JP2022130557A - Cd37を標的にするキメラ抗原受容体 - Google Patents
Cd37を標的にするキメラ抗原受容体 Download PDFInfo
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Abstract
Description
便宜上、本明細書、実施例、及び貼付の特許請求の範囲において用いられるいくつかの用語及び語句の意味は下記に提供される。特に断りのない限り、又は文脈から示唆されるように、以下の用語及び語句は、以下に提供される意味を含む。技術の範囲があくまで特許請求の範囲によって限定されないことから、定義は、特定の実施形態の記述に役立つように提供され、特許請求される技術を限定することが意図されない。特段の定義がされていない限り、本明細書で用いられるすべての科学技術用語は、この技術が属する当業者により一般に理解される意味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提供されるその定義との間に明白な矛盾が存在する場合、本明細書中に提供される定義が採用されるものとする。
本明細書に記載の技術は、免疫療法における使用を意図した改善されたCARを提供する。以下、CAR及び様々な改善について論じる。
様々な実施形態では、本明細書に記載のCARは、抗体試薬又はその抗原結合ドメインを細胞外標的結合ドメインとして含む。
任意の細胞表面部分は、CARにより標的にされうる。最も多くは、標的は、T細胞応答について標的にすることが所望される細胞上で差次的に又は優先的に発現される細胞表面ポリペプチドとなる。これに関連して、腫瘍抗原又は腫瘍関連抗原は、魅力的な標的を提供し、腫瘍細胞を標的にする一方で、非腫瘍細胞又は組織へのコラテラルダメージを回避するか又は少なくとも限定するための手段を提供する。腫瘍抗原又は腫瘍関連抗原の非限定例として、CD37、BCMA(腫瘍壊死因子受容体スーパーファミリーメンバー17(TNFRSF17);NCBI Gene ID:608;NCBI Ref Seq NP_001183.2)及びmRNA(例えば、NCBI Ref Seq NM_001192.2)、CEA、未熟ラミニン受容体、TAG-72、HPV E6及びE7、BING-4、カルシウム活性化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、メソテリン、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、Melan-A/MART-1、Gp100/pmel17、チロシナーゼ、TRP-1/-2、MC1R、BRCA1/2、CDK4、MART-2、p53、Ras、MUC1、及びTGF-βRIIが挙げられる。
本明細書に記載のような各CARは、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連結する膜貫通ドメインを必然的に含む。
本明細書に記載の各CARは、任意選択的には、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。本明細書で用いられるとき、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、Tリンパ球の抗原への結合時の効率的な活性化及び機能に要求される第2のシグナルを提供する抗原受容体又は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例示的例として、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が挙げられる。一実施形態では、細胞内ドメインは、4-1BBの細胞内ドメインである。
本明細書に記載のような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の結合のメッセージを免疫エフェクター細胞の内部に形質導入し、エフェクター細胞機能を誘導すること、例えば、活性化、サイトカイン産生、増殖及び細胞傷害性活性、例えば、細胞傷害性因子のCAR結合標的細胞への放出、又は細胞外CARドメインへの抗原結合後に誘発される他の細胞応答などに関与するCARポリペプチドの一部を指す。技術において特に用いられるITAM含有細胞内シグナル伝達ドメインの非限定例として、TCRζ、FcRγ、FcRβ、CD3γ、CD3θ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b、及びCD66dに由来するものが挙げられる。
いくつかの実施形態では、本明細書に記載の方法は、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又は有すると診断された対象を、本明細書に記載のCARポリペプチドのいずれか、又は本明細書に記載のCARポリペプチドのいずれかをコードする核酸を含む哺乳動物細胞を用いて治療することに関する。本明細書で用いられるとき、「本明細書に記載のようなCAR T細胞」は、本明細書に記載のCARポリペプチドのいずれか、又は本明細書に記載のCARポリペプチドのいずれかをコードする核酸を含む哺乳動物細胞を指す。本明細書で用いられるとき、「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、医師により状態を診断する現行の方法を用いて同定されうる。状態の症状及び/又は合併症は、これらの状態を特徴づけ、診断を補助するものであり、当該技術分野で周知であり、限定はされないが、疲労、持続性感染、及び持続性出血を含む。例えば状態の診断を補助することがある試験は、限定はされないが、血液スクリーニング及び骨髄検査が挙げられ、所与の状態にとって当該技術分野で公知である。状態における家族歴、又は状態におけるリスク因子への曝露もまた、対象が状態を有する可能性が高いか否かを判定する、又は状態の診断を行うことを補助しうる。
「単位剤形」は、用語が本明細書で用いられるとき、好適な単回投与のための用量を指す。例として、単位剤形は、送達装置、例えばシリンジ又は静脈内点滴バッグで処理される治療薬の量でありうる。一実施形態では、単位剤形は、単回投与で投与される。別の実施形態では、2以上の単位剤形が同時に投与されうる。
本明細書に記載の活性化CAR T細胞は、他の公知の薬剤及び治療法と併用されうる。一実施形態では、対象は、抗BCMA療法がさらに施される。一実施形態では、対象は、抗BCMA療法に対して抵抗性を示す。「組み合わせ」投与は、本明細書で用いられるとき、障害による対象の苦悩の過程において2(又は3以上)の異なる治療薬が対象に送達され、例えば、対象が障害を有すると診断されてから、また障害が治癒又は除去されている、又は他の理由で治療が終了している以前に2つ以上の治療薬が送達される。いくつかの実施形態では、一方の治療薬の送達が、第2の送達が開始する時、依然として行われていることで、投与については重複がある。これは、時として本明細書中で「同時」又は「併用送達」と称される。他の実施形態では、一方の治療薬の送達は、他方の治療薬の送達が開始する前に終了する。いずれかの場合のいくつかの実施形態では、治療薬は、組み合わせ投与が理由でより有効である。例えば、第2の治療薬がより有効であり、例えば、等価な効果が第2の治療薬の低減とともに見られる、又は第2の治療薬が、第2の治療薬が第1の治療薬の不在下で投与された場合に見られるよりも広範囲に症状を低減する、又は類似の状況が第1の治療薬の存在下で見られる。いくつかの実施形態では、送達は、症状における低減、又は障害に関する他のパラメータの程度が、一方の治療薬が他方の不在下で送達される場合に認められる場合よりも大きいようになされる。2つの治療薬の効果は、部分的に相加的、完全に相加的、又は相加的以上でありうる。送達は、送達される第1の治療薬の効果が、第2の治療薬が送達されるときに依然として検出可能であるようになされうる。本明細書に記載の活性化CAR T細胞及び少なくとも1つの追加的治療薬は、同時に、同じ組成物中で又は別々の組成物中で、又は逐次的に投与されうる。逐次投与においては、本明細書に記載のCARを発現する細胞が最初に投与可能であり、追加的薬剤が2番目に投与可能であり、又は投与順序が逆転可能である。CAR T療法及び/又は他の治療薬、手順又は様式は、活動的な障害の期間中、又は寛解若しくはあまり活動的でない疾患の期間中に実施することができる。CAR T療法は、別の治療前、治療と並行して、治療後、又は障害の寛解中に施すことができる。
としても公知);メルファラン(L-PAM、L-サルコリシン、及びフェニルアラニンマスタード、Alkeran(登録商標)としても公知);アルトレタミン(ヘキサメチルメラミン(HMM)、Hexalen(登録商標)としても公知);カルムスチン(BiCNU(登録商標));ベンダムスチン(Treanda(登録商標));ブスルファン(Busulfex(登録商標)及びMyleran(登録商標));カルボプラチン(Paraplatin(登録商標));ロムスチン(CCNU、CeeNU(登録商標)としても公知);シスプラチン(CDDP、Platinol(登録商標)及びPlatinol(登録商標)-AQとしても公知);クロラムブシル(Leukeran(登録商標));シクロホスファミド(Cytoxan(登録商標)及びNeosar(登録商標));ダカルバジン(DTIC、DIC及びイミダゾールカルボキサミド、DTIC-Dome(登録商標)としても公知);アルトレタミン(ヘキサメチルメラミン(HMM)、Hexalen(登録商標)としても公知);イホスファミド(Ifex(登録商標));プレドヌムスチン(Prednumustine);プロカルバジン(Matulane(登録商標));メクロレタミン(ナイトロジェンマスタード、ムスチン及びメクロレタミン塩酸塩、Mustargen(登録商標)としても公知);ストレプトゾシン(Zanosar(登録商標));チオテパ(チオホスホアミド、TESPA及びTSPA、Thioplex(登録商標)としても公知);シクロホスファミド(Endoxan(登録商標)、Cytoxan(登録商標)、Neosar(登録商標)、Procytox(登録商標)、Revimmune(登録商標));及びベンダムスチンHC1(Treanda(登録商標))が挙げられる。例示的なmTOR阻害剤として、例えば、テムシロリムス;リダフォロリムス(以前はデフェロリムスとして公知、(lR,2R,45)-4-[(2R)-2[(1R,95,125,15R,16E,18R,19R,21R,235,24E,26E,28Z,305,325,35R)-l,18-ジヒドロキシ-19,30-ジメトキシ-15,17,21,23,29,35-ヘキサメチル-2,3,10,14,20-ペンタオキソ-ll,36-ジオキサ-4-アザトリシクロ[30.3.1.04’9]ヘキサトリアコンタ-16,24,26,28-テトラエン-12-イル]プロピル]-2-メトキシシクロヘキシルジメチルホスフィネートとして公知であり、AP23573及びMK8669としても公知、またPCT公開の国際公開第03/064383号パンフレットに記載);エベロリムス(Afinitor(登録商標)又はRADOOl);ラパマイシン(AY22989、Sirolimus(登録商標));シマピモド(simapimod)(CAS164301-51-3);エムシロリムス(emsirolimus)、(5-{2,4-ビス[(35,)-3-メチルモルホリン-4-イル]ピリド[2,3-(i]ピリミジン-7-イル}-2-メトキシフェニル)メタノール(AZD8055);2-アミノ-8-[iraw5,-4-(2-ヒドロキシエトキシ)シクロヘキシル]-6-(6-メトキシ-3-ピリジニル)-4-メチル-ピリド[2,3-JJピリミジン-7(8H)-オン(PF04691502,CAS1013101-36-4);及びN2-[l,4-ジオキソ-4-[[4-(4-オキソ-8-フェニル-4H-l-ベンゾピラン-2-イル)モルホリニウム-4-イル]メトキシ]ブチル]-L-アルギニルグリシル-L-a-アスパルチルL-セリン-、分子内塩(SF1126、CAS936487-67-1)、及びXL765が挙げられる。例示的な免疫調節薬として、例えば、アフツズマブ(Roche(登録商標)から入手可能);ペグフィルグラスチム(Neulasta(登録商標));レナリドミド(CC-5013、Revlimid(登録商標));サリドマイド(Thalomid(登録商標))、アクチミド(CC4047);及びIRX-2(インターロイキン1、インターロイキン2、及びインターフェロンγを含むヒトサイトカインの混合物、CAS951209-71-5、IRX Therapeuticsから入手可能)が挙げられる。例示的なアントラサイクリンとして、例えば、ドキソルビシン(Adriamycin(登録商標)及びRubex(登録商標));ブレオマイシン(lenoxane(登録商標));ダウノルビシン(ダウノルビシン塩酸塩、ダウノマイシン、及びルビドマイシン塩酸塩、Cerubidine(登録商標));ダウノルビシンリポソーム(ダウノルビシンクエン酸塩リポソーム、DaunoXome(登録商標));ミトキサントロン(DHAD、Novantrone(登録商標));エピルビシン(Ellence(商標));イダルビシン(Idamycin(登録商標)、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;及びデアセチルラビドマイシン(desacetylravidomycin)が挙げられる。例示的なビンカアルカロイドとして、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、Alkaban-AQ(登録商標)及びVelban(登録商標)としても公知);及びビノレルビン(Navelbine(登録商標))が挙げられる。例示的なプロテオソーム阻害剤として、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-モルホリノアセトアミド)-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塩(MLN-9708);デランゾミブ(CEP-18770);及び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-セリナミド(ONX-0912)が挙げられる。
例えば、本明細書に記載の状態の治療における、又は本明細書に記載のような応答(例えばがん細胞における減少)を誘導するための活性化CAR T細胞の有効性は、熟練した臨床医により判定されうる。しかし、治療は、用語が本明細書で用いられ、本明細書に記載の状態の徴候又は症状の1つ以上が有利な様式で改変される場合、他の臨床的に認められた症状が改善され、又はさらに寛解され、又は所望される応答が誘導されるとき(例えば本明細書に記載の方法に従う治療後に少なくとも10%)、「有効な治療」と考えられる。有効性は、例えば、本明細書に記載の方法に従って治療される状態のマーカー、指標、症状、及び/若しくは発生率、又は任意の他の測定可能な適切なパラメータを測定することにより評価されうる。本明細書に記載の方法に従う治療は、状態のマーカー又は症状のレベルを、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%若しくは少なくとも90%又はそれ以上低下させうる。
本明細書では、例えばB細胞-NHLを含むCD37陽性悪性腫瘍を治療するための抗CD37キメラ抗原受容体(CAR)を発現する遺伝子組換えT細胞の使用について述べる。これらの例示的なCARは、CD37結合ドメイン、CD8膜貫通ドメイン、4-1BB同時刺激シグナル伝達領域、及びCD3ζシグナル伝達ドメインを含む。他の実施形態では、CD8膜貫通ドメイン、4-1BB同時刺激シグナル伝達領域、及び/又はCD3ζドメインは、別の対応する配列、例えば本明細書に記載のようなもので置き換えることができる。CAR T細胞は、CD37-CARを含むレンチウイルスベクターを一次ヒトT細胞に導入することにより作製することができる。本明細書に記載のインビトロデータは、抗CD37CAR T細胞によるCD37陽性がん細胞の特異的活性化、増殖、及び死滅を示す。
抗CD37キメラ抗原受容体T細胞:B細胞悪性腫瘍に対する新しい有望な治療選択肢
CD37は、成熟B細胞上に発現されるが、初期前駆細胞又は高分化型形質細胞上で不在であるテトラスパニンである。CD37は、非ホジキンリンパ腫(NHL)、例えば、マントル細胞リンパ腫(MCL)、びまん性大細胞型B細胞リンパ腫(DLBCL)、濾胞性リンパ腫(FL)、バーキットリンパ腫及びB細胞慢性リンパ性白血病(CLL)における悪性B細胞上に高度に発現される。したがって、CD37は、B細胞悪性腫瘍、特に共通のB細胞抗原CD19及びCD20を標的にする既存の治療法を回避する変異体における有望な標的を表す。
CAR T-37細胞のインビトロ細胞傷害性活性を、CAR T-37細胞をCD37を発現するヒト腫瘍細胞株(RAJI、OSU-CLL、及びJEKO-1)と異なるエフェクター対標的比で共培養することにより評価した。B細胞悪性腫瘍の複数のモデルにおいて、CD37駆動性のCAR T細胞により、抗原特異的活性化、増殖、サイトカイン産生、及び細胞傷害性活性がインビトロで示された。次に、抗リンパ腫の有効性を、マントル細胞リンパ腫モデルにおいてインビボで評価した。CAR-37治療により、腫瘍細胞が2週以内に除去され、マウスは耐久性寛解を維持した。注射の7日後、CAR T細胞はマウスの血液中で検出可能であった。進行中の試験では、マウスにおけるCAR T細胞の長期持続性を評価中である。
CD37は、B細胞悪性腫瘍において高度に発現される(図10)。抗CD37 CARを、ヒト化抗CD37 mAb BI836826(Boehringer Ingelheim)を用いて構築し、レンチウイルスベクターにクローン化した。細胞内ドメインは、CD3ζに連結された41BB(CD137)ICDである。
scFv配列
CD37 scFv VH-VL(配列番号1)は、VH鎖(アミノ酸1~116(配列番号2))、リンカー領域(アミノ酸117~136(配列番号3))、及びVL鎖(アミノ酸137~244(配列番号4))を含む。
GGGGSGGGGSGGGGSGGGGS(配列番号3)
GGGGSGGGGSGGGGSGGGGS(配列番号7)
CAR配列
pMGH8-CD8リーダー配列(アミノ酸1~21(配列番号10));抗CD37 L-H(アミノ酸22~265(配列番号11));CD8ヒンジ及びTMドメイン(アミノ酸266~334(配列番号12));4-1BB(アミノ酸335~376(配列番号13));及びCD3ζ(アミノ酸377~488(配列番号14))を含むCD8リーダー/抗CD37 L-H/CD8ヒンジ+TM/4-1BB/CD3ζ(配列番号9)
MALPVTALLLPLALLLHAARP(配列番号10)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号13)
MALPVTALLLPLALLLHAARP(配列番号16)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号19)
B細胞悪性腫瘍に対して有効な抗CD37 CAR-T細胞
上記の通り、CD37は、成熟B細胞上に発現されるが、初期前駆細胞又は高分化型形質細胞上で不在であるテトラスパニンである。それは悪性B細胞上に高度に発現され、B細胞悪性腫瘍、特に共通のB細胞抗原CD19及びCD20を標的にする既存の治療法を回避する変異体における有望な標的を表す。本発明者は、B細胞悪性腫瘍を治療するための第1の抗CD37 CAR(CAR-37)を設計した。CART-37細胞のインビトロ細胞傷害性活性を、CART-37細胞をCD37を発現するヒト腫瘍細胞株と異なるエフェクター対標的比で共培養することにより評価した。B細胞悪性腫瘍の複数のモデルにおいて、CD37駆動性のCAR T細胞により、抗原特異的増殖、サイトカイン産生、及び細胞傷害性活性がインビトロで示された。本発明者は、抗リンパ腫の有効性を、マントル細胞リンパ腫モデルにおいてインビボで評価した。CAR-37治療により、腫瘍細胞が2週以内に除去され、マウスは耐久性寛解を維持した。まとめると、これらの結果は、抗CD37 CARを発現するT細胞が、B細胞悪性腫瘍に対してインビトロ及びインビボで実質的活性を有することを示す。これらの知見は、CD37-CAR T細胞が、CD37発現腫瘍を有する患者を治療するための新規な有望な治療薬であることを示した。
ヒト腫瘍細胞株におけるCD37及びCD19の発現
ヒト腫瘍細胞株におけるCD37及びCD19の発現を評価した。図24の上パネルは、図18Aに示すデータを再現し、CD37が、MCL(JEKO-1)、バーキットリンパ腫(RAJI)、及びB細胞慢性リンパ性白血病(OSU-CLL)を含む非ホジキンリンパ腫において高度に発現されるが、ALL細胞株NALM6中に不在であることを示す。図24の下パネルは、MCL患者由来の異種移植片(PDX)株PDX_44685、PDX_98848、及びPDX_96069におけるCD37及びCD19の発現、並びにPDX細胞株におけるCD19及びCD37のパーセント発現を示す。MCL PDX細胞株は、CD37とCD19の双方を発現した。
抗CD37 CAR-T細胞はMCL PDX腫瘍に対して有効である
MCL PDX細胞に対する抗CD37 CAR-T細胞の有効性をインビボで評価した。図25Aは実験模式図を示し;非肥満糖尿病/重症複合免疫不全マウスに1×106のPDX_98848細胞を静脈内注射した。0日目、マウスは、3×106の対照T細胞(UTD)、CAR-37 H-L、又はCAR-19を受けた。3日目、7日目、10日目、14日目、17日目、21日目、及び35日目、腫瘍増殖をBLIにより評価した。PDX増殖の経時的な代表的生物発光画像を図25Bに示す。抗CD37 CARを発現するT細胞は、インビボでMCL PDXに対して強力な抗腫瘍活性を有する(図25A~25C)。
末梢性T細胞リンパ腫(PTCL)におけるCD37の発現
HUT78(皮膚T細胞リンパ腫(CTCL))及びFEPD(未分化大細胞リンパ腫(ALCL))を含むPTCL細胞株において、CD37の発現を評価した(図26A)。両方の細胞株においてCD37が発現された。CAR刺激後、初期活性化マーカーCD69の発現を試験した(図26B及び26C)。
抗CD37 CAR-T細胞はPTCL細胞株に対するインビトロ細胞傷害性活性を有する
PTCL株に対する抗CD37 CAR-T細胞のインビトロ細胞傷害性活性を評価した(図27)。抗CD37 CARを発現するT細胞は、CTCL及びALCL腫瘍モデルを含むPTCL株に対して実質的なインビトロ活性を有する(図27)。これらの知見は、CD37-CAR T細胞が、CTCL及びALCLを含むPTCLを有する患者を治療するための治療薬として有用であることを示した。
AMLにおけるCD37の発現
AMLサンプル中でCD37の発現が検出されている(Pereira et al.,Mol.Cancer Ther.14(7):1650-1660,2015)。AML細胞株におけるCD37の発現を、AML細胞株TF1、MOLM13、及びTHPにおいてフローサイトメトリーにより評価した(図28)。3つ全部のAML細胞株がCD37を発現した(図28)。これらの知見は、CD37-CAR T細胞が、AMLを有する患者を治療するための治療薬として有用であることを示した。
a.CD37結合配列を含む細胞外ドメイン;
b.膜貫通ドメイン;及び
c.T細胞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。
b.パラグラフ1~17のいずれか1つのCARポリペプチドのいずれか1つをコードする核酸
を含む哺乳動物細胞。
a.T細胞を、T細胞表面上のパラグラフ1~17のいずれか1つのCARポリペプチドを含むように改変することと;
b.改変されたT細胞を対象に投与することと、
を含む、方法。
a.抗CD19及び/又は抗CD20療法に対して非応答性である対象を選択することと;
b.T細胞を、T細胞表面上のパラグラフ1~17のいずれか1つのCARポリペプチドを含むように改変することと;
c.改変されたT細胞を対象に投与することと、
を含み、対象が抗CD19及び/又は抗CD20療法に対して非応答性である、方法。
a.抗CD19及び/又は抗CD20療法に対して非応答性である対象を選択することと;
b.パラグラフ18~21のいずれか1つの細胞を対象に投与することと、
を含み、ここで細胞がCD37結合配列を含む細胞外ドメインを含むCARを含み、且つ対象が抗CD19及び/又は抗CD20療法に対して非応答性である、方法。
a.T細胞を、T細胞表面上のパラグラフ1~17のいずれか1つのCARポリペプチドを含むように改変することと;
b.改変されたT細胞を対象に投与することと;
を含み、対象に抗CD19及び/又は抗CD20療法が同時に施される、方法。
対象に抗CD19及び/又は抗CD20療法が同時に施される、方法。
Claims (35)
- a)CD37結合配列を含む細胞外ドメイン;
b)膜貫通ドメイン;及び
c)T細胞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。 - 共刺激ドメインをさらに含む、請求項1に記載のCARポリペプチド。
- 前記CD37結合配列が抗体試薬を含む、請求項1又は2に記載のCARポリペプチド。
- 前記抗体試薬が一本鎖抗体(scFv)を含む、請求項3に記載のCARポリペプチド。
- 前記scFvが、抗体重鎖に対する抗体軽鎖N末端を含む、請求項4に記載のCARポリペプチド。
- 前記scFvが、抗体軽鎖に対する抗体重鎖N末端を含む、請求項4に記載のCARポリペプチド。
- 前記抗体軽鎖が、配列番号4若しくは6の配列、若しくはその変異体を含み、且つ/又は前記重鎖が、配列番号2若しくは8の配列、若しくはその変異体を含む、請求項5又は6に記載のCARポリペプチド。
- 前記抗体試薬が、配列番号1若しくは5から選択される配列、又はその変異体を含む、請求項3~7のいずれか一項に記載のCARポリペプチド。
- 前記膜貫通ドメインが、CD8又は4-1BBからの前記膜貫通ドメインを含む、請求項1~7のいずれか一項に記載のCARポリペプチド。
- 前記膜貫通ドメインが、配列番号12若しくは18の配列、又はその変異体を含む、請求項8に記載のCARポリペプチド。
- 前記共刺激ドメインが、4-1BBの前記共刺激ドメインを含む、請求項2~8のいずれか一項に記載のCARポリペプチド。
- 前記共刺激ドメインが、配列番号13若しくは19の配列、又はその変異体を含む、請求項11に記載のCARポリペプチド。
- 前記T細胞細胞内ドメインが、CD3ζ細胞内シグナル伝達ドメインを含む、請求項1~12のいずれか一項に記載のCARポリペプチド。
- 前記CD3ζ細胞内シグナル伝達ドメインが、配列番号14若しくは20の配列、又はその変異体を含む、請求項13に記載のCARポリペプチド。
- 前記CD3ζ細胞内シグナル伝達ドメインが、1、2、又は3の免疫受容体チロシンに基づく活性化モチーフ(ITAM)を含み、且つ前記ITAMの天然チロシン残基が維持される、請求項14に記載のCARポリペプチド。
- 前記CD3ζ細胞内シグナル伝達ドメインが、配列番号14又は20の配列を含む、請求項14に記載のCARポリペプチド。
- 配列番号9若しくは15の配列、又はその変異体を含む、請求項1~16のいずれか一項に記載のCARポリペプチド。
- a)請求項1~16のいずれか一項に記載のCARポリペプチド;又は
b)請求項1~17のいずれか一項に記載のCARポリペプチドのいずれか1つをコードする核酸
を含む哺乳動物細胞。 - T細胞である、請求項18に記載の細胞。
- ヒト細胞である、請求項18又は19に記載の細胞。
- がん、形質細胞障害、又は自己免疫疾患を有する又は有すると診断された個体から得られる、請求項18~20のいずれか一項に記載の細胞。
- がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、
a)T細胞を、前記T細胞表面上に請求項1~17のいずれか一項に記載のCARポリペプチドを含むように改変することと;
b)前記改変されたT細胞を前記対象に投与することと、
を含む、方法。 - がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、請求項18~21のいずれか一項に記載の細胞を前記対象に投与することを含む、方法。
- 前記がんがCD37+がんである、請求項22又は23に記載の方法。
- 前記CD37+がんが、リンパ腫又は白血病である、請求項24に記載の方法。
- 前記リンパ腫が、B細胞非ホジキンリンパ腫(NHL)、マントル細胞リンパ腫、バーキットリンパ腫、B細胞リンパ芽球性リンパ腫、又はT細胞リンパ腫である、又は前記白血病が、急性骨髄性白血病(AML)である、請求項25に記載の方法。
- 前記T細胞リンパ腫が、末梢性T細胞リンパ腫(PTCL)である、請求項26に記載の方法。
- 前記PTCLが、皮膚T細胞リンパ腫(CTCL)又は未分化大細胞リンパ腫(ALCL)である、請求項27に記載の方法。
- がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、請求項18~21のいずれか一項に記載の細胞を前記対象に投与することを含み、前記細胞がCD37結合配列を含む細胞外ドメインを含むCARを含み、且つ前記対象が抗CD19及び/又は抗CD20療法に対して非応答性である、方法。
- がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、
a)抗CD19及び/又は抗CD20療法に対して非応答性である対象を選択することと;
b)T細胞を、前記T細胞表面上に請求項1~17のいずれか一項に記載のCARポリペプチドを含むように改変することと;
c)前記改変されたT細胞を前記対象に投与することと、
を含み、前記対象が抗CD19及び/又は抗CD20療法に対して非応答性である、方法。 - がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、
a)抗CD19及び/又は抗CD20療法に対して非応答性である対象を選択することと;
b)請求項18~21のいずれか一項に記載の細胞を前記対象に投与することと、
を含み、前記細胞がCD37結合配列を含む細胞外ドメインを含むCARを含み、且つ前記対象が抗CD19及び/又は抗CD20療法に対して非応答性である、方法。 - がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、
a)T細胞を、前記T細胞表面上に請求項1~17のいずれか一項に記載のCARポリペプチドを含むように改変することと;
b)前記改変されたT細胞を前記対象に投与することと、
を含み、前記対象に抗CD19及び/又は抗CD20療法が同時に施される、方法。 - がん、形質細胞障害、又は自己免疫疾患の治療を、それを必要とする対象において行う方法であって、請求項18~21のいずれか一項に記載の細胞を前記対象に投与することを含み、前記細胞がCD37結合配列を含む細胞外ドメインを含むCARを含み、
前記対象に抗CD19及び/又は抗CD20療法が同時に施される、方法。 - がんの治療用に処方される、請求項1~17のいずれか一項に記載のCARポリペプチド又は請求項18~21のいずれか一項に記載の細胞を含む組成物。
- 薬学的に許容できる担体をさらに含む、請求項34に記載の組成物。
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