介して可溶性APRILを測定することにより、可溶性タンパク質としてAPRILを分泌し、切断しないことを、検証する。
処置での最近の利点にもかかわらず、多発性骨髄腫は、依然、治癒不可能な疾患のままである。B細胞成熟抗原(BCMA)に対して指向化させたCAR T細胞のいくつかの最近の臨床試験は、多発性骨髄腫を有する患者において完全寛解を含む臨床応答を導いた。しかしながら、BCMAの抗原喪失に起因した処置の失敗が、幾人かの患者において記載されている。膜貫通型活性化因子及びカルシウムモジュレーター及びシクロフィリンリガンド相互作用物質(TACI)は、形質細胞生存の維持においてBCMAに対する重複する役割を有すると考えられ、多発性骨髄腫細胞上でも高度に発現する。本明細書に記載する仕事において、BCMA及びTACIについての天然のリガンドであるAPRILを、CAR結合部分として利用した。アプローチは、多発性骨髄腫において、複数の表面抗原の二重標的化により、抗原回避に起因する、疾患の再発を予防する(図3)。
scFvベースの抗BCMA、並びに全て4-1BB及びCD3ゼータに融合した、異なるヒンジ並びに膜貫通型ドメイン(CD8又は4-1BB)を生じるAPRILベースのCARで、CARコンストラクトを生成した(図2)。ヒト初代T細胞に、抗BCMA-CAR又はAPRILベースのCARの何れかをレンチウイルスにより形質導入した。変動する発現レベルのBCMA及びTACIを有する細胞株のパネルに対してインビトロで、並びに多発性骨髄腫の異種移植片モデルにおいてインビボで、細胞毒性、増殖及びサイトカイン産生を評価した。
APRILベースのCARについて、BCMA+又はTACI+標的細胞に応答した増大した活性化を観察した。BCMA+標的細胞に応答して、抗BCMA-CARのみを活性化した。BCMAとAPRIL-CD8ヒンジ/膜貫通型CARの両方が、抗原特異的細胞傷害性を示した。興味深いことに、抗BCMA-CARと比較して、APRIL-CD8ヒンジ/膜貫通型CARについてのサイトカイン産生において、より低いレベルを見出した。この知見は、恐らく、APRILをCAR結合部分として使用するか、又はscFvをCAR結合部分として使用するかの間の、結合親和性における差を反映する。APRIL-CARにおける4-1BBにヒンジ/膜貫通型ドメインを変えることは、細胞傷害性における低減及び制限されたサイトカイン産生を導く。異種移植片モデルを使用した、進行中の研究は、抗BCMA-CAR又はAPRIL-CD8ヒンジ/膜貫通型CARで処置したいくつかのマウスにおいて、完全な腫瘍寛解を示した。
多発性骨髄腫における可能性のある抗原回避を制限するためにBCMAとTACIの両方を認識することができる、天然のリガンドAPRILに基づく、CARの設計を本明細書に記載する。CD8ヒンジ及び膜貫通型領域の包含は、APRIL CAR機能に最適であった。腫瘍細胞に対するAPRIL CARの細胞傷害有効性にもかかわらず、より低いレベルの効果又はサイトカイン産生を観察した。CAR T細胞療法は、サイトカイン放出症候群を導き得るので、これは、重要な知見である。
ヒトT細胞を、0日目にCD3/28ビーズで刺激し、APRIL-CD8TM-4-1BBζCARを発現したAPRIL-CD8TM-4-1BBzCAR又はBCMA-CD8TM-4-1BBζARをコードするレンチウイルスベクターを形質導入した。0日目の開始時に、細胞をカウントし、それらの成長を集団倍加としてプロットした(図4)。mCherry(レポーター)陽性により、形質導入効率を測定した(図5A-5B)。
BCMA及びTACIの表面発現を、多発性骨髄腫細胞株において測定し(図8)、RPMI8226を操作して、様々なレベルのBCMAを発現させた(図9)。TACIをRPMI-BCMA KOに形質導入した。
pMGH71-APRIL/CD8TM/4-1BB/CD3ζ(配列番号1)は、CD8リーダー(ヌクレオチド1-63(配列番号2));APRIL配列(ヌクレオチド64-471(配列番号3));CD8ヒンジ及びTM配列(ヌクレオチド472-678(配列番号4));4-1BB ICD配列(ヌクレオチド679-804(配列番号5));並びにCD3ゼータ配列(ヌクレオチド805-1140(配列番号6))を含む。
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCCCACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG(配列番号1)
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCC(配列番号2)
CACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTG(配列番号3)
ACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT(配列番号4)
AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTG(配列番号5)
CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG(配列番号6)
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCCCACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTGCCATCTCCAGCCGACCTCTCTCCGGGAGCATCCTCTGTGACCCCGCCTGCCCCTGCGAGAGAGCCAGGACACTCTCCGCAGATCATCTCCTTCTTTCTTGCGCTGACGTCGACTGCGTTGCTCTTCCTGCTGTTCTTCCTCACGCTCCGTTTCTCTGTTGTTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG(配列番号7)
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCC(配列番号8)
CACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTG(配列番号9)
CCATCTCCAGCCGACCTCTCTCCGGGAGCATCCTCTGTGACCCCGCCTGCCCCTGCGAGAGAGCCAGGACACTCTCCGCAGATCATCTCCTTCTTTCTTGCGCTGACGTCGACTGCGTTGCTCTTCCTGCTGTTCTTCCTCACGCTCCGTTTCTCTGTTGTT(配列番号10)
AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTG(配列番号11)
CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG(配列番号12)
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCCCACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTGCCATCTCCAGCCGACCTCTCTCCGGGAGCATCCTCTGTGACCCCGCCTGCCCCTGCGAGAGAGCCAGGACACTCTCCGCAGATCATCTCCTTCTTTCTTGCGCTGACGTCGACTGCGTTGCTCTTCCTGCTGTTCTTCCTCACGCTCCGTTTCTCTGTTGTTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGACAGCCACTTCCAAGCAGTTCCAGTACAGGAAAAGAAAAAAAGGCTCAGAAGGGCACCGTGGCGTGCATTCGCCCAGCCCCAGAGGTTAAAGCACCGAAACAATGAACTACCTGACTCCCTAGAGCCCATATATAAAAACATTTGGAACAAAACATTTATAGGAGAG(配列番号13)
ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCC(配列番号14)
CACTCTGTCCTGCACCTGGTTCCCATTAACGCCACCTCCAAGGATGACTCCGATGTGACAGAGGTGATGTGGCAACCAGCTCTTAGGCGTGGGAGAGGCCTACAGGCCCAAGGATATGGTGTCCGAATCCAGGATGCTGGAGTTTATCTGCTGTATAGCCAGGTCCTGTTTCAAGACGTGACTTTCACCATGGGTCAGGTGGTGTCTCGAGAAGGCCAAGGAAGGCAGGAGACTCTATTCCGATGTATAAGAAGTATGCCCTCCCACCCGGACCGGGCCTACAACAGCTGCTATAGCGCAGGTGTCTTCCATTTACACCAAGGGGATATTCTGAGTGTCATAATTCCCCGGGCAAGGGCGAAACTTAACCTCTCTCCACATGGAACCTTCCTGGGGTTTGTGAAACTG(配列番号15)
CCATCTCCAGCCGACCTCTCTCCGGGAGCATCCTCTGTGACCCCGCCTGCCCCTGCGAGAGAGCCAGGACACTCTCCGCAGATCATCTCCTTCTTTCTTGCGCTGACGTCGACTGCGTTGCTCTTCCTGCTGTTCTTCCTCACGCTCCGTTTCTCTGTTGTT(配列番号16)
AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTG(配列番号17)
CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACCAACAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGACAGCCACTTCCAAGCAGTTCCAGTACAGGAAAAGAAAAAAAGGCTCAGAAGGGCACCGTGGCGTGCATTCGCCCAGCCCCAGAGGTTAAAGCACCGAAACAATGAACTACCTGACTCCCTAGAGCCCATATATAAAAACATTTGGAACAAAACATTTATAGGAGAG(配列番号18)
本明細書において他の場所で記載した通り、特定の残基が、BCMA/TACI、すなわち、APRILのD132、T175、D205、R206、R231への結合に関与する。これらの残基の位置を、以下で太字で描く。
MALPVTALLLPLALLLHAARPHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号19)
MALPVTALLLPLALLLHAARP(配列番号20)
HSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL(配列番号21)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC(配列番号22)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号23)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号24)
MALPVTALLLPLALLLHAARPHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKLPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号25)
MALPVTALLLPLALLLHAARP(配列番号26)
HSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL(配列番号27)
4-1BBヒンジ及びTM配列(配列番号28(配列番号25のアミノ酸158-211))
PSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVV(配列番号28)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号29)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(配列番号30)
MALPVTALLLPLALLLHAARPHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKLPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQDSHFQAVPVQEKKKRLRRAPWRAFAQPQRLKHRNNELPDSLEPIYKNIWNKTFIGE(配列番号31)
MALPVTALLLPLALLLHAARP(配列番号32)
HSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL(配列番号33)
PSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVV(配列番号34)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号35)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQDSHFQAVPVQEKKKRLRRAPWRAFAQPQRLKHRNNELPDSLEPIYKNIWNKTFIGE(配列番号36)
多量体抗原を標的にするCARを増強するためのリガンドオリゴマー形成
本研究において記載する仕事において、天然のオリゴマー形成(例えば、ホモトリマー形成)を使用して、それらのコグネート受容体を発現する細胞に対して増大した活性を有するリガンドベースのCARを開発した。TNFスーパーファミリーのリガンドを含む、細胞表面受容体についてのある特定のリガンドは、オリゴマー形成して(例えば、トリマー形成して)、それらのコグネート受容体に結合することが知られている。例えば、上で記載した通り、ヒト骨髄腫は、有効な抗腫瘍抗原:BCMA及びTACIについて標的化し得る2種の表面抗原を発現することが知られている。BCMI及びTACIは、TACI及びBCMAに対するナノモルの親和性で結合する小型の自己形成トリマーである、一般的なリガンド、APRILを共有する。
Claims (32)
- a)A増殖誘導リガンド(APRIL)の部分を含む一又は複数の細胞外ドメイン、ここで、前記APRILの部分が、膜貫通型活性化因子及びカルシウムモジュレーター及びシクロフィリンリガンド相互作用物質(TACI)及びB細胞成熟抗原(BCMA)に結合する;
b)ヒンジ及び4-1BB膜貫通型ドメイン;
c)共刺激ドメイン;及び
d)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)ポリペプチド。 - APRILの部分が、配列番号21のアミノ酸配列又は配列番号3の核酸配列によりコードされるアミノ酸配列を含む、請求項1に記載のCARポリペプチド。
- CD8リーダー配列をさらに含む、請求項1に記載のCARポリペプチド。
- CD8リーダー配列が、配列番号20の配列を含む、請求項3に記載のCARポリペプチド。
- APRILの部分が、APRILのリジンリッチな領域を含まない、請求項1に記載のCARポリペプチド。
- ヒンジ及び膜貫通型ドメインが、4-1BBのヒンジ及び膜貫通型ドメインを含む、請求項1に記載のCARポリペプチド。
- 4-1BBヒンジ及び膜貫通型ドメイン配列が、配列番号28の配列を含む、請求項6に記載のCARポリペプチド。
- 細胞内シグナル伝達ドメインが、CD3ζ、CD3ε、又はCD3θのシグナル伝達ドメインを含む、請求項1に記載のCARポリペプチド。
- CD3ζ細胞内シグナル伝達ドメイン配列が、配列番号24の配列を含む、請求項8に記載のCARポリペプチド。
- CD3θ細胞内シグナル伝達ドメイン配列が、配列番号36の配列を含む、請求項8に記載のCARポリペプチド。
- 共刺激ドメインが、4-1BB ICD、CD28 ICD、CD27 ICD、ICOS ICD、及びOX40 ICDからなる群から選択される細胞内ドメインである、請求項1に記載のCARポリペプチド。
- 共刺激ドメインが、4-1BBの細胞内ドメインである、請求項1に記載のCARポリペプチド。
- 4-1BB配列の細胞内ドメインが、配列番号23のアミノ酸配列を含む、請求項12に記載のCARポリペプチド。
- CARポリペプチドが、APRILの部分を含む2個以上の細胞外ドメインを含む、請求項1に記載のCARポリペプチド。
- CARポリペプチドが、APRILの部分を含む3個の細胞外ドメインを含む、請求項14に記載のCARポリペプチド。
- 配列番号25若しくは31から選択されるアミノ酸配列と少なくとも95%の同一性を含むか、又は配列番号7若しくは13から選択される配列と少なくとも95%の同一性を含む核酸配列によりコードされる、CARポリペプチド。
- 配列番号25若しくは31から選択されるアミノ酸配列を含むか、又は配列番号7若しくは13から選択される核酸配列によりコードされる、CARポリペプチド。
- 2個以上の請求項1に記載のCARポリペプチドを含むポリペプチド複合体。
- ポリペプチド複合体が、3個の請求項1から17の何れか一項に記載のCARポリペプチドを含む、請求項18に記載のポリペプチド複合体。
- a)請求項1に記載のCARポリペプチド;
b)請求項1に記載のCARポリペプチドをコードする核酸;又は
c)2個以上の請求項1に記載のCARポリペプチドを含むポリペプチド複合体
を含む哺乳類細胞。 - 細胞がT細胞である、請求項20に記載の細胞。
- 細胞がヒト細胞である、請求項20に記載の細胞。
- 細胞が、がん、形質細胞障害、若しくは自己免疫疾患を有するか、又は有すると診断された個体から得られ、前記個体から得られた細胞が、a)請求項1に記載のCARポリペプチド;b)請求項1に記載のCARポリペプチドをコードする核酸;又はc)2個以上の請求項1に記載のCARポリペプチドを含むポリペプチド複合体を含むように操作される、請求項20に記載の細胞。
- 対象においてがん、形質細胞障害、アミロイドーシス、又は自己免疫疾患を処置するための医薬であって、請求項21に記載の哺乳類T細胞を含み、前記哺乳類T細胞が対象に投与される、医薬。
- 対象においてがん、形質細胞障害、又は自己免疫疾患を処置するための医薬であって、請求項21に記載の哺乳類T細胞を含み、前記哺乳類T細胞が対象に投与される、医薬。
- がんが、BAFF+、BCMA+及び/又はTACI+である、請求項25に記載の医薬。
- 対象が、抗BCMA療法剤をさらに投与される、請求項25に記載の医薬。
- 対象が、抗BCMA療法に抵抗性である、請求項25に記載の医薬。
- がんが、多発性骨髄腫又はくすぶり型多発性骨髄腫である、請求項25に記載の医薬。
- 自己免疫疾患が、凝固因子に対する抗体を有する血友病、重症筋無力症、多発性硬化症、及び慢性移植片対宿主病からなる群から選択される、請求項25に記載の医薬。
- がんの処置のため製剤された、請求項1に記載のCARポリペプチドを含む組成物。
- 薬学的に許容される担体をさらに含む、請求項31に記載の組成物。
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