JP2021531004A - Bcma特異性を有するキメラ抗原受容体およびその使用 - Google Patents
Bcma特異性を有するキメラ抗原受容体およびその使用 Download PDFInfo
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Abstract
Description
本出願は、2019年7月17日に作成され、66,907バイトを含むファイル10455WO01−Sequence.txtとしてコンピュータ可読形式で提出された配列表を参照により組み入れる。
本明細書で使用される「BCMA」という表現は、B細胞成熟抗原を指す。BCMA(TNFRSF17およびCD269としても既知)は、悪性形質細胞上に発現する細胞表面タンパク質であり、B細胞の成熟および免疫グロブリン産生形質細胞への分化の調節において中心的な役割を果たす。本明細書で使用される場合、「BCMA」は、非ヒト種(例えば、「マウスBCMA」、「サルBCMA」など)に由来するものとして特定されない限り、ヒトBCMAタンパク質を指す。ヒトBCMAタンパク質は、配列番号101に示されるアミノ酸配列を有する。
キメラ抗原受容体(CAR)は、細胞表面上に発現する抗体認識抗原(例えば、癌細胞)に対するT細胞特異性をリダイレクトするが、T細胞受容体(TCR)は標的の範囲を拡大して細胞内抗原(例えば、腫瘍抗原)を含む。
本明細書で使用される場合、キメラ抗原受容体または対応する抗体が、例えば、細胞表面タンパク質もしくはそのフラグメントなどの所定の抗原のいずれかへ結合する文脈における「結合」という用語は、最低2つの実体もしくは抗原結合ドメイン:抗原相互作用などの分子構造間の相互作用または会合を指す。
本明細書のキメラ抗原受容体は、対応する抗体の個々の抗原結合ドメインが由来した対応する生殖系列配列と比較して、重鎖および軽鎖可変ドメインのフレームワークおよび/またはCDR領域に1つ以上のアミノ酸置換、挿入および/または欠失を含み得る。そのような変異は、本明細書に開示されるアミノ酸配列を、例えば、公共の抗体配列データベースから入手可能な生殖系列配列と比較することによって容易に確認することができる。本発明のキメラ抗原受容体は、本明細書に開示する例示的なCDRまたは可変領域アミノ酸配列のいずれかに由来する抗原結合ドメインを含んでもよく、1つ以上のフレームワークおよび/またはCDR領域内の1つ以上のアミノ酸は、対応する抗体が由来した生殖系列配列の対応する残基(複数可)へ、または別のヒト生殖系列配列の対応する残基(複数可)へ、または対応する生殖系列残基(複数可)の保存的アミノ酸置換へ変異する(このような配列変化はまとめて、「生殖系列変異」と本明細書で呼ばれる)。当業者であれば、本明細書に開示される重鎖可変領域配列および軽鎖可変領域配列から出発して、1つ以上の個々の生殖系列変異またはこれらの組み合わせを含む多数の抗体を容易に産生することができる。特定の実施形態において、VHドメインおよび/またはVLドメイン内のフレームワークおよび/またはCDR残基はすべて、抗原結合ドメインが由来した元の生殖系列配列において認められる残基へと戻り変異する。他の実施形態では、ある特定の残基のみが元の生殖系列配列へと変異し戻され、例えば、変異した残基はFR1の最初の8個のアミノ酸内に、もしくは変異した残基はFR4の最後の8個のアミノ酸内に認められ、または変異した残基は、CDR1、CDR2もしくはCDR3内にのみ認められる。他の実施形態では、フレームワークおよび/またはCDR残基(複数可)の1つ以上は、異なる生殖系列配列(すなわち、抗原結合ドメインが本来由来した生殖系列配列とは異なる生殖系列配列)の対応する残基(複数可)へ変異する。さらに、抗原結合ドメインは、フレームワークおよび/またはCDR領域内に2つ以上の生殖系列変異のいずれかの組み合わせを含有してもよく、例えば、特定の個々の残基は、特定の生殖系列配列の対応する残基へ変異するのに対し、元の生殖系列配列とは異なるある特定の他の残基は維持され、または異なる生殖系列配列の対応する残基へ変異する。
本発明は、高い親和性(例えば、ナノモル以下のKD値)を有するヒトBCMAに結合する抗体に由来する抗原結合ドメインを有するキメラ抗原受容体を含む。
特定の抗原(例えば、BCMA)に特異的な、本発明のキメラ抗原受容体の抗原結合ドメインは、当技術分野で既知の任意の抗体産生技術によって調製することができる。ある特定の実施形態では、本発明の対応する抗体の1つ以上の個々の成分(例えば、重鎖および軽鎖)は、キメラ抗体、ヒト化抗体または完全ヒト型抗体に由来する。そのような抗体を作製するための方法は、当技術分野で周知である。例えば、重鎖および/または軽鎖のうちの1つ以上は、VELOCIMMUNE(商標)技術を使用して調製することができる。VELOCIMMUNE(商標)技術(または任意の他のヒト抗体生成技術)を使用して、特定の抗原(例えば、BCMA)に対する高親和性キメラ抗体が、ヒト可変領域およびマウス定常領域を有して最初に単離される。抗体は、親和性、選択性、エピトープなどを含む望ましい特性について特徴付けられ、選択される。本明細書で論じられるように、次に、これらのヒト可変領域(またはCDR)は、キメラ抗原受容体の抗原結合ドメインに組み込まれ得る。
本発明はまた、本明細書で論じられるキメラ抗原受容体をコードするポリヌクレオチドおよびベクターに関する。
本発明は、エクスビボで、そのような免疫細胞に、本明細書に記載のBCMA特異的キメラ抗原受容体の1つをコードするポリヌクレオチドまたはベクターを導入することを含む免疫療法のための免疫細胞を調製する方法を包含する。
本発明のキメラ抗原受容体を含む免疫細胞(または操作された免疫細胞)は、本発明の別の目的である。場合によっては、免疫細胞は、免疫エフェクター細胞である。場合によっては、免疫細胞は、T細胞である。場合によっては、免疫細胞は、炎症性Tリンパ球、細胞傷害性Tリンパ球、制御性Tリンパ球、またはヘルパーTリンパ球から選択されるTリンパ球である。場合によっては、免疫細胞は、CD8+細胞傷害性Tリンパ球である。
本発明は、本明細書に開示される例示的な分子のものとは異なるが、BCMAに結合する能力を保持し、BCMAを発現する細胞の存在下でキメラ抗原受容体を発現する免疫細胞を活性化し、またはBCMAを発現する腫瘍細胞の成長もしくは増殖を抑制するアミノ酸配列を有するキメラ抗原受容体およびキメラ抗原受容体を発現する操作された細胞を包含する。このような変異体抗体は、親配列と比較してアミノ酸の1つ以上の付加、欠失、または置換を含むが、説明された二重特異性抗原結合分子の生物学的活性とは本質的に等価である生物学的活性を呈する。
本発明の特定の実施形態によると、ヒトBCMAに結合するが他の種由来のBCMAには結合しない抗原結合ドメインが提供される。本発明はまた、ヒトBCMAおよび1つ以上の非ヒト種由来のBCMAに結合する抗原結合ドメインを含む。
操作された細胞(例えば、T細胞)の遺伝子改変の前または後であるかどうかにかかわらず、本発明の遺伝子改変免疫細胞が活性化され、抗原結合機序とは無関係に増殖したとしても、免疫細胞、特に本発明のT細胞は、例えば、米国特許第6,352,694号;第6,534,055号;第6,905,680号;第6,692,964号;第5,858,358号;第6,887,466号;第6,905,681号;第7,144,575号;第7,067,318号;第7,172,869号;第7,232,566号;第7,175,843号;第5,883,223号;第6,905,874号;第6,797,514号;第6,867,041号;および米国特許出願公開第2006/0121005号に記載されるような方法を使用して一般的にさらに活性化ならびに拡大することができる。T細胞は、インビトロまたはインビボで拡大させることができる。
本発明は、本発明のキメラ抗原受容体を発現する操作された細胞(例えば、T細胞)および薬学的に許容されるビヒクルを含む組成物を含む。場合によっては、操作された細胞は、特に免疫療法のための薬剤を形成する。場合によっては、操作された細胞は、癌(例えば、多発性骨髄腫)の治療に使用される。場合によっては、操作された細胞は、免疫療法および/または癌(例えば、BCMAを発現する癌)の治療のための薬剤の製造に使用される。
本発明は、本明細書に記載のキメラ抗原受容体のいずれかを含む操作された細胞または細胞の集団を、1つ以上の追加の治療剤と組み合わせて、投与することを含む方法を提供する。本発明の細胞もしくは細胞の集団と組み合わせて、または組み合わせて投与することができる例示的な追加の治療剤は、例えば、抗腫瘍剤(例えば、メルファラン、ビンクリスチン(オンコビン)、シクロホスファミド(シトキサン)、エトポシド(VP−16)、ドキソルビシン(アドリアマイシン)、リポソームドキソルビシン(ドキシル)、オベンダムスチン(Treanda)を含む化学療法剤、または対象における形質細胞腫瘍の治療に有効であることが知られている任意の他のもの)を含む。いくつかの実施形態では、第2の治療剤は、ステロイドを含む。いくつかの実施形態では、第2の治療剤は、サリドマイド、レナリドマイド、およびボルテゾミブを含む標的療法を含み、これらは、新たに診断された患者を治療するために承認された療法である。レナリドミド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、パノビノスタット、イキサゾミブ、エロツズマブ、およびダラツムマブは、再発性骨髄腫を治療するために有効な第2の治療剤の例である。ある特定の実施形態では、第2の治療剤は、放射線療法または幹細胞移植を含むレジメンである。ある特定の実施形態では、第2の治療剤は、免疫調節剤であり得る。ある特定の実施形態では、第2の治療剤は、ボルテゾミブ(Velcade)、カルフィルゾミブ(Kyprolis)、イキサゾミブ(Ninlaro)を含むプロテアソーム阻害剤であり得る。ある特定の実施形態では、第2の治療剤は、パノビノスタット(Farydak)などのヒストンデアセチラーゼ阻害剤であり得る。ある特定の実施形態では、第2の治療剤は、モノクローナル抗体、抗体薬物コンジュゲート、抗腫瘍剤にコンジュゲートした二重特異性抗体、チェックポイント阻害剤、またはそれらの組み合わせであり得る。本発明の抗原結合分子と組み合わせて有益に投与され得る他の薬剤には、小分子サイトカイン阻害剤およびIL−1、IL−2、IL−3、IL−4、IL−5、IL−6、IL−8、IL−9、IL−11、IL−12、IL−13、IL−17、IL−18などのサイトカインに結合する抗体、またはそれらのそれぞれの受容体を含むサイトカイン阻害剤が含まれる。本発明の薬学的組成物(例えば、本明細書に開示される、操作された細胞または細胞の集団を含む薬学的組成物)はまた、形質細胞表面上の異なる抗原と相互作用し得る本明細書に記載の抗体以外のモノクローナル抗体、腫瘍細胞表面上の抗原に結合する一方のアームおよびT細胞上の抗原に結合する他方のアームを有する二重特異性抗体、抗体薬物コンジュゲート、抗腫瘍剤にコンジュゲートした二重特異性抗体、チェックポイント阻害剤、例えば、PD−1またはCTLA−4を標的化するもの、またはそれらの組み合わせ、から選択される1つ以上の治療的組み合わせを含む治療レジメンの一部として投与され得る。ある特定の実施形態では、チェックポイント阻害剤は、ペンブロリズマブ(Keytruda)、ニボルマブ(Opdivo)、またはセミプリマブ(REGN2810)などのPD−1阻害剤から選択され得る。ある特定の実施形態では、チェックポイント阻害剤は、アテゾリズマブ(Tecentriq)、アベルマブ(Bavencio)、またはデュルバルマブ(Imfinzi)などのPD−L1阻害剤から選択され得る。ある特定の実施形態では、チェックポイント阻害剤は、イピリムマブ(Yervoy)などのCTLA−4阻害剤から選択され得る。
本発明のある特定の実施形態によれば、操作された細胞の複数回用量は、既定される時間経過にわたって対象に投与され得る。本発明のこの態様による方法は、細胞の複数回用量を対象に連続的に投与することを含む。本発明で使用する場合、「連続的に投与すること」は、各用量が、異なる時点、例えば、所定の間隔(例えば、数時間、数日、数週間、または数か月)よって分けられた異なる日に、対象へ投与されることを意味する。本発明には、単回の一次用量と、それに続く1回以上の二次用量、次いで場合により1回以上の三次用量を患者へ連続的に投与することを含む方法が含まれる。
抗BCMA抗体は、遺伝子改変されたマウスをヒトBCMA抗原(例えば、hBCMA、配列番号101)で免疫することによって、またはヒト免疫グロブリン重鎖およびカッパ軽鎖可変領域をコードするDNAを含む操作されたマウスをヒトBCMA抗原で免疫することによって得られた。
6つの抗BCMA抗体(mAb16711、mAb16716、mAb16732、mAb16747およびmAb21581)をVL−VH一本鎖可変フラグメント(ScFv)に再フォーマットし、CD8αヒンジおよび膜貫通ドメイン、4−1BB共刺激ドメインならびにCD3ζ刺激ドメインに使用するキメラ抗原受容体(CAR)構築物に配置した。BCMA特異的CARを、(Lenti−X(商標)バイシストロン性発現システム(Neo)、Clontech カタログ番号632181)にクローニングし、レンチウイルス粒子を、Lenti−X Packaging Single−Shot(VSV−G)システム(Clontech カタログ番号631276)を介して、製造元のプロトコルに従って生成した。NFAT−ルシフェラーゼレポーター(Jurkat/NFATLuc.3C7)を発現するように操作されたJurkat細胞を、次に、RetroNectin(登録商標)プレコートディッシュ(Clontech、カタログ番号T110a)を使用して、製造元のプロトコルに従って異なるCAR構築物で形質導入した。500μg/ml G418(Gibco、カタログ番号11811−098)中で少なくとも2週間選択した後、次のCAR−T細胞株を生成した;Jurkat/NFATLuc cl.3C7/BCMA 16716 VL−VH CART、Jurkat/NFATLuc cl.3C7/BCMA 16711 VL−VH CART、Jurkat/NFATLuc cl.3C7/BCMA 16732VL−VH CART、Jurkat/NFATLuc cl.3C7/BCMA 16747VL−VH CART、Jurkat/NFATLuc cl.3C7/BCMA 21581VL−VH CART。これらのCAR−T細胞株の生成に使用されるCAR構築物のヌクレオチド配列は、図1に示すように、配列番号81(mAb16711 VL/VH)、配列番号83(mAb16716 VL/VH)、配列番号85(mAb16732 VL/VH)、配列番号87(mAb16747 VL/VH)および配列番号89(mAb21581 VL/VH)に示される。これらの6つのCAR−T細胞株は、実施例3で論じられるように、BCMA CAR−T細胞の細胞表面発現および活性化を評価するために使用された。
Jurkat/NFATLuc細胞におけるBCMA CAR構築物の関連する細胞表面発現は、フローサイトメトリーによってアクセスされた。染色するために、細胞を、96ウェルV字底プレートのウェルあたり200,000個の細胞の密度で、染色緩衝液(PBS、カルシウムおよびマグネシウムを含まない(Irving 9240)+2%FBS(ATCC 30−2020)に播き、hIgG1−Fc(BCMA ecto−hFc)に融合された10ug/mlのBCMA細胞外ドメインまたはhIgG1−Fc(Fcアイソタイプ対照)に融合された無関係のタンパク質によって4℃で30分間染色した。BCMA−hFcまたはFcアイソタイプ対照と一緒にインキュベートした後、細胞を染色緩衝液で1回洗浄し、10μg/mlのAlexa−Flour647コンジュゲート二次抗体(Jackson ImmunoResearch、カタログ番号109−606−170)を用いて30分間4℃で染色した。次に、細胞を洗浄し、染色緩衝液で希釈したBD Cytofix(BD、カタログ番号554655)の50%溶液を使用して、固定した。サンプルをIntellicyt iQueフローサイトメーターで実行し、Flowjo 10.2で分析し、平均蛍光強度(MFI)を計算した。信号対雑音比(S:N)は、BCMA−hFcまたはFcアイソタイプ対照 MFIと二次抗体単独 MFIの比率をとることによって決定される。
BCMA標的キメラ抗原受容体(CAR)T細胞のインビボでの有効性を決定するために、高レベルのBCMAを発現するOPM−2ヒト多発性骨髄腫細胞を使用して、マウスにおいて異種腫瘍研究を実施した。
BCMA標的キメラ抗原受容体(CAR)T細胞のインビボでの有効性を決定するために、低レベルのBCMAを発現するMOLP−8ヒト多発性骨髄腫細胞を使用して、マウスにおいて異種腫瘍研究を実施した。
実施例2において上記で論じられるように、CD3+T細胞は、ヒト末梢血単核細胞(PBMC)からを単離され、CD3/CD28マイクロビーズ+100U/ml組換えヒトIL−2で刺激され、MOI=5でレンチウイルスによって形質導入された。形質導入細胞は、CD3/CD28マイクロビーズ+100U/ml組換えヒトIL−2で3週間拡大させた後、細胞溶解アッセイを設定した。
実施例2において上記で論じられるように、CD3+T細胞は、ヒト末梢血単核細胞(PBMC)からを単離され、CD3/CD28マイクロビーズ+100U/ml組換えヒトIL−2で刺激され、MOI=5でレンチウイルスによって形質導入された。形質導入細胞は、CD3/CD28マイクロビーズ+100U/ml組換えヒトIL−2で3週間拡大させた後、細胞傷害性アッセイを設定した。
Claims (68)
- N末端からC末端へ、(a)抗BCMA抗原結合ドメインを含む細胞外リガンド結合ドメインと、(b)ヒンジと、(c)膜貫通ドメインと、(d)共刺激ドメインおよびシグナリングドメインを含む細胞質ドメインと、を含むB細胞成熟抗原(BCMA)特異的キメラ抗原受容体。
- 前記細胞外リガンド結合ドメインは、軽鎖可変領域(LCVR)および重鎖可変領域(HCVR)を含む抗BCMA一本鎖可変フラグメント(scFv)ドメインを含み、任意に、前記抗BCMAscFvドメインは、前記LCVRと前記HCVRとの間のリンカーを含む、請求項1に記載のキメラ抗原受容体。
- 前記細胞外リガンド結合ドメインと前記ヒンジとの間のリンカーをさらに含む、請求項1または2に記載のキメラ抗原受容体。
- 前記リンカーは、配列番号93〜96からなる群から選択されるアミノ酸配列を含む、請求項1〜3のいずれか一項に記載のキメラ抗原受容体。
- 前記ヒンジ、前記膜貫通ドメイン、またはそれらの両方はCD8αポリペプチドに由来する、請求項1〜4のいずれか一項に記載のキメラ抗原受容体。
- 前記共刺激ドメインは、4−1BB共刺激ドメインを含む、請求項1〜5のいずれか一項に記載のキメラ抗原受容体。
- 前記シグナリングドメインは、CD3ゼータシグナリングドメインを含む、請求項1〜6のいずれか一項に記載のキメラ抗原受容体。
- 前記LCVRは、配列番号10、26、42、58および74からなる群から選択されるアミノ酸配列を含むLCVRの相補性決定領域(CDR)を含む、請求項1〜7のいずれか一項に記載のキメラ抗原受容体。
- 前記LCVRは、それぞれ、配列番号12−14−16、28−30−32、44−46−48、60−62−64、または76−78−80のアミノ酸配列を含むLCDR1−LCDR2−LCDR3ドメインを含む、請求項8に記載のキメラ抗原受容体。
- 前記HCVRは、配列番号2、18、34、50および66からなる群から選択されるアミノ酸配列を含むHCVRのCDRを含む、請求項1〜9のいずれか一項に記載のキメラ抗原受容体。
- 前記HCVRは、それぞれ、配列番号4−6−8、20−22−24、36−38−40、52−54−56、または68−70−72のアミノ酸配列を含むHCDR1−HCDR2−HCDR3ドメインを含む、請求項10に記載のキメラ抗原受容体。
- 前記LCVRは、配列番号10、26、42、58および74からなる群から選択されるアミノ酸配列、または配列番号10、26、42、58および74からなる群から選択されるアミノ酸配列と95%〜99%の配列同一性を有するアミノ酸配列を含み、前記HCVRは、配列番号2、18、34、50および66からなる群から選択されるアミノ酸配列、または配列番号2、18、34、50および66からなる群から選択されるアミノ酸配列と95%〜99%の配列同一性を有するアミノ酸配列を含む、請求項1〜11のいずれか一項に記載のキメラ抗原受容体。
- 前記LCVRは、配列番号10、26、42、58および74からなる群から選択されるアミノ酸配列を含み、前記HCVRは、配列番号2、18、34、50および66からなる群から選択されるアミノ酸配列を含む、請求項12に記載のキメラ抗原受容体。
- 前記scFvドメインは、配列番号10/2、26/18、42/34、58/50または74/66のアミノ酸配列を含むLCVR/HCVRアミノ酸配列対を含む、請求項13に記載のキメラ抗原受容体。
- 前記ヒンジは、配列番号97のアミノ酸配列を含む、請求項1〜14のいずれか一項に記載のキメラ抗原受容体。
- 前記膜貫通ドメインは、配列番号98のアミノ酸配列を含む、請求項1〜15のいずれか一項に記載のキメラ抗原受容体。
- 前記4−1BB共刺激ドメインは、配列番号99のアミノ酸配列を含む、請求項1〜16のいずれか一項に記載のキメラ抗原受容体。
- 前記CD3ゼータシグナリングドメインは、配列番号100のアミノ酸配列を含む、請求項1〜17のいずれか一項に記載のキメラ抗原受容体。
- 配列番号82、配列番号84、配列番号86、配列番号88、または配列番号90のアミノ酸配列を含む、請求項1に記載のキメラ抗原受容体。
- 配列番号82のアミノ酸配列を含む、請求項19に記載のキメラ抗原受容体。
- 配列番号84のアミノ酸配列を含む、請求項19に記載のキメラ抗原受容体。
- 配列番号86のアミノ酸配列を含む、請求項19に記載のキメラ抗原受容体。
- 配列番号88のアミノ酸配列を含む、請求項19に記載のキメラ抗原受容体。
- 配列番号90のアミノ酸配列を含む、請求項19に記載のキメラ抗原受容体。
- 請求項1〜24のいずれか一項に記載のキメラ抗原受容体をコードする単離された核酸分子。
- 配列番号81、83、85、87および89からなる群から選択されるヌクレオチド配列を含む、請求項25に記載の核酸分子。
- 請求項25または26に記載の核酸分子を含むベクター。
- 前記ベクターは、DNAベクター、RNAベクター、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、またはレトロウイルスベクターである、請求項27に記載のベクター。
- 前記ベクターはレンチウイルスベクターである、請求項28に記載のベクター。
- 請求項25もしくは26に記載の核酸分子、または請求項27〜29のいずれか一項に記載のベクターを含む細胞。
- 前記細胞はヒトT細胞である、請求項30に記載の細胞。
- 請求項1〜24のいずれか一項に記載のキメラ抗原受容体を含む操作された細胞。
- 免疫細胞である、請求項32に記載の操作された細胞。
- 前記免疫細胞は免疫エフェクター細胞である、請求項33に記載の操作された細胞。
- 前記免疫エフェクター細胞はTリンパ球である、請求項34に記載の操作された細胞。
- 前記Tリンパ球は、炎症性Tリンパ球、細胞傷害性Tリンパ球、制御性Tリンパ球、またはヘルパーTリンパ球である、請求項35に記載の操作された細胞。
- CD8+細胞傷害性Tリンパ球である、請求項36に記載の操作された細胞。
- BCMAを発現する癌の治療に使用するための、請求項32〜37のいずれか一項に記載の操作された細胞。
- 前記BCMAを発現する癌は多発性骨髄腫である、請求項38に記載の操作された細胞。
- N末端からC末端へ、(a)軽鎖可変領域(LCVR)および重鎖可変領域(HCVR)を含む抗BCMA一本鎖可変フラグメント(scFv)ドメインを含む細胞外リガンド結合ドメインと、(b)ヒンジと、(c)膜貫通ドメインと、(d)4−1BB共刺激ドメインおよびCD3ゼータシグナリングドメインを含む細胞質ドメインと、を含むキメラ抗原受容体を含む操作されたヒトT細胞。
- 前記scFvドメインは、配列番号10/2、26/18、42/34、58/50または74/66のアミノ酸配列を含むLCVR/HCVRアミノ酸配列対を含む、請求項40に記載の操作されたヒトT細胞。
- 前記ヒンジは、配列番号97のアミノ酸配列を含む、請求項40または41に記載の操作されたヒトT細胞。
- 前記膜貫通ドメインは、配列番号98のアミノ酸配列を含む、請求項40〜42のいずれか一項に記載の操作されたヒトT細胞。
- 前記4−1BB共刺激ドメインは、配列番号99のアミノ酸配列を含む、請求項40〜43のいずれか一項に記載の操作されたヒトT細胞。
- 前記CD3ゼータシグナリングドメインは、配列番号100のアミノ酸配列を含む、請求項40〜44のいずれか一項に記載の操作されたヒトT細胞。
- 配列番号82のアミノ酸配列を含むキメラ抗原受容体を含む、請求項40に記載の操作されたヒトT細胞。
- 配列番号84のアミノ酸配列を含むキメラ抗原受容体を含む、請求項40に記載の操作されたヒトT細胞。
- 配列番号86のアミノ酸配列を含むキメラ抗原受容体を含む、請求項40に記載の操作されたヒトT細胞。
- 配列番号88のアミノ酸配列を含むキメラ抗原受容体を含む、請求項40に記載の操作されたヒトT細胞。
- 配列番号90のアミノ酸配列を含むキメラ抗原受容体を含む、請求項40に記載の操作されたヒトT細胞。
- 遺伝子改変ヒトT細胞および薬学的に許容される担体を含む薬学的組成物であって、前記遺伝子改変ヒトT細胞は、請求項1〜24のいずれか一項に記載のキメラ抗原受容体を含む、薬学的組成物。
- 請求項32〜37のいずれか一項に記載の操作された細胞および薬学的に許容される担体を含む薬学的組成物。
- 請求項40〜50のいずれか一項に記載の操作された細胞および薬学的に許容される担体を含む薬学的組成物。
- BCMAを発現する癌の治療に使用するための、請求項51〜53のいずれか一項に記載の薬学的組成物。
- 前記BCMAを発現する癌は多発性骨髄腫である、請求項54に記載の薬学的組成物。
- BCMAを発現する癌の治療のための薬剤の製造における、請求項1〜24のいずれか一項に記載のキメラ抗原受容体、請求項25もしくは26に記載の核酸分子、請求項27〜29のいずれか一項に記載のベクター、請求項30もしくは31に記載の細胞、または請求項32〜37もしくは40〜50のいずれか一項に記載の操作された細胞、の使用。
- 前記BCMAを発現する癌は多発性骨髄腫である、請求項56に記載の使用。
- 対象におけるTリンパ球活性を強化する方法であって、請求項1〜24のいずれか一項に記載のキメラ抗原受容体を含むTリンパ球を前記対象に導入することを含む、方法。
- 癌に罹患している対象を治療するための方法であって、請求項1〜24のいずれか一項に記載のキメラ抗原受容体を含むTリンパ球の治療有効量を前記対象に導入することを含む、方法。
- 対象の標的細胞集団または組織に対するT細胞媒介性免疫応答を刺激するための方法であって、請求項1〜24のいずれか一項に記載のキメラ抗原受容体を発現するために遺伝子改変された細胞の有効量を前記対象に投与することを含む、方法。
- 対象に抗腫瘍免疫を提供する方法であって、請求項1〜24のいずれか一項に記載のキメラ抗原受容体を発現するために遺伝子改変された細胞の有効量を前記対象に投与することを含む、方法。
- 前記対象はヒトである、請求項58〜61のいずれか一項に記載の方法。
- 前記対象は、多発性骨髄腫、B系統急性リンパ芽球性白血病、B細胞慢性リンパ性白血病、B細胞非ホジキンリンパ腫、白血病およびリンパ腫、急性リンパ芽球性白血病、ホジキンリンパ腫、または小児急性リンパ芽球性白血病に罹患している、請求項58〜62のいずれか一項に記載の方法。
- 前記対象は多発性骨髄腫に罹患している、請求項63に記載の方法。
- キメラ抗原受容体を発現するために細胞の集団を操作する方法であって、
(a)免疫細胞の集団を提供することと、
(b)請求項1〜24のいずれか一項に記載のキメラ抗原受容体をコードする核酸分子を前記免疫細胞に導入することと、
(c)前記核酸分子を発現する条件下で前記免疫細胞を培養することと、
(d)前記細胞表面で前記キメラ抗原受容体を発現する前記免疫細胞を単離することと、を含む、方法。 - 前記核酸分子を導入する前に、対象から前記免疫細胞の集団を取得することをさらに含む、請求項65に記載の方法。
- 対象におけるBCMAを発現する癌を治療する方法であって、
(a)請求項66に記載の細胞の集団を操作することと、
(b)前記キメラ抗原受容体を発現する前記免疫細胞の集団を前記対象に再導入することと、を含む、方法。 - 前記BCMAを発現する癌は多発性骨髄腫である、請求項67に記載の方法。
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