JP2020515282A - 多標的キメラ抗原受容体 - Google Patents
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- A61K2239/29—Multispecific CARs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
Abstract
Description
加えて、キメラ抗原受容体の1つが免疫チェックポイント関連部位になる場合、免疫細胞の活性は、免疫学的チェックポイントによって伝達される負のシグナルを遮断することによって大きく増強され得る。例えば、PD−1(プログラム細胞死1)およびその受容体のPD−L1、PD−L2は、T細胞の活性の重要な調節因子である(OkazakiおよびHonjo、2007年)。他の細胞におけるPD−L1/2に対して、T細胞の表面におけるPD−1の結合は、T細胞の阻害を引き起こし、これは、ヒトにおける自己免疫疾患の回避および免疫寛容を生じさせるプロセスにおいて重要な役割を果たすが、病原微生物に感染した一部の細胞およびがん細胞は、これらのPD−L1/2のアップレギュレーション、次いで、またはT細胞におけるPD−1発現によってT細胞の監視から逃れることもでき、疾患をもたらす(Freemanら、2000年;Keirら、2008年;Parryら、2005年)。したがって、研究者らは、このシグナル伝達経路を遮断するために、抗原と結合するPD−1またはPD−L1に対する抗体を探索し、これは、T細胞の活性を有意に改善し、病原微生物およびがんに対する身体の抵抗性を増強することができる(Topalianら、2012年;Yanan Guo1、2016年)。MSLNを標的とするCAR−T療法とPD1抗体の組合せは、この組合せが腫瘍細胞を死滅させるCAR−T細胞の能力を向上させることを示している(Cherkassky L、Morello A、Villenavargas Jら、2016年)。さらにまた、研究者らは、免疫チェックポイント分子であるPD1またはCTLA−4を細胞内シグナル領域と連結させることによって、いわゆるキメラ抗原受容体スイッチングシステムを構築した。この方法では、腫瘍細胞および腫瘍内微小環境からの免疫チェックポイントによる負のシグナルが変化して、処置する腫瘍におけるCAR−T細胞の有効性を向上させ、オフターゲット効果の危険性を低減する(Liu X、Ranganathan R、Jiang Sら、2016年;Fedorov VD、Themeli M、Sadelain M.、2013年)。多くの臨床試験は、メラノーマ(Choら、2016年;Hamidら、2013年)、多発性骨髄腫(Badrosら、2015年)、白血病(Porkkaら、2014年)の処置のためのPD−1/PD−L1抗体が良好な治療効果を有することを実証している(特許番号:200380109929.8、201310258289.2、201180019629.5)。したがって、複数の標的を認識するCAR分子の改変は、細胞の免疫療法において重要な役割を果たす。
1. 多標的キメラ抗原受容体(RaceCar)タンパク質を、主ペプチド鎖Xおよび補助ペプチド鎖Yを複合体化することによって得る。
Claims (27)
- 主ペプチド鎖および補助ペプチド鎖で構成される多標的キメラ抗原受容体であって、前記主ペプチド鎖が、抗原結合ドメインA、補助ペプチド鎖連結ドメインB、膜貫通ドメインCおよび細胞内シグナル伝達構造ドメインDからなり;前記補助ペプチド鎖が、主ペプチド鎖連結ドメインFを含み;前記抗原結合ドメインAが、抗原と結合する能力を有するポリペプチドであり;前記補助ペプチド鎖連結ドメインBが、互いに前記主ペプチド鎖連結ドメインFと結合することができ;前記補助ペプチド鎖連結ドメインBおよび前記主ペプチド鎖連結ドメインFが、互いに結合することができる、サイトカインおよび完全長の対応するサイトカイン受容体、またはサイトカインおよび対応するサイトカイン受容体断片であり;前記膜貫通ドメインCが、任意の膜結合性タンパク質の膜貫通領域または膜貫通タンパク質の膜貫通領域であり;前記細胞内シグナル伝達ドメインDが、一次シグナル伝達領域を含む、多標的キメラ抗原受容体。
- 前記補助ペプチド鎖が、抗原結合ドメインEをさらに含み;前記抗原結合ドメインEが、抗原結合機能を有するポリペプチドであり;前記抗原結合ドメインEおよび前記抗原結合ドメインAが、同一または相違し得る、請求項1に記載の多標的キメラ抗原受容体。
- 前記細胞内シグナル伝達ドメインDが、共刺激シグナル伝達領域をさらに含む、請求項1または2に記載の多標的キメラ抗原受容体。
- 抗原結合能力を有する前記ポリペプチドが、抗原と結合することが可能な抗体、抗原と結合することが可能なリガンドまたは抗原と結合する能力を有する受容体である、請求項2または3に記載の多標的キメラ抗原受容体。
- 抗原と結合することが可能な前記抗体が、完全長抗体、抗体のFab、抗体のFc、scFv、VHH、抗体のVH、抗体のVLの完全長ポリペプチドまたは抗体のVLの部分断片であり;前記抗原結合リガンドまたは前記抗原結合受容体が、リガンドまたは受容体の完全長ポリペプチドまたは部分断片である、請求項4に記載の多標的キメラ抗原受容体。
- 前記抗原結合ドメインAまたは前記抗原結合ドメインEによって結合される前記抗原が、細胞表面抗原またはペプチドを有するMHC分子のいずれかである、請求項2〜5のいずれか一項に記載の多標的キメラ抗原受容体。
- 前記抗原が、がん関連抗原であるか;あるいは、前記抗原が、脳がん、膀胱がん、乳がん、子宮頸がん、結腸直腸がん、肝臓がん、腎臓がん、リンパ腫、白血病、肺がん、メラノーマ、転移性メラノーマ、中皮腫、神経芽細胞腫、卵巣がん、前立腺がん、膵臓がん、腎臓がん、皮膚がん、胸腺腫、肉腫、非ホジキンリンパ腫、ホジキンリンパ腫、子宮がんまたはこれらの任意の組合せに関する抗原である、請求項6に記載の多標的キメラ抗原受容体。
- 前記抗原結合ドメインAおよび前記抗原結合ドメインEによって結合される前記抗原が、以下:CD123、CD19、CD20、CD22、CD37、ROR1、メソテリン、CD33/IL3Ra、c−Met、BCMA、PSMA、EGFRvIII、GD−2、NY−ESO−1、MAGEA3、β−ヒト絨毛性ゴナドトロピン、AFP、RAGE−1、MN−CA IX、ヒトテロメラーゼ逆転写酵素、RU1、RU2(AS)、hsp70−2、M−CSF、PSA、PAP、LAGE−la、p53、プロステイン、PSMA、Her2/neu、テロメラーゼ、PCTA−1、MAGE、ELF2M、IGF−I、IGF−II、IGF−I受容体、BCR−ABL、E2A−PRL、H4−RET、1GH−IGK、MYL−RAR、GP100、Mart1、TSP−180、MAGE−4、MAGE−5、MAGE−6、RAGE、p185erbB2、p180erbB−3、c−met、nm−23H1、TAG−72、CA 19−9、CA 72−4、CAM 17.1、NuMa、K−ras、β−カテニン、CDK4、Mum−1、p15、p16、43−9F、5T4、791Tgp72、β−HCG、BCA225、BTAA、CA 125、CA 15−3\CA 27.29\BCAA、CA 195、CA 242、CA−50、WT1、CD68、FGF−5、G250、EpCAM、MA−50、MG7−Ag、MOV 18、NB/70K、RCAS1、SDCCAG16、TA−90、TAAL6、TAG72、TLP、p53、Ras、TPS、エプスタインバーウイルス抗原EBVAならびにヒトパピローマウイルス(HPV)抗原E6およびE7、またはこれらの組合せであるか;あるいは前記抗原結合ドメインAおよび前記抗原結合ドメインEによって結合される前記抗原が、MHCおよび上述のいずれか1つの抗原の短いペプチドの複合体である、請求項2〜7のいずれか一項に記載の多標的キメラ抗原受容体。
- 前記抗原結合ドメインAおよび前記抗原結合ドメインEによって結合される前記抗原が、CD19、CD20、BCMA、CD22、CD33/IL3Ra、Her2、PDL1、NY−ESO−1、GP100、Mart1、WT1、またはこれらの任意の組合せであるか;あるいは前記抗原結合ドメインAおよび前記抗原結合ドメインEによって結合される前記抗原が、MHCおよび上記の抗原の1つの短いペプチドの複合体である、請求項8に記載の多標的キメラ抗原受容体。
- 前記サイトカインおよび前記対応するサイトカイン受容体が、γcサイトカインファミリーにおけるサイトカインおよび対応するサイトカインならびにその受容体である、請求項1〜9のいずれか一項に記載の多標的キメラ抗原受容体。
- γcサイトカインファミリーにおける前記サイトカインおよび前記対応するサイトカイン受容体が、IL15およびIL15Rα、IL4およびIL4Rα、またはIL2およびIL2Rαであるか;あるいはγcサイトカインファミリーにおける前記サイトカインおよび前記対応するサイトカイン受容体が、IL15およびIL15Rα、IL4およびIL4Rα、IL2またはIL2Rαと75%より高い相同性を有するポリペプチドである、請求項10に記載の多標的キメラ抗原受容体。
- 前記一次シグナル伝達領域が、以下のタンパク質の1つ、または複数の以下のタンパク質の任意の組合せのシグナル伝達領域:CD3−ζ、FcεRIγ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79bおよびCD66dであるか;あるいは前記一次シグナル伝達領域が、配列6で示されるCD3−ζシグナル伝達領域のアミノ酸配列を有するCD3−ζシグナル伝達領域、または配列6で示されるCD3−ζシグナル伝達領域と75%より高い相同性を有するポリペプチドである、請求項1〜11のいずれか一項に記載の多標的キメラ抗原受容体。
- 前記共刺激シグナル伝達領域が、以下:CD27、CD28、4−1BB(CD137)、OX40、CD30、CD40、PD−1、ICOS、リンパ球機能関連抗原−1、CD2、CD7、LIGHT、NKG2C、B7−H3、およびCD83と特異的に結合するシグナル伝達領域の分子のうちの1つまたは複数の任意の組合せであるか、あるいは前記共刺激シグナル伝達領域が、特に、アミノ酸配列7のCD28シグナル伝達領域またはアミノ酸配列8の4−1BBシグナル伝達領域の1つまたは両方の組合せであるか;あるいは、前記共刺激シグナル伝達領域が、CD28シグナル伝達領域および4−1BBシグナル伝達領域のそれぞれと75%より高い相同性を有する2つのポリペプチドの1つまたは組合せである、請求項3〜12のいずれか一項に記載の多標的キメラ抗原受容体。
- 前記多標的キメラ抗原受容体において、前記抗原結合ドメインAまたはEが、抗CD19−ScFv、抗MHC/GP100−VHH、抗MHC/WT1−VH、抗CD20−ScFv、抗CD22−ScFvまたはPD1細胞外領域の1つまたは両方の組合せであり;前記補助ペプチド鎖連結ドメインが、IL15Rαsushi、IL4Rα−N−FN3、IL15またはIL4であり;前記膜貫通ドメインが、CD8の膜貫通領域またはCD28の膜貫通領域であり;前記細胞内シグナル伝達ドメインが、CD3ζシグナル伝達領域、CD3ζシグナル伝達領域および4−1BBシグナル伝達領域が融合することによって得られるポリペプチド、またはCD3ζシグナル伝達領域がCD28シグナル伝達領域と融合することによって得られるポリペプチドであり;前記主ペプチド鎖連結ドメインが、IL15、IL4、IL15RαsushiまたはIL4RαもしくはN−FN3であるか;あるいは、前記多標的キメラ抗原受容体において、前記抗原結合ドメインAが、抗CD19−ScFvであり;前記補助ペプチド鎖連結ドメインが、IL15Rαsushiであり;前記膜貫通ドメインが、CD8の膜貫通領域であり;前記細胞内シグナル伝達ドメインが、CD3ζシグナル伝達領域が4−1BB(CD137)シグナル伝達領域と融合することによって得られるポリペプチドであり;前記抗原結合ドメインEが、PD1の細胞外領域であり;前記主ペプチド鎖連結ドメインが、IL15である、請求項2〜12のいずれか一項に記載の多標的キメラ抗原受容体。
- 前記抗CD19−ScFvのアミノ酸配列が、配列1であり;前記抗MHC/GP100−VHHのアミノ酸配列が、配列15であり;抗MHC/Mart1−VHHのアミノ酸配列が、配列16であり;前記抗CD20−ScFvのアミノ酸配列が、配列17であり;前記抗CD22−ScFvのアミノ酸配列が、配列18であり;前記抗MHC/WT1−VHのアミノ酸配列が、配列19であり;PD1の細胞外領域のアミノ酸配列が、配列2であり;IL15Rαsushiのアミノ酸配列が、配列4であり;前記IL4Rα−N−FN3のアミノ酸配列が、配列20であり;CD8の膜貫通領域のアミノ酸配列が、配列5であり;CD28の膜貫通領域のアミノ酸配列が、配列22であり;前記CD3ζシグナル伝達領域のアミノ酸配列が、配列6であり;4−1BBシグナル伝達領域のアミノ酸配列が、配列8であり;CD28シグナルのアミノ酸配列が、配列7であり;IL15のアミノ酸配列が、配列3であり;IL4のアミノ酸配列が、配列21である、請求項14に記載の多標的キメラ抗原受容体。
- 前記多標的キメラ抗原受容体の前記主ペプチド鎖のアミノ酸配列が、配列9、配列23、配列24、配列25、配列26、配列27、配列28または配列29の1つであり;前記受容体の前記補助ペプチド鎖のアミノ酸配列が、配列3、配列4、配列10、配列30、配列31、配列32、配列33または配列34の1つである、請求項1〜15のいずれか一項に記載の多標的キメラ抗原受容体。
- 主ペプチド鎖をコードする核酸分子および補助ペプチド鎖をコードする核酸分子で構成される、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体をコードする核酸分子。
- 組換えベクター、発現カセット、組換え微生物株、細胞または組換えウイルスに含まれる、請求項17に記載の核酸分子。
- 前記細胞が、原核細胞、酵母細胞もしくは哺乳動物細胞であるか;または前記哺乳動物細胞が、特に、ヒト細胞であるか;または前記ヒト細胞が、特に、免疫細胞であるか;あるいは前記免疫細胞が、特に、T細胞もしくはNK細胞である、請求項18に記載の細胞。
- 請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項16、17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞または組換えウイルス、組換えプラスミドを含む、キット。
- 免疫療法の適用のための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換えプラスミド、細胞もしくは組換えウイルスまたは請求項20に記載のキットの使用;あるいは、免疫療法製品の調製のための、請求項1〜16のいずれかに記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、または請求項20に記載のキットの使用。
- 免疫細胞を培養するため、および/または免疫細胞の増殖を促進するための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換えプラスミド、細胞もしくは組換えウイルスまたは請求項20に記載のキットの使用;あるいは、免疫細胞の培養の調製の製品のため、および/または免疫細胞の増殖を促進するための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、または請求項20に記載のキットの使用。
- イムノアッセイの適用のための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換えプラスミド、細胞もしくは組換えウイルスまたは請求項20に記載のキットの使用;あるいは、免疫検出製品の調製のための、請求項1〜16のいずれかに記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、または請求項20に記載のキットの使用。
- 腫瘍の処置または検出のための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルスまたは請求項20に記載のキットの使用;あるいは、腫瘍治療製品または腫瘍検出製品の調製のための、請求項1〜16のいずれかに記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、または請求項20に記載のキットの使用。
- 腫瘍細胞を阻害または死滅させる適用のための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、請求項20に記載のキットの使用;あるいは、腫瘍細胞を阻害または死滅させるための製品の調製のための、請求項1〜16のいずれかに記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、請求項18に記載の組換えベクター、発現カセット、組換え微生物株、細胞もしくは組換えウイルス、または請求項20に記載のキットの使用。
- 言及した抗原を発現する標的細胞を阻害または死滅させるための、請求項1〜19のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、または請求項18に記載の組換えベクター、発現カセット、組換え微生物株、トランスジェニック細胞もしくは組換えウイルス、請求項20に記載のキットの使用;あるいは、前記抗原を阻害または死滅させるための標的細胞製品の調製における使用のための、請求項1〜16のいずれか一項に記載の多標的キメラ抗原受容体、請求項17に記載の核酸分子、請求項18に記載の組換えベクター、発現カセット、組換え微生物株、トランスジェニック細胞、もしくは組換えウイルス、または請求項20に記載のキットの使用。
- 前記免疫療法が、免疫細胞によって腫瘍細胞を阻害または死滅させるためであるか;あるいは前記免疫細胞が、T細胞またはNK細胞であるか;あるいは前記抗原が、がん関連抗原であるか;あるいは前記抗原が、脳がん、膀胱がん、乳がん、子宮頸がん、結腸直腸がん、肝臓がん、腎臓がん、リンパ腫、白血病、肺がん、メラノーマ、転移性メラノーマ、中皮腫、神経芽細胞腫、卵巣がん、前立腺がん、膵臓がん、腎臓がん、皮膚がん、胸腺腫、肉腫、非ホジキンリンパ腫、ホジキンリンパ腫、子宮がんに関する抗原またはこれらの任意の組合せであるか;前記腫瘍が、脳がん、膀胱がん、乳がん、子宮頸がん、結腸直腸がん、肝臓がん、腎臓がん、リンパ腫、白血病、肺がん、メラノーマ、転移性メラノーマ、中皮腫、神経芽細胞腫、卵巣がん、前立腺がん、膵臓がん、腎臓がん、皮膚がん、胸腺腫、肉腫、非ホジキンリンパ腫、ホジキンリンパ腫、子宮がん、またはこれらの1つもしくは任意の組合せであるか;あるいは前記標的細胞が、原核細胞、酵母細胞または哺乳動物細胞であるか;あるいは特に、前記哺乳動物細胞が、ヒト細胞であるか;あるいは特に、ヒト細胞が、前記免疫細胞であるか;あるいは免疫細胞が、T細胞またはNK細胞である、請求項21〜26のいずれか一項に記載の使用。
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WO2020190771A1 (en) * | 2019-03-15 | 2020-09-24 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric adaptor and kinase signaling proteins and their use in immunotherapy |
CN112279923B (zh) * | 2019-07-22 | 2023-07-18 | 南京助天中科科技发展有限公司 | 一种嵌合抗原受体及其应用 |
CN113461824A (zh) * | 2020-03-31 | 2021-10-01 | 普米斯生物技术(珠海)有限公司 | 一种构建多特异性抗体的平台 |
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CN112877346B (zh) * | 2020-08-12 | 2023-01-03 | 山东兴瑞生物科技有限公司 | 抗b7-h3嵌合抗原受体的编码基因、制备方法、具有该基因的质粒、免疫细胞及其应用 |
CN113234685A (zh) * | 2021-05-25 | 2021-08-10 | 临沂大学 | 一种双靶点cd19/cd20联用嵌合抗原受体t细胞及其制备方法和应用 |
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CN114634580B (zh) * | 2022-03-21 | 2024-01-30 | 皖南医学院第一附属医院(皖南医学院弋矶山医院) | 一种膜锚定式il-15超级复合物的研制及其在肿瘤免疫细胞治疗中的应用 |
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