JP2022164858A - 免疫調整性il2r融合タンパク質およびその使用 - Google Patents
免疫調整性il2r融合タンパク質およびその使用 Download PDFInfo
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Abstract
Description
本出願と関連する配列表は、紙によるコピーの代わりにテキスト形式で提供され、本明細書に参考として援用される。その配列表を含むテキストファイルの名称は、360056_442WO_SEQUENCE_LISTING.txtである。そのテキストファイルは、48.8 KBであり、2017年4月20日に作成され、EFS-Webを介して電子的に提出されている。
T細胞ベースの免疫療法は、腫瘍反応性T細胞が腫瘍浸潤リンパ球(TILs)の集団の中で見出されたときに開発され始めた(Clarkら, Cancer Res. 29:705, 1969)。養子T細胞移入として公知の1つのストラテジーは、状況によっては、腫瘍反応性に関して予め選択された腫瘍浸潤リンパ球の単離、IL-2の存在下で抗CD3および抗CD28抗体によって誘導される腫瘍反応性T細胞のクローン性拡大、および最終的には、腫瘍を有する患者に拡大した細胞集団を(化学療法およびIL-2の反復投与とともに)注入して戻すことを含む(Dudleyら, Science 298:850, 2002)。腫瘍浸潤リンパ球での養子T細胞治療のこの形態は、技術的に扱いづらい可能性があり、黒色腫を有する患者の僅かな割合においてのみ完全寛解をもたらし、他のがんにおいては希に有効である(Besserら, Clin. Cancer Res. 16:2646, 2010)。
本開示は、宿主細胞(例えば、免疫細胞)におけるシグナル伝達を調整する融合タンパク質を提供する。例えば、本開示の融合タンパク質は、ヒトT細胞への活性化または増殖シグナルを提供し得、ここで上記T細胞は、必要に応じて、好ましい抗原特異的T細胞レセプター(TCR)もしくはキメラ抗原レセプター(CAR)、または両方を有するように操作され得る。例えば、これらの融合タンパク質は、目的のサイトカインまたはケモカインと相互作用して、抗原特異的TCRまたはCARを含むT細胞などのT細胞に、生存および/または拡大の利点を提供することができ、これは、腫瘍微小環境における効力の改善を含む、持続性および移入した細胞への曝露を改善するための構築物の有用性と一致する。
と送達し、この場合、ペプチド:MHC(またはペプチド:ヒトにおけるHLA)複合体は、CD8+ T細胞によって認識される。MHC(HLA)クラスII分子は、小胞系に由来するペプチドを細胞表面へと送達し、この場合、それらは、CD4+ T細胞によって認識される。MHC分子は、種々の動物種(ヒト、マウス、ラット、または他の哺乳動物が挙げられる)に由来し得る。
ある種の局面において、本開示は、本明細書で記載される融合タンパク質のうちのいずれか1種またはこれより多くの種をコードする核酸分子を提供し、その本明細書で記載される融合タンパク質は、サイトカイン結合ドメインの全てまたは一部を含む細胞外構成要素、膜貫通ドメインおよび1種またはこれより多くの種のIL-2R鎖のシグナル伝達ドメインまたはそのシグナル伝達部分(複数可)を含む細胞内構成要素を含む融合タンパク質であり得、ここで上記サイトカイン結合ドメインは、IL-2結合ドメインではない。このような核酸分子は、目的の宿主細胞(例えば、T細胞)の中に導入するための適切なベクター(例えば、ウイルスベクターまたは非ウイルスプラスミドベクター)へと挿入され得る。
Emerging Viral Vectors. pp 209-40)、またはプラスミドベクター(例えば、sleeping beautyベクターまたは他のトランスポゾンベクター)が挙げられる。いくつかの実施形態において、ウイルスベクターまたはプラスミドベクターはさらに、形質導入に関する遺伝子マーカー(例えば、緑色蛍光タンパク質、huEGFRt)を含む。
M-1に等しいかまたはこれより大きなKaで)結合する。さらなる実施形態において、そのコードされる抗原特異的TCRは、その宿主細胞に対して、またはその宿主細胞が投与される被験体に対して異種である。特定の実施形態において、そのコードされるTCRは、HLAクラスI拘束性抗原に対して特異的である。前述の実施形態のうちのいずれかにおいて、その抗原結合タンパク質は、がん特異的抗原(例えば、WT-1、メソテリン、ROR1またはサイクリン-A1)に対して特異的である。いくつかの実施形態において、そのTCRは、C4と称されるWT-1特異的TCRである。
TCM細胞に関して富化されたT細胞の集団へと導入される。さらに他の実施形態において、本開示の融合タンパク質をコードする核酸分子は、ナイーブCD4+ T細胞およびCD4+ TCM細胞に関して富化されたT細胞の集団へと導入される。前述の実施形態のうちのいずれかにおいて、そのT細胞はさらに、操作された抗原特異的T細胞レセプター(TCR)、操作された抗原特異的高親和性TCR、外因性共刺激分子、キメラ抗原レセプター(CAR)、またはこれらのうちのいずれかの組み合わせをコードする核酸分子を含む。
本開示で記載されるとおりの融合タンパク質を発現する細胞で処置され得る疾患としては、がん、感染性疾患(ウイルス感染症、細菌感染症、原生動物感染症)、および免疫疾患(例えば、自己免疫)が挙げられる。養子免疫治療および遺伝子治療は、種々のタイプのがん(Morganら, Science 314:126, 2006; Schmittら, Hum. Gene Ther. 20:1240, 2009; June, J. Clin. Invest. 117:1466, 2007)および感染性疾患(Kitchenら, PLoS One 4:38208, 2009; Rossiら, Nat. Biotechnol. 25:1444, 2007; Zhangら, PLoS Pathog. 6:e1001018, 2010; Luoら, J. Mol. Med. 89:903, 2011)に有望な処置である。
lymphoma of mucosa-associated(MALT) lymphoid tissue)、節性辺縁帯B細胞性リンパ腫、濾胞性リンパ腫、マントル細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、縦隔(胸腺)大細胞型B細胞性リンパ腫、血管内大細胞型B細胞性リンパ腫、原発性滲出性リンパ腫、バーキットリンパ腫/白血病、悪性の可能性のあるB細胞増殖(B-cell proliferations of uncertain malignant potential)、リンパ腫様肉芽腫症、および移植後リンパ増殖性障害。
癌細胞におけるサイトカインおよびケモカインプロフィール
培養物中の精製膵臓癌細胞によって発現される可溶性因子を、定量的PCRによってプロファイリングした。簡潔には、全RNAを、KPC腫瘍上皮細胞および同じ動物の肝臓への対の転移性細胞(各々n=3)の初代培養物から抽出し(RNeasy Miniprep Kit, Qiagen)、浸潤前膵管上皮細胞からも抽出した。RNAを、High Capacity Reverse Transcriptase Kit(Applied Biosystems)を使用してcDNAへと変換した。定量的PCRを、SYBR Greenマスターミックスを使用して行い、三連のサンプルをC1000 Thermal Cycler(BioRad)で実行した。プライマーは、刊行された文献に基づいたか、またはPrimer-BLASTソフトウェアを使用して設計した。定量を内因性cycAに対して正規化し、浸潤前細胞と比較した浸潤細胞および転移性細胞における遺伝子発現の倍数変化を、ΔΔCT法を使用して計算した。PDAの遺伝子操作したKrasLSL-G12D/+;Trp53LSL-R172H/+;Cre(KPC)マウスモデルは、Hingoraniら(Cancer Cell 7:469, 2005)によって以前に記載された。
高親和性メソテリン特異的TCRの生成
B6 Msln-/-マウスおよび野生型(WT)マウスを、マウスMsln(Ad-Msln)を発現する組換えアデノウイルスで免疫して、反応性T細胞を誘発した。エピトープMsln343-351、Msln484-492、Msln544-552、およびMsln583-591に対して特異的なT細胞を、WTマウスからではなくMsln-/-マウスから単離し、。これは、中枢性トレランスと一致した(Stromnesら, Cancer Cell 28:638, 2015)。しかし、Msln-/-マウスおよびWTマウスはともに、B6卵巣がん細胞株によってプロセシングされかつ提示されることが以前に示された(Hungら, Gene Ther. 14:921,
2007)Msln406-414への応答を生じた。WTマウスから単離されたMsln406-414特異的T細胞はVβ9 TCR鎖を、Msln-/-マウスに由来するMsln406-414特異的T細胞の大部分が発現した(Stromnesら, 2015)のと同様に、一様に発現した。Vβ9の類似のレベルを発現するにも拘わらず、Msln-/-マウスに由来するMsln406-414特異的T細胞系統は、テトラマーでより明るく染色され、これは、より高い親和性と一致した(Stromnesら, 2015)。Msln-/- Msln406-414特異的T細胞クローンはまた、その相当するWTクローンより低い抗原濃度に応答した(Stromnesら, 2015)。WTマウスおよびMsln-/-マウスから単離した大部分のT細胞クローンは、同じ生殖細胞系列Vα4およびVβ9 TCR鎖を使用し、それぞれの系統からの最も高親和性のクローンの間でのいかなる配列差異をもCDR3に制限した(図3A)。
マウスモデルにおける例示的CSF2R::IL-2R構築物の評価
例示的CSF2R::IL-2Rキメラ構築物、および抗原特異的操作T細胞の機能に対するそれらの影響を、マウスC57BL/6フレンドウイルス誘導性赤白血病(FBL)およびTCRgagトランスジェニックマウスに基づいて、播種性の白血病の前臨床マウスモデルにおいて評価した。
特定の実施形態では、例えば、以下が提供される:
(項目1)
融合タンパク質および抗原結合タンパク質を含む宿主細胞であって、
ここで該融合タンパク質は、サイトカイン結合ドメインまたはその一部を含む細胞外構成要素と、IL-2R細胞内部分、細胞内シグナル伝達ドメインまたはその一部を含む細胞内構成要素との間に配置された膜貫通ドメインを含み;そして
ここで該抗原結合タンパク質は、T細胞レセプター(TCR);キメラ抗原レセプター(CAR);または必要に応じて複数の抗原結合タンパク質、例えば、TCRおよびCARである、
宿主細胞。
(項目2)
第1の融合タンパク質、第2の融合タンパク質および必要に応じて抗原結合タンパク質を含む宿主細胞であって、
ここで該第1の融合タンパク質は、サイトカイン結合ドメインまたはその一部を含む細胞外構成要素と、IL-2Rγ、必要に応じてヒトIL-2Rγ、細胞内部分または細胞内シグナル伝達ドメインもしくはその一部から構成されるか、これと少なくとも90%同一性を有するか、あるいは必要に応じて配列番号10と少なくとも90%同一性を有する細胞内構成要素との間に配置された膜貫通ドメインを含み;
ここで該第2の融合タンパク質は、サイトカイン結合ドメインまたはその一部を含む細胞外構成要素と、IL-2Rβ、必要に応じてヒトIL-2Rβ、細胞内シグナル伝達ドメインもしくはその一部および/またはIL-4R、IL-7R、IL-9R、IL-15RもしくはIL-21R鎖のシグナルドメインもしくはその一部から構成されるか、またはこれと少なくとも90%同一性を有するか、あるいは必要に応じて、配列番号12と少なくとも90%同一性を有する細胞内構成要素との間に配置された膜貫通ドメインを含み;そして
ここで必要に応じた該抗原結合タンパク質は、T細胞レセプター(TCR);キメラ抗原レセプター(CAR)を含み;そして必要に応じて複数の抗原結合タンパク質、例えば、TCRおよびCARを含む、
宿主細胞。
(項目3)
前記第1および/または第2の融合タンパク質の前記細胞外構成要素および/または前記細胞外構成要素は、CSF2R、CSF1R、CSF3R、CXCR2、またはCCR8の、必要に応じてヒトCSF2R、CSF1R、CSF3R、CXCR2、またはCCR8の細胞外部分を含む、項目1または2に記載の宿主細胞。
(項目4)
前記融合タンパク質の前記サイトカイン結合ドメインは、GM-CSF、M-CSF、G-CSF、CXCL1、CXCL2、もしくはCCL1の結合部位の少なくとも一部に特異的に結合するか、またはこれを含み、そして必要に応じてヒト配列を含むかまたはこれからなる、先行する項目のいずれか1項に記載の宿主細胞。
(項目5)
前記サイトカイン結合ドメインは、GM-CSF結合ドメインであり、そして/または、必要に応じてヒトCSF2RであるCSF2Rの細胞外部分に由来するか、または該細胞外部分と少なくとも90%同一性を有するか、あるいは必要に応じて配列番号9または配列番号11に示される配列の細胞外部分と少なくとも90%同一性を有する、先行する項目のいずれか1項に記載の宿主細胞。
(項目6)
前記融合タンパク質のならびに/または前記第1および/もしくは第2の融合タンパク質の前記膜貫通ドメインは、IL-2RG、IL-2RB、IL-2RA、IL-4R、IL-7R、IL-9R、IL-15RまたはIL-21Rの、必要に応じてヒト起源のものの膜貫通ドメインを含む、先行する項目のいずれか1項に記載の宿主細胞。
(項目7)
前記融合タンパク質の前記膜貫通ドメインは、CSF2RA、CSF2RB、CSF1R、CSF3R、CXCR2、もしくはCCR8の、必要に応じてヒト起源のものの膜貫通ドメインを含むか、または必要に応じて、配列番号22または23と少なくとも90%アミノ酸配列同一性を有する、先行する項目のいずれか1項に記載の宿主細胞。
(項目8)
前記膜貫通ドメインは、CD2、CD3ε、CD3δ、CD3ζ、CD25、CD27、CD28、CD40、CD79A、CD79B、CD80、CD86、CD95(Fas)、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD200R、CD223(LAG3)、CD270(HVEM)、CD272(BTLA)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、CD279(PD-1)、CD300、CD357(GITR)、A2aR、DAP10、FcRα、FcRβ、FcRγ、Fyn、GAL9、KIR、Lck、LAT、LRP、NKG2D、NOTCH1、NOTCH2、NOTCH3、NOTCH4、PTCH2、ROR1、ROR2、Ryk、Slp76、SIRPα、pTα、TCRα、TCRβ、TIM3、TRIM、LPA5、またはZap70の、必要に応じてヒト起源のものの膜貫通ドメインを含む、先行する項目のいずれか1項に記載の宿主細胞。
(項目9)
前記宿主細胞は、該宿主細胞表面上でヘテロマルチマーを形成するように会合できる少なくとも2種の融合タンパク質を含む、先行する項目のいずれか1項に記載の宿主細胞。
(項目10)
前記融合タンパク質は各々、異なる細胞外構成要素を含み、ここで該異なる細胞外構成要素は、機能的サイトカイン結合ドメインを形成するように互いと会合できる、項目9に記載の宿主細胞。
(項目11)
前記異なる細胞外構成要素のうちの一方は、CSF2Rα、必要に応じてヒトCSF2Rα、細胞外部分、細胞外サイトカイン結合ドメインもしくはその一部から構成されるか、またはこれと少なくとも90%同一性を有するか、あるいは必要に応じて配列番号9と少なくとも90%同一性を有し、他方の異なる細胞外構成要素は、CSF2Rβ、必要に応じてヒトCSF2Rβ、細胞外部分、細胞外サイトカイン結合ドメインもしくはその一部から構成されるか、またはこれと少なくとも90%同一性を有するか、あるいは必要に応じて配列番号11と少なくとも90%同一性を有する、項目10に記載の宿主細胞。
(項目12)
前記融合タンパク質は各々、異なる細胞内構成要素を含み、ここで該異なる細胞内構成要素は、機能的細胞内シグナル伝達ドメインを形成するように互いと会合できる、項目9~11のいずれか1項に記載の宿主細胞。
(項目13)
前記異なる細胞内構成要素のうちの少なくとも一方は、IL-2Rγ細胞内部分、細胞内シグナル伝達ドメインもしくはその一部から構成されるか、またはこれと少なくとも90%同一性を有するか、あるいは必要に応じて配列番号10と少なくとも90%同一性を有する、項目12に記載の宿主細胞。
(項目14)
前記異なる細胞内構成要素のうちの少なくとも一方は、IL-2Rβ、IL-4RA、IL-7R、IL-15RA、またはIL-21R細胞内部分、細胞内シグナル伝達ドメインもしくはその一部から構成されるか、またはこれと少なくとも90%同一性を有し、いずれの場合にも、個々に、必要に応じてヒト由来であるか、あるいは必要に応じて配列番号12と少なくとも90%同一性を有する、項目12または13に記載の宿主細胞。
(項目15)
前記宿主細胞表面上の前記ヘテロマルチマーは、ヘテロダイマーまたはヘテロトリマーである、項目9~14のいずれか1項に記載の宿主細胞。
(項目16)
前記一方の融合タンパク質は、配列番号1からなるか、配列番号1を含むか、または配列番号1と少なくとも90%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも98%、もしくは少なくとも99%の同一性を有し、前記他方の融合タンパク質は、配列番号2からなるか、配列番号2を含むか、または配列番号2と少なくとも90%%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも98%、もしくは少なくとも99%の同一性を有する、項目15に記載の宿主細胞。
(項目17)
前記抗原結合タンパク質は、T細胞レセプター(TCR)であるか、または必要に応じて抗原特異的TCRである、先行する項目のいずれか1項に記載の宿主細胞。
(項目18)
前記抗原特異的TCRは、前記宿主細胞および/または該宿主細胞が投与される宿主に対して外因性である、先行する項目のいずれか1項に記載の宿主細胞。
(項目19)
前記TCRは、抗原::HLA複合体に高親和性で結合する、項目17または18に記載の宿主細胞。
(項目20)
前記高親和性結合は、107 M-1に等しいかまたはこれより大きなKaを有する、項目19に記載の宿主細胞。
(項目21)
前記TCRは、HLAクラスI拘束性抗原に対して特異的である、項目17~20のいずれか1項に記載の宿主細胞。
(項目22)
前記抗原は、がん特異的抗原である、先行する項目のいずれか1項に記載の宿主細胞。
(項目23)
前記がん特異的抗原は、WT-1、メソテリン、ROR1またはサイクリン-A1を含む、項目22に記載の宿主細胞。
(項目24)
前記TCRは、C4と称されるWT-1特異的TCRである、先行する項目のいずれか1項に記載の宿主細胞。
(項目25)
前記抗原結合タンパク質は、CARである、先行する項目のいずれか1項に記載の宿主細胞。
(項目26)
前記キメラ抗原レセプターは、細胞外抗原結合ドメインおよびT細胞に一次シグナルを送達できる細胞内シグナル伝達ドメイン、ならびに必要に応じて共刺激ドメインを含む、項目25に記載の宿主細胞。
(項目27)
前記細胞内シグナル伝達ドメインは、共刺激分子の細胞内シグナル伝達ドメインを含む、項目26に記載の宿主細胞。
(項目28)
前記共刺激分子は、CD28、CD137(4-1BB)、またはICOSを含む、項目27に記載の宿主細胞。
(項目29)
前記細胞内シグナル伝達ドメインは、CD3ε、CD3δ、CD3ζ、CD25、CD27、CD28、CD40、CD47、CD79A、CD79B、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD278(ICOS)、CD357(GITR)、CARD11、DAP10、DAP12、FcRα、FcRβ、FcRγ、Fyn、Lck、LAT、LRP、NKG2D、NOTCH1、NOTCH2、NOTCH3、NOTCH4、ROR2、Ryk、Slp76、pTα、TCRα、TCRβ、TRIM、Zap70、PTCH2の細胞内シグナル伝達ドメイン、もしくはこれらのうちのいずれかの組み合わせを含み、そして/または前記キメラ抗原レセプターの該細胞内シグナル伝達部分は、必要に応じてCD3 ζに由来する一次活性化シグナル伝達ドメインを含み、共刺激ドメインを含まず、そして/またはCD28シグナル伝達ドメイン、4-1BBシグナル伝達ドメインおよび/もしくはICOSシグナル伝達ドメインを含まない、項目26~28のいずれか1項に記載の宿主細胞。
(項目30)
前記細胞内シグナル伝達ドメインは、CD137(4-1BB)、CD27、CD28、ICOS、OX40(CD134)の共刺激ドメイン、またはこれらのうちのいずれかの組み合わせを含む、項目26~29のいずれか1項に記載の宿主細胞。
(項目31)
前記細胞内シグナル伝達ドメインは、CD137(4-1BB)もしくはCD28の共刺激ドメイン、またはこれらのうちのいずれかの組み合わせを含む、項目26~30のいずれか1項に記載の宿主細胞。
(項目32)
前記細胞内シグナル伝達ドメインは、CD28の共刺激ドメインを含む、項目26~31のいずれか1項に記載の宿主細胞。
(項目33)
前記細胞内シグナル伝達ドメインは、CD137(4-1BB)の共刺激ドメインを含む、項目26~32のいずれか1項に記載の宿主細胞。
(項目34)
前記細胞内シグナル伝達ドメインは、第2の細胞内シグナル伝達ドメインを含む、項目26~33のいずれか1項に記載の宿主細胞。
(項目35)
前記第2の細胞内シグナル伝達ドメインは、CD137(4-1BB)の細胞内シグナル伝達ドメインを含む、項目34に記載の宿主細胞。
(項目36)
前記CAR抗原結合ドメインは、前記抗原に対して特異的な抗体結合フラグメントまたはscFvである、項目26~33のいずれか1項に記載の宿主細胞。
(項目37)
前記宿主細胞は、少なくとも2種の抗原結合タンパク質を含み、ここで該少なくとも2種の抗原結合タンパク質は、TCRおよびCARを含む、先行する項目のいずれか1項に記載の宿主細胞。
(項目38)
抗原に対して特異的なTCRまたはキメラ抗原レセプターを含むT細胞における前記融合タンパク質の発現は、該T細胞と実質的に同じであるが、該融合タンパク質を含まない細胞と比較して、該抗原の結合に応答しておよび/または被験体への投与後に、該T細胞によって、生存、拡大、細胞毒性、サイトカイン分泌、および/または複数回の刺激への応答において、少なくとも約1.5倍、2倍、または3倍の増加を生じる、ならびに/あるいは該細胞が投与される被験体の生存の時間、無病生存期間、または1もしくはこれより多くの疾患症状の改善において少なくとも約1.5倍、2倍、または3倍の増加を生じる、項目1~37のいずれかに記載の宿主細胞。
(項目39)
前記宿主細胞は、免疫系細胞である、先行する項目のいずれか1項に記載の宿主細胞。
(項目40)
前記免疫系細胞は、T細胞である、項目39に記載の宿主細胞。
(項目41)
前記T細胞は、CD4+ T細胞である、項目40に記載の宿主細胞。
(項目42)
前記T細胞は、CD8+ T細胞である、項目40に記載の宿主細胞。
(項目43)
項目1~42のいずれか1項に記載の融合タンパク質および抗原結合タンパク質をコードする核酸分子を含む、宿主細胞。
(項目44)
ベクターを含む宿主細胞であって、ここで該ベクターは、項目1~42のいずれか1項に記載の融合タンパク質および抗原結合タンパク質をコードする核酸分子を含む、宿主細胞。
(項目45)
前記ベクターは、ウイルスベクターである、項目44に記載の宿主細胞。
(項目46)
前記ウイルスベクターは、レンチ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、項目45に記載の宿主細胞。
(項目47)
前記ウイルスベクターは、レンチウイルスベクターである、項目46に記載の宿主細胞。(項目48)
前記TCRは、抗原特異的TCRである、先行する項目のいずれか1項に記載の宿主細胞。
(項目49)
被験体において疾患を処置するための方法であって、該方法は、項目1~48のいずれか1項に記載の宿主細胞、および/または項目62~66のいずれかに記載の融合タンパク質、核酸、ベクター、組成物、または複合体を、該被験体に投与するステップを包含する方法。
(項目50)
前記疾患は、ウイルス感染症、細菌感染症、がん、および自己免疫疾患からなる群より選択される、項目49に記載の方法。
(項目51)
前記疾患は、がんである、項目50に記載の方法。
(項目52)
前記がんは、腫瘍である、項目51に記載の方法。
(項目53)
前記腫瘍は、血液腫瘍であり、該血液腫瘍は、必要に応じてCLLもしくはMCLであり、そして/または固形腫瘍であり、該固形腫瘍は、必要に応じて乳がん、肺がん、卵巣がん、もしくは膵臓がんの腫瘍であり、該固形腫瘍は、必要に応じて肺腺癌、腺癌、扁平上皮癌、小細胞癌、非定型カルチノイド、またはトリプルネガティブ乳がんである、項目52に記載の方法。
(項目54)
前記腫瘍は、原発性腫瘍、転移性腫瘍、または両方を含む、項目52または53に記載の方法。
(項目55)
前記腫瘍細胞は、WT-1、メソテリン、ROR1またはサイクリン-A1を過剰発現する、項目52~54のいずれか1項に記載の方法。
(項目56)
前記被験体は、ヒトである、項目49~55のいずれか1項に記載の方法。
(項目57)
ウイルス感染症、細菌感染症、がん、または自己免疫疾患を処置することにおける使用のための項目1~48のいずれか1項に記載の宿主細胞。
(項目58)
サイトカイン結合ドメインの全てまたは一部を含む細胞外構成要素、膜貫通ドメインおよび1種もしくはこれより多くの種のIL-2R鎖のシグナル伝達ドメインまたはそのシグナル伝達部分(複数可)を含む細胞内構成要素を含む融合タンパク質であって、ここで該サイトカイン結合ドメインは、IL-2結合ドメインではない、融合タンパク質。
(項目59)
項目58に記載の融合タンパク質をコードするヌクレオチド配列を含む核酸であって、必要に応じて、ここで融合タンパク質は、配列番号6もしくは7のポリヌクレオチド配列を含むか、または該ポリヌクレオチドからなるか、または該ポリヌクレオチドと少なくとも80%、少なくとも85%、少なくとも90%、少なくとも95%、もしくは少なくとも98%の同一性を有するポリヌクレオチドによってコードされる、核酸。
(項目60)
(a)前記融合タンパク質は、第1の融合タンパク質であり、前記サイトカイン結合ドメインの前記全てまたは一部は、該サイトカイン結合ドメインの第1の部分であり、(b)前記核酸は、第2の融合タンパク質をコードするヌクレオチド配列をさらに含み、該第2の融合タンパク質は、該サイトカイン結合ドメインの第2の部分、第2の膜貫通ドメインおよび第2のIL-2R鎖シグナル伝達ドメインもしくはそのシグナル伝達部分を含む第2の細胞内構成要素を含み、そして必要に応じて抗原レセプターもしくはその一部をコードするヌクレオチド配列をさらに含む、項目59に記載の核酸。
(項目61)
項目59または60に記載の核酸を含む、ベクター。
(項目62)
項目59に記載の核酸およびさらなる核酸を含む組成物であって、ここで(a)前記融合タンパク質は、第1の融合タンパク質であり、前記サイトカイン結合ドメインの前記全てもしくは一部は、該サイトカイン結合ドメインの第1の部分であり、そして(b)該さらなる核酸は、第2の融合タンパク質をコードするヌクレオチド配列を含み、該第2の融合タンパク質は、該サイトカイン結合ドメインの第2の部分、第2の膜貫通ドメイン、および第2のIL-2R鎖シグナル伝達ドメインもしくはそのシグナル伝達部分を含む第2の細胞内構成要素を含み、ここで該核酸およびさらなる核酸は、必要に応じて同じまたは異なるベクターから発現され、そして必要に応じて抗原レセプターもしくはその一部をコードする核酸をさらに含む、組成物。
(項目63)
第1の融合タンパク質である項目58に記載の融合タンパク質を含み、そして第2の融合タンパク質をさらに含む分子複合体であって、該第2の融合タンパク質は、前記サイトカイン結合ドメインの第2の部分、第2の膜貫通ドメインおよび第2のIL-2R鎖シグナル伝達ドメインもしくはそのシグナル伝達部分を含む第2の細胞内構成要素を含み、ここで該第1のおよび第2の融合タンパク質は、共有結合的相互作用または非共有結合的相互作用を介して、複合体で存在する、分子複合体。
(項目64)
項目58~63のいずれかに記載の融合タンパク質、核酸、ベクター、組成物、または複合体であって、ここで前記第1および/または第2の融合タンパク質は、必要に応じて配列番号9もしくは配列番号11と少なくとも90%同一性を有する、ヒトGM-CSFRの細胞外構成要素、および必要に応じて配列番号10もしくは配列番号12と少なくとも90%同一性を有する、ヒトIL-2R複合鎖の細胞内シグナル伝達部分を含む、融合タンパク質、核酸、ベクター、組成物、または複合体。
(項目65)
前記第1のおよび/もしくは第2の融合タンパク質のうちの一方は、ヒトCSF2Rβ鎖の細胞外構成要素およびヒトIL-2Rβ鎖の細胞内シグナル伝達部分を含み、ここで該CSF2Rβ鎖およびヒトIL-2Rβ鎖の細胞内シグナル伝達部分は、必要に応じてそれぞれ、配列番号11および配列番号12と少なくとも90%同一性を有し、そして/または該第1のおよび/もしくは第2の融合タンパク質のうちの一方は、ヒトCSF2Rα鎖の細胞外構成要素およびヒトIL-2Rγ鎖の細胞内シグナル伝達部分を含み、ここで該CSF2Rβ鎖およびヒトIL-2Rβ鎖の細胞内シグナル伝達部分は、必要に応じてそれぞれ、配列番号9および配列番号10と少なくとも90%同一性を有する、項目64に記載の融合タンパク質、核酸、ベクター、組成物、または複合体。
(項目66)
項目1~48のいずれかに記載の宿主細胞の1種または複数種の融合タンパク質をコードする、項目58~63のいずれかに記載の融合タンパク質、核酸、ベクターまたは組成物。
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