JP2014058525A - カチオン脂質による免疫応答の刺激 - Google Patents
カチオン脂質による免疫応答の刺激 Download PDFInfo
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Abstract
【解決手段】対象の免疫系の細胞にてMAPキナーゼ(mitogen-activated protein kinase)のシグナル伝達経路を活性化し、且つ、該対象にて免疫応答を誘導するのに十分な用量の、下記一般式で表される1種の非ステロイド性カチオン脂質を含有する組成物。
(式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択され、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル、及びそれらの組み合わせから選択される)
【選択図】図1
Description
本出願は、「疾患の治療のためのカチオン脂質系の免疫賦活剤」と題するLeaf Huangによって2007年3月22日に出願された米国特許仮出願、出願番号60/896,412号;「疾患の治療のためのカチオン脂質系二重機能送達システム及び免疫賦活剤」と題するLeaf Huang及びWeishu Chenによって2007年4月13日に出願された同60/911,549号;「疾患の治療のためのカチオン脂質系二重機能送達システム及び免疫賦活剤」と題するLeaf Huang, Weishu Chen及びWeili Yanによって2007年7月9日に出願された同60/948,512号;及び「リポソームペプチド製剤による免疫応答の誘導」と題するWeishu Chen及びLeaf Huangによって2007年10月30日に出願された同60/983,799号の利益を請求する、「カチオン脂質による免疫応答の刺激」と題するWeishu Chen, Weili Yan, Kenya Toney, Gregory Conn, Frank Bedu−Addo及びLeaf Huangによって2008年3月17日に出願された米国特許出願第12/049,957号の利益を請求する。なおこれらの文書の開示の全体を参照することにより本明細書に組み入れる。
本発明のカチオン脂質複合体は、リポソームを形成してもよく、このリポソームは、任意で抗原と混合されるか、また、カチオン脂質だけを含有してもよいし、中性脂質との併用でカチオン脂質を含有してもよい。好適なカチオン脂質種には、3−β[4N(1N8−ジグアニジノスペルミジン)−カルバモイル]コレステロール(BGSC);3−β[N,N−ジグアニジノエチル−アミノエタン)−カルバモイル]コレステロール(BGTC);N,N1,N2,N3テトラ−メチルテトラパルミチルスペルミン(セルフェクチン);N−t−N’−ブチル−N’−テトラデシル−3−テトラデシル−アミノプロピオン−アミジン(CLONフェクチン);ジメチルジオクタデシルアンモニウムブロミド(DDAB);1,2−ミリスチロキシプロピル−3−ジメチル−ヒドロキシエチルアンモニウムブロミド(DMRIE);2,3−ジオレオイルオキシ−N−[2(スペルミンカルボキサミド)エチル]−N,N−ジメチル−1−p−ロパナミニウムトリフルオロアセテート)(DOSPA);1,3−ジオレオイルオキシ−2−(6−カルボキシスペルミル)−プロピルアミド(DOSPER);4−(2,3−ビス−パルミトイルオキシ−プロピル)−1−メチル−1H−イミダゾール(DPIM);N,N,N’,N’−テトラメチル−N,N’−ビス(2−ヒドロキシエチル)−2,3−ジオレオイルオキシ−1,4−ブタンジアンモニウムイオジド(Tfx−50);N−1−(2、3−ジオレオイルオキシ)プロピル−N,N,N−トリメチルアンモニウムクロリド(DOTMA)又はそのほかのN−(N,N−1−ジアルコキシ)−アルキル−N,N,N−三置換アンモニウム界面活性剤;トリメチルアンモニウム基がブタノールスペーサーアームを介して二重鎖(DOTBについて)又はコレステリル基(ChOTBについて)に接続する1,2−ジオレオイル−3−(4’−トリメチルアンモニオ)ブタノール−sn−グリセロール(DOBT)又はコレステリル(4’−トリメチルアンモニア)ブタノエート(ChOTB);WO93/03709で開示されたようなDORI(DL−1,2−ジオレオイル−3−ジメチルアミノプロピル−β−ヒドロキシエチルアンモニウム)又はDORIE(DL−1,2−O−ジオレオイル−3−ジメチルアミノプロピル−β−ヒドロキシエチルアンモニウム)(DORIE)又はその類縁体;1,2−ジオレオイル−3−スシニル−sn−グリセロールコリンエステル(DOSC);コレステリルヘミスクシネートエステル(ChOSC);たとえば、ジオクタデシルアミドグリシルスペルミン(DOGS)及びジパルミトイルホスファチジルエタノールアミルスペルミン(DPPES)又は米国特許第5,283,185号で開示されたカチオン脂質、コレステリル−3β−カルボキシ−アミド−エチレントリメチルアンモニウムクロリド、1−ジメチルアミノ−3−トリメチルアンモニオ−DL−2−プロピル−コレステリルカルボキシレートイオジド、コレステリル−3−O−カルボキシアミドエチレンアミン、コレステリル−3−β−オキシスクシンアミド−エチレントリメチルアンモニウムイオジド、1−ジメチルアミノ−3−トリメチルアンモニオ−DL−2−プロピル−コレステリル−3−β−オキシスクシネートイオジド、2−(2−トリメチルアンモニオ)−エチルメチルアミノエチル−コレステリル−3−β−オキシスクシネートイオジド、3−β−N−(N’,N’−ジメチルアミノエタン)カルバモイルコレステロール(DC−chol)、及び3−β−N−(ポリエチレンイミン)−カルバモイルコレステロール;O,O−ジミリスチル−N−リシル−アスパルテート(DMKE);O,O−ジミリスチル−N−リシル−グルタメート(DMKD):1,2−ジミリスチルオキシプロピル−3−ジメチル−ヒドロキシエチルアンモニウムブロミド(DMRIE);1,2−ジラウロイル−sn−グリセロ−3−エチルホスホコリン(DLEPC);1,2−ジミリスチル−sn−グリセロ−3−エチルホスホコリン(DMEPC);1,2−ジオレオイル−sn−グリセロ−3−エチルホスホコリン(DOEPC);1,2−ジパルミトイル−sn−グリセロ−3−エチルホスホコリン(DPEPC);1,2−ジステアロイル−sn−グリセロ−3−エチルホスホコリン(DSEPC);1,2−ジオレオイル−3−トリメチルアンモニウムプロパン(DOTAP);ジオレオイルジメチルアミノプロパン(DODAP);1,2−パルミトイル−3−トリメチルアンモニウムプロパン(DPTAP);1,2−ジステアロイル−3−トリメチルアンモニウムプロパン(DSTAP);1,2−ミリストイル−3−トリメチルアンモニウムプロパン(DMTAP);及びドデシル硫酸ナトリウム(SDS)が挙げられるが、これらに限定されない。本発明は、本出願で開示されたカチオン脂質の構造的変異体及び誘導体の使用を企図する。
式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択され、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル、及びそれらの組み合わせから選択される。DOTAP、DMTAP、DSTAP、DPTAP、DPEPC、DSEPC、DMEPC、DLEPC、DOEPC、DMKE、DMKD、DOSPA及びDOTMAは、この一般構造を有する脂質の例である。
実施態様の1つでは、そのほかの免疫調節剤の産生を含む種々の免疫応答を押し上げる又は低下させるために、及び免疫応答を押し上げて疾患と闘うために、カチオン脂質は追加の作用剤なしで投与される。別の実施態様では、カチオン脂質は抗原(単数又は複数)との併用で投与される。この場合、目的は、カチオン脂質と併用で送達された抗原に特異的である免疫応答を生成することである。生成される応答としては、結果としてそれら抗原に関連する特定の疾患の予防又はそれへの治療的応答を生じるような、特異的な細胞傷害性T細胞、記憶T細胞又はB細胞の産生が含まれてもよい。抗原は、腫瘍関連抗原又は微生物抗原又は当業者に既知のほかの抗原であることができる。
特定の用量組成のカチオン脂質による免疫系及び抗原提示細胞への抗原送達に対する効果的な刺激は、疾患の予防及び治療において強力な免疫応答をもたらす
カチオン脂質の免疫賦活活性のメカニズム:MAPキナーゼ、ERKのリン酸化及びケモカインの誘導
A.材料及び方法
1.細胞株及びペプチド
ヒト免疫系の細胞におけるカチオン脂質/抗原複合体の免疫賦活能の実証。
Claims (28)
- 対象の免疫系の細胞にてMAPキナーゼ(mitogen-activated protein kinase)のシグナル伝達経路を活性化し、且つ、該対象にて免疫応答を誘導するするのに十分な用量の、少なくとも1種のカチオン脂質を含む、組成物。
- カチオン脂質が、ERK1(extracellular signal-regulated kinase 1)、ERK2及びp38の少なくとも1つを刺激することによって、MAPキナーゼシグナル伝達経路を活性化する、請求項1の組成物。
- カチオン脂質が以下の式
(式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択されるスペーサーであり、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル及びそれらの組み合わせから選択される)
によって表される構造を有する非ステロイド性カチオン脂質を含む、請求項1の組成物。 - カチオン脂質が、DOTAP、DOTMA、DOEPC及びそれらの組み合わせから選択される、請求項3の組成物。
- 少なくとも1つの抗原をさらに含んでカチオン脂質/抗原複合体を形成し、該カチオン脂質/抗原複合体が抗原特異的な免疫応答を刺激する、請求項1の組成物。
- カチオン脂質が、ERK1、ERK2及びp38の少なくとも1つを刺激することによって、MAPキナーゼのシグナル伝達経路を活性化する、請求項5の組成物。
- 少なくとも1つの抗原が、腫瘍関連抗原、ウイルス抗原、微生物抗原及びそれらの組み合わせから選択される、請求項5の組成物。
- 少なくとも1つの抗原が、脂質化された抗原又はその疎水性を高めるように修飾された抗原を含み、抗原と連結された疎水性基との間にリンカー配列を含有してもよい、請求項5の組成物。
- 少なくとも1つの抗原が、リポタンパク質、リポペプチド、高い疎水性を有するアミノ酸配列で修飾されたタンパク質又はペプチド、及びそれらの組み合わせから選択される、請求項8の組成物。
- 少なくとも1つの抗原に結合させたアミノ酸配列をさらに含み、得られた抗原のアミノ酸配列は、該抗原が由来する母体タンパク質に見い出されない、請求項5の組成物。
- 少なくとも1つの抗原に結合させたアミノ酸配列をさらに含み、該アミノ酸配列は、セリンに共有結合するセリンに共有結合するリジンである、請求項5の組成物。
- 少なくとも1つの抗原が、該抗原上の負の電荷を高めるように操作された抗原を含む、請求項5の組成物。
- 対象に免疫応答を誘導する方法であって、対象の免疫系の細胞にてMAPキナーゼのシグナル伝達経路の活性化を誘導するのに十分な用量の少なくとも1つのカチオン脂質を、対象に投与することを含む、方法。
- カチオン脂質が、ERK1、ERK2及びp38の少なくとも1つを刺激することによって、MAPキナーゼのシグナル伝達経路を活性化する、請求項13の方法。
- カチオン脂質が、式:
(式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択され、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル、及びそれらの組み合わせから選択される)
によって表される構造を有する非ステロイド性カチオン脂質を含む、請求項13の方法。 - カチオン脂質が、DOTAP、DOTMA、DOEPC及びそれらの組み合わせから選択される、請求項15の方法。
- 少なくとも1つの抗原をカチオン脂質と共に複合体化してカチオン脂質/抗原複合体を形成させることをさらに含み、該カチオン脂質/抗原複合体は、抗原特異的な免疫応答を刺激する、請求項13の方法。
- カチオン脂質が、ERK1、ERK2及びp38の少なくとも1つを刺激することによって、MAPキナーゼのシグナル伝達経路を活性化する、請求項17の方法。
- 少なくとも1つの抗原が、腫瘍関連抗原、ウイルス抗原、微生物抗原、及びそれらの組み合わせから選択される、請求項17の方法。
- 少なくとも1つの抗原が、脂質化された抗原又はその疎水性を高めるように修飾された抗原を含み、該抗原と連結された疎水性基との間にリンカー配列を含有してもよい、請求項17の方法。
- 少なくとも1つの抗原が、リポタンパク質、リポペプチド、高い疎水性を有するアミノ酸配列で修飾されたタンパク質又はペプチド、及びそれらの組み合わせから選択される、請求項20の方法。
- 少なくとも1つの抗原にアミノ酸配列を結合させることをさらに含み、得られた抗原のアミノ酸配列は、該抗原が由来する母体タンパク質に見い出されない、請求項17の方法。
- 少なくとも1つの抗原にアミノ酸配列を結合させることをさらに含み、該アミノ酸配列は、セリンに共有結合するセリンに共有結合するリジンである、請求項17の方法。
- 少なくとも1つの抗原上の負の電荷を高めるように、少なくとも1つの抗原を操作することをさらに含む、請求項17の方法。
- 対象の免疫系の細胞にて反応性酸素種(「ROS」)の産生を誘導するのに十分な用量の、少なくとも1つのカチオン脂質を含む組成物であって、誘導されるROSのレベルは、少なくとも1つのカチオン脂質の非存在下で存在する免疫応答を上回って免疫応答を高めるのに十分である、組成物。
- 少なくとも1つのカチオン脂質が、式:
(式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択され、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル、及びそれらの組み合わせから選択される)
によって表される構造を有する非ステロイド性カチオン脂質を含む、請求項25の組成物。 - 免疫応答を刺激するのに十分な反応性酸素種(「ROS」)を対象にて誘導する方法であって、対象の免疫系の細胞にてROSの産生を誘導するのに十分な用量の少なくとも1つのカチオン脂質を、対象に投与することを含み、誘導されるROSのレベルは、少なくとも1つのカチオン脂質の非存在下で存在する免疫応答を上回って免疫応答を高めるのに十分である、方法。
- 少なくとも1つのカチオン脂質が、式:
(式中、R1は四級アンモニウム基であり、Y1は、炭化水素鎖、エステル、ケトン及びペプチドから選択され、R2及びR3は独立して飽和脂肪酸、不飽和脂肪酸、エステル結合炭化水素、蛍光体−ジエステル、及びそれらの組み合わせから選択される)
によって表される構造を有する非ステロイド性カチオン脂質を含む、請求項27の方法。
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US12/049,957 US8877206B2 (en) | 2007-03-22 | 2008-03-17 | Stimulation of an immune response by cationic lipids |
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WO2008116078A2 (en) | 2008-09-25 |
WO2008116078A9 (en) | 2008-11-20 |
JP6211383B2 (ja) | 2017-10-11 |
US11911359B2 (en) | 2024-02-27 |
TW200902060A (en) | 2009-01-16 |
CN101702882A (zh) | 2010-05-05 |
TWI558412B (zh) | 2016-11-21 |
EP2125011B1 (en) | 2015-11-11 |
EP2125011A4 (en) | 2010-04-07 |
WO2008116078A4 (en) | 2009-10-15 |
EA200901270A1 (ru) | 2010-04-30 |
JP2010522206A (ja) | 2010-07-01 |
WO2008116078A8 (en) | 2009-07-16 |
WO2008116078A3 (en) | 2009-06-04 |
US20150093410A1 (en) | 2015-04-02 |
ES2562714T3 (es) | 2016-03-07 |
US8877206B2 (en) | 2014-11-04 |
AU2008228798A1 (en) | 2008-09-25 |
US20220031650A1 (en) | 2022-02-03 |
EP2125011A2 (en) | 2009-12-02 |
US20090017057A1 (en) | 2009-01-15 |
CN107670031A (zh) | 2018-02-09 |
US20210346333A1 (en) | 2021-11-11 |
PL2125011T3 (pl) | 2016-05-31 |
AU2008228798B2 (en) | 2014-05-15 |
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