JP2022513652A - 機能および抑制性環境に対する抵抗性を増強するための免疫細胞のマルチプレックスゲノム編集 - Google Patents
機能および抑制性環境に対する抵抗性を増強するための免疫細胞のマルチプレックスゲノム編集 Download PDFInfo
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Abstract
Description
本願は、2018年11月28日出願の米国仮特許出願第62/772,406号に対する優先権を主張する。この仮出願は、その全体が参照により本明細書中に援用される。
I.定義
II.マルチプレックス遺伝子編集
III.阻害性遺伝子の遺伝子座におけるCARおよび/またはTCRの挿入
IV.免疫細胞
A.T細胞
B.NK細胞
C.幹細胞
V.遺伝的に操作された抗原レセプター
A.キメラ抗原レセプター
B.T細胞レセプター(TCR)
C.抗原提示細胞
D.抗原
E.自殺遺伝子
F.送達方法
a.ウイルスベクター
b.調節エレメント
(i)プロモーター/エンハンサー
(ii)開始シグナルおよび連結発現
(iii)複製開始点
宿主細胞においてベクターを増殖させるために、そのベクターは、1つ以上の複製開始部位(「ori」と呼ばれることが多い)、例えば、複製が開始される特異的な核酸配列である、上に記載されたようなEBVのoriPまたはプログラミングにおける機能が似ているかもしくは高められた遺伝的に操作されたoriPに対応する核酸配列を含み得る。あるいは、上に記載されたような染色体外で複製する他のウイルスの複製起点、または自律複製配列(ARS)を使用することができる。
c.選択マーカーおよびスクリーニング可能なマーカー
d.他の核酸送達方法
VI.処置方法
A.薬学的組成物
B.併用療法
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
1.化学療法
2.放射線療法
3.免疫療法
4.手術
5.他の作用物質
VII.製品またはキット
以下の実施例は、本発明の好ましい実施形態を実証するために含められる。以下の実施例に開示される手法は、本発明の実施において十分に機能すると本発明者が発見した手法であり、ゆえにその実施に対する好ましい形式であると考えることができることが当業者によって認識されるべきである。しかしながら、当業者は、本開示に鑑みて、開示される具体的な実施形態において多くの変更を行うことができ、それらの変更は、本発明の趣旨および範囲から逸脱することなく、なおも同様または類似の結果をもたらすと認識するはずである。
実施例1-マルチプレックス遺伝子編集
実施例2-方法
文献
以下の参考文献は、それらが本明細書に記載されたものを補足する例示的な手順または他の詳細を提供する範囲で、参照により本明細書に具体的に組み込まれる。
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Claims (148)
- 免疫細胞の少なくとも2つの遺伝子を破壊するためのインビトロ方法であって、前記少なくとも2つの遺伝子は、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される、方法。
- 破壊が、各遺伝子に対するガイドRNA(gRNA)を前記免疫細胞に導入することを含む、請求項1に記載の方法。
- 前記少なくとも2つの遺伝子が、(a)NKG2AおよびCISH、(b)NKG2AおよびTGFBRII、(c)CISHおよびTGFBRII、(d)TIGITおよびFOXO1、(e)TIGITおよびTGFBRII、(f)CD96およびFOXO1、(g)CD96およびTGFBRII、(h)FOXO1およびTGFBRII、(i)CD96およびTIGIT、(j)CISHおよびTIGIT、(k)TIM3およびCISH、(l)TIM3およびTGFBRII、(m)FOXO1およびTGFBRII、(n)TIM3およびTIGIT、(o)SIGLEC7およびCISH、(p)SIGLEC7およびTGFBRII、(q)CD47およびCISH、(r)CD47およびTGFBRII、(s)SIRPAおよびCISH、(t)SIRPAおよびTGFBRII、(u)CD47およびTIGIT、(v)CD47およびSIRPA、(w)A2ARおよびCISH、(x)A2ARおよびTGFBRII、(y)ADAM17およびCISH、(z)TGFBRIIおよびADAM17、(a1)A2ARおよびTIGIT、(b1)SHP1およびCISH、(c1)CISHおよびTGFBRII、(d1)SHP1およびTGFBRII、(e1)SHP1およびTIGIT、ならびに(f1)SHP1およびTIM3からなる群より選択される、請求項1または2に記載の方法。
- 少なくとも3つの遺伝子が、破壊される、請求項1~3のいずれかに記載の方法。
- 前記少なくとも3つの遺伝子が、(1)NKG2A、CISHおよびTGFBRII、(2)TIGIT、FOXO1およびTGFBRII、(3)TGFBRII、CD96およびTIGIT、(4)TGFBR2、CISHおよびTIGIT、(5)TIM3、CISHおよびTGFBRII、(6)CD96、FOXO1およびTGFBRII、(7)TGFBRII、TIM3およびTIGIT、(8)SIGLEC7、CISHおよびTGFBRII、(9)CD47、CISHおよびTGFBRII、(10)SIRPA、CISHおよびTGFBRII、(11)TGFBRII、CD47およびTIGIT、(12)TGFBRII、CD47およびSIRPA、(13)A2AR、CISHおよびTGFBRII、(14)TGFBRII、CISHおよびADAM17、(15)TGFBRII、TIM3およびTIGIT、(16)TGFBRII、A2ARおよびTIGIT、(17)SHP1、CISHおよびTGFBRII、(18)TGFBRII、CISHおよびSHP1、(19)TGFBRII、SHP1およびTIGIT、ならびに(20)TGFBRII、SHP1およびTIM3からなる群より選択される、請求項4に記載の方法。
- RNAガイドエンドヌクレアーゼを導入する工程をさらに含む、請求項2に記載の方法。
- 前記RNAガイドエンドヌクレアーゼが、Cas9である、請求項6に記載の方法。
- 前記RNAガイドエンドヌクレアーゼを導入する工程が、前記RNAガイドエンドヌクレアーゼをコードする核酸を前記免疫細胞に導入する工程を含む、請求項6に記載の方法。
- 前記核酸が、mRNAである、請求項8に記載の方法。
- 3つ、4つ、5つまたは6つの遺伝子が、破壊される、請求項1~9のいずれかに記載の方法。
- 前記遺伝子が、(a)~(j1)のサブグループのうちの2つを含む、請求項10に記載の方法。
- 前記遺伝子が、(a)~(j1)のうちの1つのサブグループおよび1~23のうちの1つのサブグループを含む、請求項10に記載の方法。
- 前記遺伝子が、1~23のサブグループのうちの2つを含む、請求項10に記載の方法。
- 前記破壊が、同時である、請求項1に記載の方法。
- 前記免疫細胞が、T細胞、NK細胞、NKT細胞、B細胞または幹細胞である、請求項1~14のいずれかに記載の方法。
- 前記免疫細胞が、キメラ抗原レセプター(CAR)および/またはT細胞レセプター(TCR)を発現するように操作されている、請求項15に記載の方法。
- 前記免疫細胞が、CARを発現するように操作されている、請求項15に記載の方法。
- 前記免疫細胞が、TCRを発現するように操作されている、請求項15に記載の方法。
- 前記免疫細胞が、CARおよびTCRを発現するように操作されている、請求項15に記載の方法。
- 前記免疫細胞が、ウイルス特異的である、請求項15に記載の方法。
- 前記T細胞が、ウイルス特異的T細胞である、請求項15に記載の方法。
- 前記T細胞が、制御性T細胞である、請求項15に記載の方法。
- 前記B細胞が、制御性B細胞である、請求項15に記載の方法。
- 前記幹細胞が、間葉系幹細胞(MSC)または人工多能性幹(iPS)細胞である、請求項15に記載の方法。
- 前記T細胞が、CD8+T細胞、CD4+T細胞、ガンマ-デルタT細胞またはそれらの混合物である、請求項15に記載の方法。
- 前記免疫細胞が、末梢血、臍帯血、骨髄またはそれらの混合物から単離される、請求項1~25のいずれかに記載の方法。
- 前記免疫細胞が、臍帯血から単離される、請求項1~26のいずれか1項に記載の方法。
- 前記臍帯血が、2単位以上の個々の臍帯血単位からプールされている、請求項27に記載の方法。
- 導入が、トランスフェクトまたは形質導入を含む、請求項2~28のいずれかに記載の方法。
- 導入が、エレクトロポレーションを含む、請求項2~28のいずれかに記載の方法。
- エレクトロポレーションが、2回以上行われる、請求項30に記載の方法。
- 2回のエレクトロポレーションが行われる、請求項31に記載の方法。
- 第1の群のCRISPR gRNAが、第1のエレクトロポレーションにおいて導入され、第2の群のCRISPR gRNAが、2回目のエレクトロポレーションにおいて導入される、請求項32に記載の方法。
- 前記第1の群および/または第2の群のCRISPR gRNAが、1つ、2つ、3つまたは4つのCRISPR gRNAを含む、請求項33に記載の方法。
- 2つのCRISPR gRNAが、第1のエレクトロポレーションにおいて導入され、2つのCRISPR gRNAが、2回目のエレクトロポレーションにおいて導入される、請求項32に記載の方法。
- 前記方法が、NKG2A、CD47、TGFβR2およびCISHを破壊する工程を含む、請求項1~35のいずれか1項に記載の方法。
- 前記方法が、NKG2A、CISH、TGFβR2およびADORA2を破壊する工程を含む、請求項1~35のいずれか1項に記載の方法。
- 前記方法が、NKG2A、TGFβR2およびCISHを破壊する工程を含む、請求項1~35のいずれか1項に記載の方法。
- 前記方法が、TIGIT、CD96、CISHおよびADORA2を破壊する工程を含む、請求項1~35のいずれか1項に記載の方法。
- 前記方法が、ADAM17、TGFβR2 NKG2AおよびSHP1を破壊する工程を含む、請求項1~35のいずれか1項に記載の方法。
- 前記破壊によって、前記免疫細胞の抗腫瘍細胞傷害性の増強、インビボ増殖、インビボ持続性および/または機能の改善がもたらされる、請求項1~40のいずれかに記載の方法。
- 前記免疫細胞が、IFN-γ、CD107および/またはTNFαの分泌を増加させている、請求項41に記載の方法。
- 前記免疫細胞が、パーフォリンおよび/またはグランザイムBの産生を増加させている、請求項41に記載の方法。
- CARまたはTCRを前記免疫細胞に導入する工程をさらに含む、請求項1~43のいずれかに記載の方法。
- 導入が、前記CARまたはTCRをコードする核酸を前記免疫細胞に導入する工程を含む、請求項44に記載の方法。
- 前記核酸が、発現ベクター内に存在する、請求項45に記載の方法。
- 前記発現ベクターが、レトロウイルスベクターである、請求項46に記載の方法。
- 前記レトロウイルスベクターが、アデノウイルス関連ベクターである、請求項47に記載の方法。
- 前記アデノウイルス関連ベクターが、AAV6である、請求項48に記載の方法。
- 前記ベクターが、阻害性遺伝子配列をさらに含む、請求項46に記載の方法。
- 前記阻害性遺伝子配列が、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される、請求項50に記載の方法。
- 前記ベクターが、前記阻害性遺伝子に対するガイドRNAをさらに含む、請求項50に記載の方法。
- 前記CARが、前記阻害性遺伝子に対する相同性アームに隣接している、請求項52に記載の方法。
- 前記CAR配列を含む前記ベクターを導入することにより、前記免疫細胞の前記阻害性遺伝子の遺伝子座に前記CARが挿入される、請求項53に記載の方法。
- 前記CARが、前記阻害性遺伝子のエキソンに挿入される、請求項54に記載の方法。
- 前記CARが、前記阻害性遺伝子の内在性プロモーターの支配下にある、請求項54に記載の方法。
- 前記ベクターの導入が、前記阻害性遺伝子の発現をさらに妨害する、請求項54に記載の方法。
- 免疫細胞の少なくとも2つの遺伝子の発現が妨害された免疫細胞であって、前記少なくとも2つの遺伝子は、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される、免疫細胞。
- 前記細胞が、請求項1~57のいずれか1項に従って作製される、請求項58に記載の細胞。
- 3つ、4つ、5つまたは6つの遺伝子が破壊されている、請求項58に記載の細胞。
- 前記免疫細胞が、T細胞、NK細胞、NKT細胞、B細胞または幹細胞である、請求項58に記載の細胞。
- 前記免疫細胞が、キメラ抗原レセプター(CAR)および/またはT細胞レセプター(TCR)を発現するように操作されている、請求項58に記載の細胞。
- 前記免疫細胞が、CARを発現するように操作されている、請求項58に記載の細胞。
- 前記免疫細胞が、TCRを発現するように操作されている、請求項58に記載の細胞。
- 前記免疫細胞が、CARおよびTCRを発現するように操作されている、請求項58に記載の細胞。
- 前記免疫細胞が、ウイルス特異的である、請求項58に記載の細胞。
- 前記T細胞が、ウイルス特異的T細胞である、請求項61に記載の細胞。
- 前記T細胞が、制御性T細胞である、請求項61に記載の細胞。
- 前記B細胞が、制御性B細胞である、請求項61に記載の細胞。
- 前記幹細胞が、間葉系幹細胞(MSC)または人工多能性幹(iPS)細胞である、請求項61に記載の細胞。
- 前記T細胞が、CD8+T細胞、CD4+T細胞またはガンマ-デルタT細胞である、請求項61に記載の細胞。
- 前記免疫細胞が、末梢血、臍帯血、骨髄またはそれらの混合物から単離される、請求項58に記載の細胞。
- 前記免疫細胞が、臍帯血から単離される、請求項58に記載の細胞。
- 前記臍帯血が、2単位以上の個々の臍帯血単位からプールされている、請求項73に記載の細胞。
- 前記免疫細胞のNKG2A、CD47、TGFβR2およびCISHが破壊されている、請求項58に記載の細胞。
- 前記免疫細胞のNKG2A、CISH、TGFβR2およびADORA2が破壊されている、請求項58に記載の細胞。
- 前記免疫細胞のNKG2A、TGFβR2およびCISHが破壊されている、請求項58に記載の細胞。
- 前記免疫細胞のTIGIT、CD96、CISHおよびADORA2が破壊されている、請求項58に記載の細胞。
- 前記免疫細胞のADAM17、TGFβR2 NKG2AおよびSHP1が破壊されている、請求項58に記載の細胞。
- 前記免疫細胞が、抗腫瘍細胞傷害性の増強、インビボ増殖、インビボ持続性および/または機能の改善を有する、請求項58に記載の細胞。
- 前記免疫細胞のIFN-γ、CD107および/またはTNFαの分泌を増加させている、請求項58に記載の細胞。
- 前記免疫細胞が、パーフォリンおよび/またはグランザイムBの産生を増加させている、請求項58に記載の細胞。
- 前記細胞が、CARおよび/またはTCRを発現するように操作されている、請求項58に記載の細胞。
- 前記CARが、前記細胞の内在性の阻害性遺伝子の遺伝子座に挿入されている、請求項83に記載の細胞。
- 前記阻害性遺伝子の遺伝子座が、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される、請求項84に記載の細胞。
- 前記CARが、前記阻害性遺伝子の内在性プロモーターの支配下にある、請求項84に記載の細胞。
- 前記CARが、CRISPR媒介性の遺伝子編集によって、前記阻害性遺伝子の遺伝子座に挿入された、請求項84に記載の細胞。
- 前記CARが、F(ab’)2、Fab’、Fab、FvおよびscFvからなる群より選択される抗原結合ドメインを含む、請求項83~87のいずれか1項に記載の細胞。
- 前記CARが、CD19、CD319(CS1)、ROR1、CD20、癌胎児抗原、アルファフェトプロテイン、CA-125、MUC-1、上皮性腫瘍抗原、黒色腫関連抗原、変異型p53、変異型ras、HER2/Neu、ERBB2、葉酸結合タンパク質、HIV-1エンベロープ糖タンパク質gp120、HIV-1エンベロープ糖タンパク質gp41、GD2、CD5、CD123、CD23、CD30、CD56、c-Met、メソテリン、GD3、HERV-K、IL-11Rアルファ、カッパー鎖、ラムダ鎖、CSPG4、ERBB2、WT-1、TRAIL/DR4、VEGFR2、CD33、CD47、CLL-1、U5snRNP200、CD200、BAFF-R、BCMAおよびCD99からなる群より選択される1つ以上の腫瘍関連抗原を標的化する、請求項83~88のいずれか1項に記載の細胞。
- 前記CARが、CD3ξ、CD28、OX40/CD134、4-1BB/CD137、FcεRIγ、ICOS/CD278、ILRB/CD122、IL-2RG/CD132、DAP12、CD70およびCD40からなる群より選択される少なくとも1つのシグナル伝達ドメインを含む、請求項83~90のいずれか1項に記載の細胞。
- 前記細胞が、IL-7、IL-2、IL-15、IL-12、IL-18、IL-21およびそれらの組み合わせからなる群より選択される異種サイトカインを発現するように操作されている、請求項58~90のいずれか1項に記載の細胞。
- 前記細胞が、自殺遺伝子をさらに含む、請求項83に記載の細胞。
- 前記自殺遺伝子が、膜結合型腫瘍壊死因子(TNF)-アルファ変異遺伝子である、請求項92に記載の細胞。
- CAR、阻害性遺伝子配列およびgRNAをコードする発現ベクター。
- 前記阻害性遺伝子配列が、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される阻害性遺伝子に由来する、請求項94に記載のベクター。
- 前記gRNAが、前記阻害性遺伝子に特異的である、請求項94に記載のベクター。
- 前記ベクターが、レトロウイルスベクターである、請求項94に記載のベクター。
- 前記レトロウイルスベクターが、AAVベクターである、請求項94に記載のベクター。
- 前記CARが、前記阻害性遺伝子に対する相同性アームに隣接している、請求項94に記載のベクター。
- 請求項94~99のいずれかに記載のベクターを発現するように操作された、宿主細胞。
- 前記細胞が、T細胞、NK細胞、B細胞または幹細胞である、請求項100に記載の細胞。
- 前記細胞が、請求項58~83のいずれか1項に記載の細胞である、請求項100に記載の細胞。
- 請求項58~93のいずれか1項に記載の免疫細胞の集団を含む、薬学的組成物。
- 免疫関連障害、感染症または癌を処置するための、請求項58~93のいずれか1項に記載の細胞の集団を含む組成物。
- 被験体の疾患または障害を処置する方法であって、有効量の請求項58~93のいずれか1項に記載の免疫細胞を前記被験体に投与する工程を含む、方法。
- 前記疾患または障害が、感染症、癌または免疫関連障害である、請求項105に記載の方法。
- 前記免疫関連障害が、自己免疫障害、移植片対宿主病、同種移植片拒絶または炎症状態である、請求項106に記載の方法。
- 前記免疫関連障害が、炎症状態であり、前記免疫細胞が、糖質コルチコイドレセプターの発現を本質的に有しない、請求項106に記載の方法。
- 前記免疫細胞が、前記被験体に対して自己である、請求項105~108のいずれか1項に記載の方法。
- 前記免疫細胞が、前記被験体に対して同種異系である、請求項105~108のいずれか1項に記載の方法。
- 前記免疫関連障害が、癌である、請求項106に記載の方法。
- 前記癌が、固形癌または血液悪性腫瘍である、請求項111に記載の方法。
- 少なくとも第2の治療薬を前記被験体に投与する工程をさらに含む、請求項105~112のいずれか1項に記載の方法。
- 前記少なくとも第2の治療薬が、化学療法、免疫療法、手術、放射線療法または生物療法を含む、請求項113に記載の方法。
- 前記免疫細胞および/または前記少なくとも第2の治療薬が、静脈内に、腹腔内に、気管内に、腫瘍内に、筋肉内に、内視鏡的に、病巣内に、経皮的に、皮下に、領域性に、または直接注射もしくは灌流によって、投与される、請求項113または114に記載の方法。
- CARを発現するように免疫細胞を操作するための方法であって、前記方法は、CRISPR gRNAを使用して、前記CARを前記免疫細胞の阻害性遺伝子の遺伝子座に挿入する工程を含む、方法。
- 前記CARが、発現ベクターによってコードされる、請求項116に記載の方法。
- 前記発現ベクターが、レトロウイルスベクターである、請求項117に記載の方法。
- 前記レトロウイルスベクターが、アデノウイルス関連ベクターである、請求項118に記載の方法。
- 前記アデノウイルス関連ベクターが、AAV6である、請求項119に記載の方法。
- 前記ベクターが、阻害性遺伝子配列をさらに含む、請求項117に記載の方法。
- 前記阻害性遺伝子配列が、NKG2A、SIGLEC-7、LAG3、TIM3、CISH、FOXO1、TGFBR2、TIGIT、CD96、ADORA2、NR3C1、PD1、PDL-1、PDL-2、CD47、SIRPA、SHIP1、ADAM17、RPS6、4EBP1、CD25、CD40、IL21R、ICAM1、CD95、CD80、CD86、IL10R、CD5およびCD7からなる群より選択される阻害性遺伝子に由来する、請求項121に記載の方法。
- 前記CRISPR gRNAが、前記阻害性遺伝子に対するものである、請求項116~122のいずれか1項に記載の方法。
- 前記CARが、前記阻害性遺伝子に対する相同性アームに隣接している、請求項116~123のいずれか1項に記載の方法。
- 前記CARが、前記阻害性遺伝子のエキソンに挿入される、請求項116~124のいずれか1項に記載の方法。
- 前記CARが、前記阻害性遺伝子の内在性プロモーターの支配下にある、請求項116~125のいずれか1項に記載の方法。
- 前記CARが、前記阻害性遺伝子の発現を妨害する、請求項116~126のいずれか1項に記載の方法。
- 前記CARが、CD19、CD319(CS1)、ROR1、CD20、癌胎児抗原、アルファフェトプロテイン、CA-125、MUC-1、上皮性腫瘍抗原、黒色腫関連抗原、変異型p53、変異型ras、HER2/Neu、ERBB2、葉酸結合タンパク質、HIV-1エンベロープ糖タンパク質gp120、HIV-1エンベロープ糖タンパク質gp41、GD2、CD5、CD123、CD23、CD30、CD56、c-Met、メソテリン、GD3、HERV-K、IL-11Rアルファ、カッパー鎖、ラムダ鎖、CSPG4、ERBB2、WT-1、TRAIL/DR4、VEGFR2、CD33、CD47、CLL-1、U5snRNP200、CD200、BAFF-R、BCMAおよびCD99からなる群より選択される1つ以上の腫瘍関連抗原を標的化する、請求項116~127のいずれか1項に記載の方法。
- 前記CARが、CD3ξ、CD28、OX40/CD134、4-1BB/CD137、FcεRIγ、ICOS/CD278、ILRB/CD122、IL-2RG/CD132、DAP12、CD70、CD40およびそれらの組み合わせからなる群より選択される少なくとも1つのシグナル伝達ドメインを含む、請求項116~128のいずれか1項に記載の方法。
- 前記細胞が、IL-7、IL-2、IL-15、IL-12、IL-18、IL-21およびそれらの組み合わせからなる群より選択される少なくとも1つの異種サイトカインを発現するように操作される、請求項116~129のいずれか1項に記載の方法。
- 前記細胞が、自殺遺伝子をさらに含む、請求項116~130のいずれか1項に記載の方法。
- 前記自殺遺伝子が、膜結合型腫瘍壊死因子(TNF)-アルファ変異遺伝子である、請求項131に記載の方法。
- 前記免疫細胞の阻害性遺伝子に挿入されたCARを有する免疫細胞。
- 前記細胞が、請求項116~132のいずれか1項に記載の方法によって作製される、請求項133に記載の免疫細胞。
- 請求項133または134に記載の免疫細胞の集団を含む、組成物。
- 前記免疫細胞が、T細胞、B細胞またはNK細胞である、請求項135に記載の組成物。
- 免疫関連障害、感染症または癌を処置するための、請求項133~136のいずれか1項に記載の細胞の集団を含む、組成物。
- 被験体の疾患または障害を処置する方法であって、有効量の請求項58~93、100または133~134のいずれか1項に記載の細胞を前記被験体に投与する工程を含む、方法。
- 前記疾患または障害が、感染症、癌または免疫関連障害である、請求項138に記載の方法。
- 前記免疫関連障害が、自己免疫障害、移植片対宿主病、同種移植片拒絶または炎症状態である、請求項139に記載の方法。
- 前記免疫関連障害が、炎症状態であり、前記免疫細胞が、糖質コルチコイドレセプターの発現の本質的に有しない、請求項139に記載の方法。
- 前記細胞が、前記被験体に対して自己である、請求項138~141のいずれか1項に記載の方法。
- 前記細胞が、同種異系である、請求項138~141のいずれか1項に記載の方法。
- 前記免疫関連障害が、癌である、請求項138に記載の方法。
- 前記癌が、固形癌または血液悪性腫瘍である、請求項144に記載の方法。
- 少なくとも第2の治療薬を前記被験体に投与する工程をさらに含む、請求項138~145のいずれか1項に記載の方法。
- 前記少なくとも第2の治療薬が、化学療法、免疫療法、手術、放射線療法または生物療法を含む、請求項146に記載の方法。
- 前記免疫細胞および/または前記少なくとも第2の治療薬が、静脈内に、腹腔内に、気管内に、腫瘍内に、筋肉内に、内視鏡的に、病巣内に、経皮的に、皮下に、領域性に、または直接注射もしくは灌流によって、投与される、請求項146または147に記載の方法。
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CN113272427A (zh) | 2021-08-17 |
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EA202191463A1 (ru) | 2021-10-13 |
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BR112021010297A2 (pt) | 2021-08-24 |
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