JP2017518053A - メソセリン標的化キメラ抗原受容体およびその使用 - Google Patents
メソセリン標的化キメラ抗原受容体およびその使用 Download PDFInfo
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Abstract
Description
本願は、2014年6月6日に出願した米国仮特許出願第62/008,851号に対する優先権を主張する。この出願はそれぞれ、その全体が、本明細書中に参考として援用され、そしてそのそれぞれに対して優先権を主張する。
本発明は、米国国防総省からの助成金番号W81XWH−11−1−0783およびW81XWH−12−1−0230の下、政府の支援を受けて行った。政府は、本発明において一定の権利を有する。
ここで開示される主題は、がんおよび病原体に対する免疫応答を増強するための方法および組成物を提供する。それは、ヒトメソセリンを特異的に標的とするキメラ抗原受容体(CAR)およびこのようなCARを含む免疫応答性細胞に関する。ここで開示されるメソセリン標的化CARは、CAR誘発性毒性および免疫原性を最小化する特徴を有しながら、抗腫瘍活性を含めた免疫活性化特性を増強した。
細胞ベースの免疫療法は、がんの治療のための治癒可能性を有する療法である。T細胞および他の免疫細胞は、選択された抗原に対して特異的なキメラ抗原受容体(CAR)と呼ばれる抗原の人工または合成受容体をコードする遺伝物質の導入によって、腫瘍抗原を標的とするよう修飾され得る。CARを使用する標的化T細胞療法は、いくつかの血液悪性腫瘍の治療において、最近、臨床上の成功を示した。しかし、CAR発現性T細胞療法を固形腫瘍にトランスレーションすると、臨床上の利益を達成するためには克服しなければならないいくつかの障害を生じる。悪性細胞は、自身を免疫認識および排除から保護するために、免疫抑制性微小環境を生成するよう適応する。この腫瘍微小環境は、標的化T細胞療法などの免疫応答の刺激を含む治療方法に対して課題をもたらす。固形腫瘍はまた、効率的なT細胞輸送を妨げ、アゴニスト共刺激リガンドの発現を欠き、および/またはT細胞機能の負の制御因子を発現する解剖学的コンパートメント内に制限され得る。したがって、固形腫瘍の排除の成功は、効率的な腫瘍浸潤および腫瘍誘発性免疫抑制を克服することを必要とする。さらに、固形腫瘍は、その標的化が、非腫瘍組織に対する最小のまたは許容できる毒性を伴って、強力なT細胞による腫瘍根絶を可能にするであろう、最適な免疫標的−抗原を選択するための課題をもたらす。したがって、がん、特に固形腫瘍を治療するためのCARを設計する新規治療戦略が必要であり、この戦略は、最小の毒性および免疫原性を伴って、強力な腫瘍根絶を誘導可能である(CAR免疫原性は、最適以下のCARに対するアナフィラキシー反応の状況において例示される、低減された有効性または急性毒性をもたらし得る)。
ここで開示される主題は、概して、メソセリン標的化キメラ抗原受容体(CAR)を提供する。1つの限定されない例では、CARは、細胞外抗原結合性ドメイン、膜貫通ドメインおよび細胞内ドメインを含み、細胞外抗原結合性ドメインは、ヒトメソセリンと、約1nM〜約25nMの結合アフィニティー(Kd)で特異的に結合する。ここで開示される主題はまた、メソセリン標的化CARを発現する免疫応答性細胞(例えば、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、制御性T細胞、ヒト胚幹細胞およびリンパ球系細胞に分化し得る多能性幹細胞)ならびに新生物および他の病理を治療するためのこのような免疫応答性細胞を使用する方法を提供する。悪性細胞は、免疫認識および排除から自身を保護する一連の機序を発達させる。本アプローチは、腫瘍根絶のために腫瘍微小環境内に免疫原性を提供し、従来の養子T細胞療法を上回る大幅な進歩に相当する。
特に定義されない限り、本明細書において使用されるすべての技術用語および科学用語は、本発明が属する技術分野の当業者によって一般的に理解される意味を有する。以下の参考文献は、本発明において使用される用語の多くの一般的な定義を当業者に提供する:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994);The Cambridge Dictionary of Science and Technology (Walker ed., 1988);The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991);およびHale & Marham, The Harper Collins Dictionary of Biology (1991)。本明細書において、以下の用語は、特に別に明記されない限り、以下のそれらに帰する意味を有する。
GGGGSGGGGSGGGGS[配列番号17]。
GGAGGTGGAGGCTCAGGAGGAGGAGGCAGTGGAGGTGGTGGGTCA[配列番号18]。
GGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCA[配列番号19]。
GGGGSGGGGSGGGGS[配列番号17]
GGAGGTGGAGGCTCAGGAGGAGGAGGCAGTGGAGGTGGTGGGTCA[配列番号18]
GGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCA[配列番号19]
MALPVTALLLPLALLLHAARP[配列番号20]
ATGGCCCTGCCAGTAACGGCTCTGCTGCTGCCACTTGCTCTGCTCCTCCATGCAGCCAGGCC [配列番号21]
(1.)iCASP9−2A左プライマー:gcgctccggaaaaaacttttctttaaaacatc aggatctggagcaacaaacttc [配列番号37]。
(2.)CD28右プライマー:ggtgtttccctttcacatgg[配列番号38].
ATNFSLLKQAGDVEENPGP[配列番号39]。
配列番号39のアミノ酸配列をコードするヌクレオチド配列は、配列番号40に示されており、これは、以下に提供されている:
GCAACAAACTTCTCACTACTCAAACAAGCAGGTGACGTGGAGGAGAATCCCGGCCC[配列番号40]。
(1)HSV−TK遺伝子と融合している、スプライスアクセプター部位を含有するMo−MLVベクターの領域をコードするSFG−TP28z.3に由来する1462bpのBglII/BssHII断片、
(2)停止コドン_GSG_2A_CD8aシグナルペプチド_J591 ScFvを含まないHSV−TK遺伝子の3’末端をコードするPCR産物に由来する、880bpのBssHII/NotI断片、ならびに
(3)キメラ抗原受容体の膜貫通_CD28_ゼータ鎖の残りをコードするSFG−TP28z.3およびレトロウイルスベクター骨格の残部に由来する、6652bpのNotI/BssHII断片
を使用してSFG−TP28z.3から導かれ得る。
(1)フォワードHSVTK_リンカー_GSG_P2A:
GCGCGCGCGCACGTTTGCCCGGGAGATGGGGGAGGCTAACGGATCTGGAGCAACAAACTTC[配列番号41]および
(2)リバース−P28z R:ggtgtttccctttcacatgg[配列番号42]。
1.序
転移性乳がんのための標的化T細胞療法
レトロウイルスベクターSFG−iCASP9−2A−M28zの生成
(1)iCASP9−2A Leftプライマー:gcgctccggaaaaaacttttctttaaaacatc aggatctggagcaacaaacttc [配列番号37]
(2)CD28 Rightプライマー:ggtgtttccctttcacatgg [配列番号38]。
P2Aのアミノ酸配列は、下に示す配列番号39に示される:
ATNFSLLKQAGDVEENPGP[配列番号39]。
配列番号39のアミノ酸配列をコードするヌクレオチド配列は、下に示される、配列番号40に示す:
GCAACAAACTTCTCACTACTCAAACAAGCAGGTGACGTGGAGGAGAATCCCGGCCC[配列番号40]。
CAR発現レベルは、CAR発現T細胞の有効性と関連する
メソセリン発現レベルは、CAR発現T細胞の有効性と関連する
最適発現レベルのMSLN特異的CARの生成
メソセリン標的化CAR T細胞療法の局所送達は、強力かつ長期持続性のCD4依存性の腫瘍免疫を生じる−実施例1の更新
固形腫瘍に対する血液悪性腫瘍のためのCAR T細胞療法の最近の成功を言い換えれば、不十分なT細胞の腫瘍浸潤および不十分な機能的な持続性を含むいくつかの障害を克服する必要がある。ヒト胸膜の悪性腫瘍を忠実に模倣する同所性モデルを利用して、M28z CARを用いるメソセリン標的化T細胞の2つの投与経路を評価した。胸膜内に投与されたCAR T細胞は、全身的に注入されたT細胞よりもかなり機能が優れており、長期の完全な寛解を誘発するのに必要なM28z T細胞が30分の1であることが見出された。胸膜内T細胞投与後、適切なin vivoの抗原誘発性のT細胞活性化が、堅調なCAR T細胞増殖およびエフェクター分化を可能にし、強化された抗腫瘍有効性および機能的なT細胞持続性を200日間生じた。局所的なT細胞投与はまた、胸郭外腫瘍部位の効率的な排除を促進した。この治療的有効性は、より高い腫瘍内CD4/CD8細胞比を伴う早期のCD4+T細胞活性化、およびCD28依存性のCD4+T細胞媒介性の細胞傷害性に依存した。対照的に、静脈内に送達されたCAR T細胞は、胸膜腫瘍で等価な数で蓄積した場合でさえ、匹敵する活性化も、腫瘍根絶も、持続性も達成しなかった。胸膜内に投与されたT細胞が循環して持続する能力によって、「局所的な分布中心」を通じて最適のCAR T細胞療法を送達するという概念が支持される。これらの結果に基づいて、原発性または二次的な胸膜悪性腫瘍を有する患者において、メソセリン標的化CAR T細胞の胸膜内投与の安全性を評価するための第1相臨床治験が進行中である。
この研究の目的は、固形の悪性腫瘍のための最適のT細胞免疫療法を創出することであった。ヒトT細胞に形質導入された場合、腫瘍抗原認識および抗原特異的エフェクター機能を提供するメソセリン標的化キメラ抗原受容体を設計した。in vitroでは、(i)細胞傷害性、(ii)サイトカイン分泌、および(iii)T細胞増殖を解析した。in vivoの実験では、T細胞および腫瘍の両方の生きたままのイメージングを用いてT細胞療法を最適化するためのストラテジーを解析した。ヒトがん細胞およびヒトT細胞を有する免疫不全マウスを用いて、CD19(Brentjens、NM、2003)およびPSMA(Gade、CR、2005)について以前行ったように、本発明者らのM28z CARの臨床へのトランスレーションを確証して容易にした。CAR T細胞と内因性の免疫系との間の機械的な相互作用の研究は、免疫適格性のマウスモデルで最もよく研究されるであろうが、ここでは、その臨床的に関連する対応物とは異なるマウスCARを利用する必要があろう。この実験手順は、メモリアルスローン・ケタリングがんセンター(Memorial Sloan−Kettering Cancer Center:MSKCC)の動物実験委員会(Institutional Animal Care and Use Committee)によって承認された。各々の実験は、異なるドナーT細胞を用いて何度も行った(T細胞は決してプールしなかった)。示したデータは、代表的な実験(3つ超の試料複製を有する)を用いて、形質導入の効率に起因する相違、ドナー関連の変動およびE:T比などの交絡変数を回避した。
MzおよびM28z形質導入のT細胞は、MSLN+標的細胞と特異的に応答する
CAR T細胞は、腫瘍媒介性の阻害に抵抗する
1.要約
一般的目的
CD28または4−1BB共刺激のCARは、最初の抗原刺激の際にin vitroで等価なエフェクターサイトカイン分泌および増殖を示す
可変MSLN発現を有する細胞に対するM28z CAT T細胞の有効性
M28z CAR T細胞の増殖能
肺がんモデルにおけるM28z CAR T細胞のin vivoにおける有効性
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Claims (97)
- 細胞外抗原結合性ドメイン、膜貫通ドメインおよび細胞内ドメインを含むキメラ抗原受容体(CAR)であって、前記細胞外抗原結合性ドメインが、ヒトメソセリンと約1nM〜約25nMの結合アフィニティー(Kd)で特異的に結合する、キメラ抗原受容体(CAR)。
- 前記細胞外抗原結合性ドメインが、一本鎖可変断片(scFv)を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、ヒトscFvを含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、Fabを含み、これは必要に応じて架橋されている、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、F(ab)2を含む、請求項1に記載のCAR。
- 前記scFV、FabおよびF(ab)2のうちの1つまたは複数が、前記細胞外抗原結合性ドメインを形成するように異種配列を有する融合タンパク質中に含まれる、請求項2から5のいずれか一項に記載のCAR。
- 前記CARの前記細胞外抗原結合性ドメインが、約1,000またはそれ超のメソセリン結合部位/細胞のメソセリン発現レベルのヒトメソセリンを認識する、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号1のアミノ酸1〜119を含む重鎖可変領域を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号5のアミノ酸1〜107を含む軽鎖可変領域を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号3のアミノ酸1〜107を含む軽鎖可変領域を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号1のアミノ酸1〜119を含む重鎖可変領域および配列番号5のアミノ酸1〜107を含む軽鎖可変領域を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号1のアミノ酸1〜119を含む重鎖可変領域および配列番号3のアミノ酸1〜107を含む軽鎖可変領域を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号11に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR1、配列番号12に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR2、および配列番号13に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR3を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号14に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR1、配列番号15に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR2、および配列番号16に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR3を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、配列番号11に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR1、配列番号12に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR2、配列番号13に示される配列を有するアミノ酸またはその保存的修飾物を含む重鎖可変領域CDR3、配列番号14に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR1、配列番号15に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR2、および配列番号16に示される配列を有するアミノ酸またはその保存的修飾物を含む軽鎖可変領域CDR3を含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、前記細胞外抗原結合性ドメインの重鎖可変領域と軽鎖可変領域との間にリンカーを含む、請求項1に記載のCAR。
- 前記細胞外抗原結合性ドメインが、前記細胞外抗原結合性ドメインの5’末端と共有結合によって連結しているリーダーを含む、請求項1に記載のCAR。
- 前記リーダーが、CD8ポリペプチドを含む、請求項17に記載のCAR。
- 前記膜貫通ドメインが、CD8ポリペプチド、CD28ポリペプチド、CD3ζポリペプチド、CD4ポリペプチド、4−1BBポリペプチド、OX40ポリペプチド、ICOSポリペプチド、CTLA−4ポリペプチド、PD−1ポリペプチド、LAG−3ポリペプチド、2B4ポリペプチド、BTLAポリペプチド、合成ペプチド(免疫応答と関連しているタンパク質をベースとしない)またはそれらの組合せを含む、請求項1に記載のCAR。
- 前記膜貫通ドメインが、CD8ポリペプチドを含む、請求項19に記載のCAR。
- 前記膜貫通ドメインが、CD28ポリペプチドを含む、請求項19に記載のCAR。
- 前記細胞内ドメインが、CD3ζポリペプチドを含む、請求項1に記載のCAR。
- 前記細胞内ドメインが、少なくとも1つの共刺激シグナル伝達領域をさらに含む、請求項1に記載のCAR。
- 前記少なくとも1つの共刺激シグナル伝達領域が、CD28ポリペプチド、4−1BBポリペプチド、OX40ポリペプチド、ICOSポリペプチド、PD−1ポリペプチド、CTLA−4ポリペプチド、LAG−3ポリペプチド、2B4ポリペプチド、BTLAポリペプチド、合成ペプチド(免疫応答と関連しているタンパク質をベースとしない)またはそれらの組合せを含む、請求項23に記載のCAR。
- 前記膜貫通ドメインが、CD8ポリペプチドを含み、前記細胞内ドメインが、CD3ζポリペプチドを含む、請求項1に記載のCAR。
- 前記膜貫通ドメインが、CD28ポリペプチドを含み、前記細胞内ドメインが、CD3ζポリペプチドと、CD28ポリペプチドを含む共刺激シグナル伝達ドメインとを含む、請求項1に記載のCAR。
- 前記膜貫通ドメインが、CD8ポリペプチドを含み、前記細胞内ドメインが、CD3ζポリペプチドと、4−1BBポリペプチドを含む共刺激シグナル伝達ドメインとを含む、請求項1に記載のCAR。
- 前記CARがMzである、請求項1に記載のCAR。
- Mzの膜貫通ドメインが、CD8ポリペプチドを含み、Mzの細胞内ドメインが、CD3ζポリペプチドを含む、請求項28に記載のCAR。
- 前記CARがM28zである、請求項1に記載のCAR。
- 膜貫通ドメインM28zが、CD28ポリペプチドを含み、M28zの細胞内ドメインが、CD3ζポリペプチドと、CD28ポリペプチドを含む共刺激シグナル伝達領域とを含む、請求項30に記載のCAR。
- 前記CARがMBBzである、請求項1に記載のCAR。
- MBBzの前記膜貫通ドメインが、CD8ポリペプチドを含み、MBBzの細胞内ドメインが、CD3ζポリペプチドと、4−1BBポリペプチドを含む共刺激シグナル伝達領域とを含む、請求項32に記載のCAR。
- 前記CARが組換え発現される、請求項1に記載のCAR。
- 前記CARがベクターから発現される、請求項1に記載のCAR。
- 前記ベクターが、γ−レトロウイルスレクター(γ−retroviral rector)である、請求項35に記載のCAR。
- 前記請求項のうちのいずれか一項に記載のCARを含む、単離された免疫応答性細胞。
- 少なくとも1種の外因性共刺激リガンドをさらに含む、請求項37に記載の単離された免疫応答性細胞。
- 前記少なくとも1種の共刺激リガンドが、4−1BBL、CD80、CD86、CD70、OX40L、CD48、TNFRSF14およびそれらの組合せからなる群から選択される、請求項38に記載の単離された免疫応答性細胞。
- 前記共刺激リガンドが、4−1BBLである、請求項39に記載の単離された免疫応答性細胞。
- 少なくとも外因性の1種のサイトカインをさらに含む、請求項37に記載の単離された免疫応答性細胞。
- 前記少なくとも1種のサイトカインが、IL−2、IL−3、IL−6、IL−7、IL−11、IL−12、IL−15、IL−17、IL−21およびそれらの組合せからなる群から選択される、請求項41に記載の単離された免疫応答性細胞。
- 前記少なくとも1種のサイトカインが、IL−12である、請求項42に記載の単離された免疫応答性細胞。
- 前記細胞がT細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、制御性T細胞、ヒト胚幹細胞およびリンパ球系細胞に分化し得る多能性幹細胞からなる群から選択される、請求項37から43のいずれか一項に記載の単離された免疫応答性細胞。
- 前記細胞がT細胞である、請求項37に記載の単離された免疫応答性細胞。
- 前記単離された免疫応答性細胞が細胞あたり約1〜約4ベクターコピー数の前記CARを発現する、請求項37から45のいずれか一項に記載の単離された免疫応答性細胞。
- ヒトメソセリンとは異なる抗原と結合する抗原認識受容体をさらに含む、請求項37から46のいずれか一項に記載の単離された免疫応答性細胞。
- 前記抗原が、腫瘍または病原体抗原である、請求項47に記載の単離された免疫応答性細胞。
- 前記腫瘍抗原が、炭酸脱水酵素IX(CAIX)、癌胎児性抗原(CEA)、CD5、CD7、CD10、CD19、CD20、CD22、CD30、CD33、CD34、CD38、CD41、CD44、CD49f、CD56、CD74、CD123、CD133、CD138、サイトメガロウイルス(CMV)感染細胞の抗原(例えば、細胞表面抗原)、上皮糖タンパク質2(EGP2)、上皮糖タンパク質−40(EGP−40)、上皮細胞接着分子(EpCAM)、受容体チロシンプロテインキナーゼerb−B2、3、4、葉酸結合タンパク質(FBP)、胎児アセチルコリン受容体(AChR)、葉酸受容体−a、ガングリオシドG2(GD2)、ガングリオシドG3(GD3)、ヒト上皮成長因子受容体2(HER−2)、ヒトテロメラーゼ逆転写酵素(hTERT)、インターロイキン−13受容体サブユニットアルファ−2(IL−13Rα2)、κ−軽鎖、キナーゼ挿入ドメイン受容体(KDR)、ルイスA(CA19.9)、ルイスY(LeY)、L1細胞接着分子(L1CAM)、黒色腫抗原ファミリーA,1(MAGE−AI)、ムチン16(Muc−16)、ムチン1(Muc−1)、NKG2Dリガンド、がん精巣抗原NY−ESO−1、癌胎児性抗原(h5T4)、前立腺幹細胞抗原(PSCA)、前立腺特異的膜抗原(PSMA)、腫瘍関連糖タンパク質72(TAG−72)、血管内皮成長因子R2(VEGF−R2)、ウィルムス腫瘍タンパク質(WT−1)、1型チロシン−プロテインキナーゼ膜貫通型受容体(ROR1)およびそれらの組合せからなる群から選択される、請求項48に記載の単離された免疫応答性細胞。
- 前記単離された免疫応答性細胞が1種または複数種の接着分子を発現する、請求項37から49のいずれか一項に記載の単離された免疫応答性細胞。
- 前記接着分子が、前記CARのアビディティーを高める、請求項50に記載の単離された免疫応答性細胞。
- 前記接着分子が、CD2、VLA−4およびそれらの組合せからなる群から選択される、請求項50または51に記載の単離された免疫応答性細胞。
- 被験体における腫瘍量を低減する方法であって、前記被験体に、有効量の、請求項37から52のいずれか一項に記載の免疫応答性細胞を投与し、それによって、前記被験体において腫瘍細胞死を誘導することを含む方法。
- 前記方法が腫瘍細胞の数を低減する、請求項53に記載の方法。
- 前記方法が腫瘍の大きさを低減する、請求項53に記載の方法。
- 前記方法が前記被験体において前記腫瘍を根絶する、請求項53に記載の方法。
- 前記腫瘍が固形腫瘍である、請求項53に記載の方法。
- 前記固形腫瘍が、中皮腫、肺がん、膵臓がん、卵巣がん、乳がん、結腸がん、胸膜腫瘍、神経膠芽腫、食道がん、胃がん(gastric cancer)、滑膜肉腫、胸腺癌、子宮内膜癌、胃がん(stomach cancer)、胆管癌およびそれらの組合せからなる群から選択される、請求項57に記載の方法。
- 新生物を有する被験体の生存を増大または延長する方法であって、前記被験体に、有効量の、請求項37から52のいずれか一項に記載の免疫応答性細胞を投与し、それによって、前記被験体の生存を増大または延長することを含む方法。
- 前記新生物が、中皮腫、肺がん、膵臓がん、卵巣がん、乳がん、結腸がん、胸膜がん、神経膠芽腫、食道がん、胃がん(gastric cancer)、滑膜肉腫、胸腺癌、子宮内膜癌、胃がん(stomach cancer)、胆管癌およびそれらの組合せからなる群から選択される、請求項59に記載の方法。
- 前記方法が前記被験体における腫瘍量を低減または根絶する、請求項59に記載の方法。
- 被験体におけるがん細胞または病原体に応じた免疫活性化サイトカイン産生を増大する方法であって、前記被験体に、請求項37から52のいずれか一項に記載の免疫応答性細胞を投与することを含む方法。
- 前記免疫活性化サイトカインが、(GM−CSF)、IFN−α、IFN−β、IFN−γ、TNF−α、IL−2、IL−3、IL−6、IL−11、IL−7、IL−12、IL−15、IL−21、インターフェロン制御因子7(IRF7)およびそれらの組合せからなる群から選択される、請求項62に記載の方法。
- 前記免疫活性化サイトカインが、(GM−CSF)、IFN−γ、TNF−αおよびそれらの組合せからなる群から選択される、請求項63に記載の方法。
- 少なくとも1種の免疫調節因子を投与することをさらに含む、請求項53から64のいずれか一項に記載の方法。
- 前記少なくとも1種の免疫調節因子が、免疫賦活因子、チェックポイント免疫遮断剤、放射線療法因子、化学療法剤およびそれらの組合せからなる群から選択される、請求項65に記載の方法。
- 前記免疫賦活剤が、IL−12、アゴニスト共刺激モノクローナル抗体およびそれらの組合せからなる群から選択される、請求項66に記載の方法。
- 前記免疫賦活剤が、IL−12である、請求項67に記載の方法。
- 前記アゴニスト共刺激モノクローナル抗体が、抗4−1BB抗体、抗OX40抗体、抗ICOS抗体およびそれらの組合せからなる群から選択される、請求項66に記載の方法。
- 前記アゴニスト共刺激モノクローナル抗体が、抗4−1BB抗体である、請求項69に記載の方法。
- 前記チェックポイント免疫遮断剤が、抗PD−L1抗体、抗CTLA−4抗体、抗PD−1抗体、抗LAG3抗体、抗B7−H3抗体、抗TIM3抗体およびそれらの組合せからなる群から選択される、請求項66に記載の方法。
- 前記チェックポイント免疫遮断剤が、抗PD−L1抗体である、請求項71に記載の方法。
- 前記被験体がヒトである、請求項53から72のいずれか一項に記載の方法。
- 前記免疫応答性細胞が、前記被験体に胸膜投与される、請求項53から73のいずれか一項に記載の方法。
- ヒトメソセリンと結合する免疫応答性細胞を製造するための方法であって、前記免疫応答性細胞に、細胞外抗原結合性ドメイン、膜貫通ドメインおよび細胞内ドメインを含むキメラ抗原受容体(CAR)コードする核酸配列を導入することを含み、前記細胞外抗原結合性ドメインが、ヒトメソセリンと、約1nM〜約25nMの結合アフィニティー(Kd)で特異的に結合する、方法。
- 請求項1から36のいずれか一項に記載のCARをコードする核酸。
- 請求項76に記載の核酸を含むベクター。
- 前記ベクターがγ−レトロウイルスベクターである、請求項77に記載のベクター。
- 医薬組成物であって、有効量の、請求項37から52のいずれか一項に記載の免疫応答性細胞と、薬学的に許容される賦形剤とを含む医薬組成物。
- 新生物を治療するための医薬組成物であって、有効量の、請求項37から52のいずれか一項に記載の免疫応答性細胞と、薬学的に許容される賦形剤とを含む、医薬組成物。
- 前記新生物が、中皮腫、肺がん、膵臓がん、卵巣がん、乳がん、結腸がん、胸膜がん、神経膠芽腫、食道がん、胃がん(gastric cancer)、滑膜肉腫、胸腺癌、子宮内膜癌、胃がん(stomach cancer)、胆管癌およびそれらの組合せからなる群から選択される、請求項80に記載の医薬組成物。
- 新生物、病原体感染、自己免疫障害、炎症性疾患、同種異系移植または移植片拒絶を治療または予防するためのキットであって、請求項37から52のいずれか一項に記載の免疫応答性細胞を含むキット。
- 新生物、病原体感染、自己免疫障害、炎症性疾患、同種異系移植または移植片拒絶を治療または予防するためのキットであって、請求項76に記載の核酸を含むキット。
- 前記キットが、新生物、病原体感染、自己免疫障害、炎症性疾患、同種異系移植または移植片拒絶を有する被験体を治療するために前記免疫応答性細胞を使用するための指示書をさらに含む、請求項82または83に記載のキット。
- 前記新生物が、中皮腫、肺がん、膵臓がん、卵巣がん、乳がん、結腸がん、胸膜がん、神経膠芽腫、食道がん、胃がん(gastric cancer)、滑膜肉腫、胸腺癌、子宮内膜癌、胃がん(stomach cancer)、胆管癌およびそれらの組合せからなる群から選択される、請求項82から84のいずれか一項に記載のキット。
- 被験体において炎症性疾患を予防または治療する方法であって、前記被験体に請求項37から52のいずれか一項に記載の免疫応答性細胞を投与することを含む方法。
- 前記免疫応答性細胞が、免疫阻害細胞である、請求項86に記載の方法。
- 前記免疫阻害細胞が、制御性T細胞である、請求項87に記載の方法。
- 前記炎症性疾患が膵炎である、請求項86から88のいずれか一項に記載の方法。
- 前記被験体がヒトである、請求項86から89のいずれか一項に記載の方法。
- 前記被験体が、臓器移植のレシピエントである、請求項86から90のいずれか一項に記載の方法。
- 前記被験体が、膵臓移植のレシピエントである、請求項91に記載の方法。
- 臓器移植のレシピエントである被験体において移植片拒絶を予防する方法であって、前記被験体に、請求項37から52のいずれか一項に記載の免疫応答性細胞を投与することを含む方法。
- 前記免疫応答性細胞が、免疫阻害細胞である、請求項93に記載の方法。
- 前記免疫阻害細胞が、制御性T細胞である、請求項94に記載の方法。
- 前記被験体がヒトである、請求項93から95のいずれか一項に記載の方法。
- 前記被験体が、膵臓移植のレシピエントである、請求項93から96のいずれか一項に記載の方法。
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EP4166148A1 (en) | 2023-04-19 |
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ES2791953T3 (es) | 2020-11-06 |
EP3151854A2 (en) | 2017-04-12 |
JP7061219B2 (ja) | 2022-04-27 |
JP2023002839A (ja) | 2023-01-10 |
WO2015188141A3 (en) | 2016-03-17 |
WO2015188141A9 (en) | 2016-01-28 |
US10633441B2 (en) | 2020-04-28 |
ES2928000T3 (es) | 2022-11-14 |
EP3685842A1 (en) | 2020-07-29 |
WO2015188141A8 (en) | 2016-10-20 |
US10538588B2 (en) | 2020-01-21 |
JP2024026280A (ja) | 2024-02-28 |
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