JP6625587B2 - Tlr2を活性化するか、またはその活性を増加させるアジュバントを含むリポソーム組成物およびその使用 - Google Patents
Tlr2を活性化するか、またはその活性を増加させるアジュバントを含むリポソーム組成物およびその使用 Download PDFInfo
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Description
本出願は、2011年10月6日に出願の米国特許仮出願第61/544,020号の利益および優先権を主張し、その全体は参照により本明細書に組み込まれる。
これらの細胞は、細胞毒性または食細胞活性を有さず、感染細胞を死滅させるか病原体を除去することができないが、本質的には、これらの作業を実施するように他の細胞に指示することによって、免疫応答を「管理する」。各々異なる型の病原体を除去するように設計されているTh1およびTh2と命名されたプロフェッショナルなAPCによって、2種類のエフェクターCD4+ヘルパーT細胞応答を誘導することができる。
本発明の組成物の適当なアジュバントは、TLR2を活性化するか、またはその活性を増加させるアジュバントである。一部の実施形態では、アジュバントは脂質をベースとしたアジュバントであり、それは少なくとも1つの脂質部分または脂質構成成分を含むいかなるアジュバントも包含する。
本発明の組成物は、1つまたは複数の抗原を含む。本明細書で用いるように、用語「抗原」は、抗体に特異的に結合することができる物質を指す。組成物の適当な抗原は、対象で体液性免疫応答を誘導することが可能なものである。
元の残基 保存的置換
Ala Ser
Arg Lys
Asn Gln、His
Asp Glu
Cys Ser
Gln Asn
Glu Asp
His Asn;Gln
Ile Leu、Val
Leu Ile;Val
Lys Arg;Gln;Glu
Met Leu;Ile
Phe Met;Leu;Tyr
Ser Thr
Thr Ser
Trp Tyr
Tyr Trp;Phe
Val Ile;Leu
ヘルパーTエピトープは、ヘルパーT活性を有するアミノ酸(天然または非天然のアミノ酸)の配列である。ヘルパーTエピトープは、免疫系の能力を確立し、最大にする重要な役割を果たすヘルパーTリンパ球によって認識され、他の免疫細胞を活性化し、指示すること、例えばB細胞抗体クラススイッチングに関与する。
組成物の担体は、疎水性物質、好ましくは液体疎水性物質の連続相を含む。連続相は、実質的に純粋な疎水性物質、または疎水性物質の混合物であってもよい。さらに、疎水性物質が連続相を構成するならば、担体は疎水性物質中の水の乳濁液、または疎水性物質の混合物中の水の乳濁液であってもよい。さらに、別の実施形態では、担体はアジュバントとして機能することができる。
リポソームは、取り込まれた水性容量を含有する、完全に密閉された脂質二重層膜である。リポソームは単層小胞(単一の二重層膜を保有する)、または多重膜二重層によって特徴づけられる多層小胞であってよく、各二重層は水層によって隣から分離されても分離されなくてもよい。リポソームの総論は、Gregoriadis G. Immunol. Today、11巻:89〜97頁、1990年;およびFrezard, F.、Braz. J. Med. Bio. Res.、32巻:181〜189頁、1999年に見出すことができる。本明細書および特許請求の範囲で用いるように、用語「リポソーム」は、限定されずに「ニオソーム」、「トランスファーソーム」および「ビロソーム」のような当技術分野で記載されるものを含む、前記の全てのそのような小胞構造を包含するものとする。
本発明のさらなる実施形態は、リポソーム;体液性免疫応答を誘導することができる抗原;疎水性物質の連続相を含む担体;TLR2を活性化するか、またはその活性を増加させるアジュバントを含む本発明の組成物の作製方法を含む。
本発明は、任意選択でキットとして使用者に提供される。例えば、本発明のキットは、本発明の組成物の1つまたは複数を含有する。キットは、1つまたは複数の追加の試薬、パッケージング材料、キットの構成成分を保持するための容器、およびキット構成成分を用いる好ましい方法を詳述するインストラクションセットまたは利用者マニュアルをさらに含んでもよい。
本発明の特定の実施形態には、それらに限定されないが以下のものが含まれる:
1.リポソーム;体液性免疫応答を誘導することができる抗原;疎水性物質の連続相を含む担体;およびTLR2を活性化するか、またはその活性を増加させるアジュバント、好ましくは脂質をベースとするアジュバントを含むか、それらからなるか、または実質的になる組成物。
本発明は次の実施態様を含む。
(1)リポソーム;
体液性免疫応答を誘導することができる抗原;
疎水性物質の連続相を含む担体;および
toll様受容体2(TLR2)を活性化するか、またはその活性を増加させるアジュバントを含む組成物。
(2)アジュバント、好ましくは脂質をベースとしたアジュバントが、TLR2またはTLR1/2もしくはTLR2/6などのTLR2二量体を活性化するか、またはその活性を増加させる、上記(1)に記載の組成物。
(3)アジュバントが、例えばリポアミノ酸、リポグリカン、リポ多糖、リポタイコ酸、またはグラム陽性菌もしくはグラム陰性菌、ロドシュードモナス・ビリディス(Rhodopseudomonas viridis)またはマイコプラズマの細胞壁構成成分を含む、少なくとも1つの天然、合成または半合成の脂質部分、脂質構成成分またはその類似体もしくは誘導体を含む化合物である、上記(1)または(2)に記載の組成物。
(4)アジュバントが、PAM 2 Cys−Ser−(Lys)4(配列番号1)、PAM 3 Cys−Ser−(Lys)4(配列番号1)、PAM 3 Cys−SKKKK(β照射)(配列番号1)、R−PAM 3 Cys−SKKKK(配列番号1)、S−PAM 3 Cys−SKKKK(配列番号1)、PAM 3 Cys−SKKKK(ビオチン−Aca−Aca)(配列番号1)、PAM 3 Cys−SKKKK(フルオレセイン−Aca−Aca)(配列番号1)、PAM 3 Cys−SKKKK(ローダミン−Aca−Aca)(配列番号1)、PAM 3 Cys−SKKKK−FLAG−タグ(配列番号1)、PHC−SKKKK(配列番号3)、PHC−SKKKK(ビオチン−Aca−Aca)(配列番号3)、PAM 3 Cys−SSNAKIDQLSSDVQT(配列番号4)、PAM 3 Cys−SSNKSTTGSGETTTA(配列番号5)、PAM 3 Cys−SSTKPVSQDTSPKPA(配列番号6)、PAM 3 Cys−SSGSKPSGGPLPDAK(配列番号7)、PAM 3 Cys−SSGNKSAPSSSASSS(配列番号8)、PAM 3 Cys−GSHQMKSEGHANMQL(配列番号9)、PAM 3 Cys−SSSNNDAAGNGAAQT(配列番号10)、PAM 3 Cys−KQNVSSLDEKNSVSV(配列番号11)、PAM 3 Cys−NNSGKDGNTSANSAD(配列番号12)、PAM 3 Cys−NNGGPELKSDEVAKS(配列番号13)、PAM 3 Cys−SQEPAAPAAEATPAG(配列番号14)、PAM 3 Cys−SSSKSSDSSAPKAYG(配列番号15)、PAM 3 Cys−AQEKEAKSELDYDQT(配列番号16)、PAM 2 Cys−SKKKK(RRおよびRS立体異性体の混合物)(配列番号1)、R−PAM 2 Cys−SKKKK(RR立体異性体)(配列番号1)、S−PAM 2 Cys−SKKKK(RS立体異性体)(配列番号1)、PAMCys(PAM)−SKKKK(配列番号3)、PAM 2 Cys−SKKKK(ビオチン−Aca−Aca)−NH 2 (配列番号1)、PAM 2 Cys−SKKKK(フルオレセイン−Aca−Aca)−NH 2 (配列番号1)、PAM 2 Cys−SKKKK(ローダミン−Aca−Aca)−NH 2 (配列番号1)、PAM 2 Cys−SKKKK−FLAG−タグ(配列番号1)、PAM−Dhc−SKKKK(配列番号3)、PAM−CSKKKK(配列番号1)、PAM−Dhc−GDPKHPKSF(配列番号17)、PAM−CGDPKHPKSF(配列番号2)、FSL−1(Pam2CGDPKHPKSF)(配列番号2)、FSL−1−Ala、マクロファージ活性化リポペプチド−2(MALP−2)、M.スメグマチス(M. smegmatis)からのリポアラビノマンナン(LAM−MS)、M.スメグマチス(M. smegmatis)からのリポマンナン(LM−MS)、P.ジンジバリス(P. gingivalis)からのリポ多糖(LPS−PG超高純度)、枯草菌(B. subtilis)(LTA−BS)もしくは黄色ブドウ球菌(S. aureus)(LTA−SA)からのリポタイコ酸、またはその誘導体もしくは類似体であるか、またはグラム陽性菌もしくはグラム陰性菌の細胞壁構成成分を含む加熱死菌である、上記(1)〜(3)のいずれかに記載の組成物。
(5)アジュバントがパルミチン酸アジュバントである、上記(1)〜(4)のいずれかに記載の組成物。
(6)アジュバントがジパルミトイル−S−グリセリル−システイン(PAM 2 Cys)またはトリパルミトイル−S−グリセリル−システイン(PAM 3 Cys)を含む、上記(1)〜(5)のいずれかに記載の組成物。
(7)アジュバントがPAM 2 Cys−Ser−(Lys)4(配列番号1)またはPAM 3 Cys−Ser−(Lys)4(配列番号1)である、上記(1)〜(6)のいずれかに記載の組成物。
(8)抗原がポリペプチドまたは炭水化物である、上記(1)〜(7)のいずれかに記載の組成物。
(9)抗原がB細胞エピトープまたは複数のB細胞エピトープを含む、上記(1)〜(8)のいずれかに記載の組成物。
(10)B細胞エピトープが、例えばインフルエンザウイルス、百日咳菌(Bordetella pertussis)または炭疽菌(Bacillus anthracis)を含むウイルスまたは細菌に由来する、上記(9)に記載の組成物。
(11)B細胞エピトープが、H5N1インフルエンザウイルスの血球凝集素タンパク質のエピトープ、百日咳トキソイドタンパク質のエピトープまたは炭疽菌組換え防御抗原のエピトープである、上記(10)に記載の組成物。
(12)抗原が、感染性疾患と関連する抗原;膜表面に結合したがん抗原;毒素;花粉などのアレルゲン;または循環中の抗原、例えばアミロイドタンパク質を隔離することが望ましい疾患と関連する抗原である、上記(1)〜(9)のいずれかに記載の組成物。
(13)抗原がリポソームに封入されるか、抗原とアジュバントの両方がリポソームに封入される、上記(1)〜(12)のいずれかに記載の組成物。
(14)単回投与で体液性免疫応答を誘導することが可能である、上記(1)〜(13)のいずれかに記載の組成物。
(15)体液性免疫応答によって改善される疾患または障害の処置または予防のための、上記(1)〜(14)のいずれかに記載の組成物。
(16)感染性疾患;膜表面に結合したがん抗原を伴うがん;または、アルツハイマー病などの、循環中の抗原を隔離することが望ましい疾患もしくは障害の処置または予防のための、上記(1)〜(14)のいずれかに記載の組成物。
(17)毒素、ウイルス、細菌またはアレルゲンを抗体で中和するための、上記(1)〜(14)のいずれかに記載の組成物。
(18)上記(1)〜(14)のいずれかに記載の組成物を対象に投与することを含む、体液性免疫応答によって改善される疾患または障害を処置または予防する方法。
(19)感染性疾患、膜表面に結合したがん抗原を伴うがん;または、アルツハイマー病などの、循環中の抗原を隔離することが望ましい疾患もしくは障害を処置または予防する方法であって、上記(1)〜(14)のいずれかに記載の組成物を対象に投与することを含む方法。
(20)毒素、ウイルス、細菌またはアレルゲンを抗体で中和する方法であって、上記(1)〜(14)のいずれかに記載の組成物を対象に投与することを含む方法。
Claims (12)
- 疎水性物質の連続相を含む担体で再構成された、抗原を含むリポソーム及びtoll様受容体2(TLR2)を活性化するか、またはその活性を増加させるアジュバントを含む無水組成物であって、
前記抗原が、B細胞エピトープを含み、体液性免疫応答を誘導することができる抗原であり、
前記アジュバントが、ジパルミトイル−S−グリセリル−システイン(PAM2Cys)またはトリパルミトイル−S−グリセリル−システイン(PAM3Cys)を含み、前記抗原がアジュバントに共有結合で結合しておらず、
前記組成物が、ポリI:Cポリヌクレオチドアジュバントを含まない、無水組成物。 - アジュバントが、TLR1/2もしくはTLR2/6のTLR2二量体と相互作用することにより、TLR2を活性化するか、またはその活性を増加させる、請求項1に記載の組成物。
- 抗原がポリペプチドまたは炭水化物である、請求項1又は2に記載の組成物。
- 抗原が複数のB細胞エピトープを含む、請求項1〜3のいずれか一項に記載の組成物。
- B細胞エピトープが、例えばインフルエンザウイルス、百日咳菌(Bordetella pertussis)または炭疽菌(Bacillus anthracis)を含むウイルスまたは細菌に由来する、請求項1〜4のいずれか一項に記載の組成物。
- B細胞エピトープが、H5N1インフルエンザウイルスの血球凝集素タンパク質のエピトープ、百日咳トキソイドタンパク質のエピトープまたは炭疽菌組換え防御抗原のエピトープである、請求項5に記載の組成物。
- 抗原が、感染性疾患と関連する抗原;膜表面に結合したがん抗原;毒素;花粉などのアレルゲン;または循環中の抗原、例えばアミロイドタンパク質を隔離することが望ましい疾患と関連する抗原である、請求項1〜4のいずれか一項に記載の組成物。
- 抗原とアジュバントの両方がリポソームに封入される、請求項1〜7のいずれか一項に記載の組成物。
- 単回投与で体液性免疫応答を誘導することが可能である、請求項1〜8のいずれか一項に記載の組成物。
- 体液性免疫応答によって改善される疾患または障害の治療または予防のための、請求項1〜9のいずれか一項に記載の組成物。
- 感染性疾患;膜表面に結合したがん抗原を伴うがん;または、アルツハイマー病などの、循環中の抗原を隔離することが望ましい疾患もしくは障害の治療または予防のための、請求項1〜9のいずれか一項に記載の組成物。
- 毒素、ウイルス、細菌またはアレルゲンを抗体で中和するための、請求項1〜9のいずれか一項に記載の組成物。
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JP2014528955A (ja) | 2014-10-30 |
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AU2012321022A1 (en) | 2014-04-17 |
CN103998058B (zh) | 2021-11-05 |
CN113876945A (zh) | 2022-01-04 |
HK1201044A1 (en) | 2015-10-23 |
CN103998058A (zh) | 2014-08-20 |
US11077184B2 (en) | 2021-08-03 |
IL231888A0 (en) | 2014-05-28 |
ES2855474T3 (es) | 2021-09-23 |
US10105435B2 (en) | 2018-10-23 |
BR112014007927A2 (pt) | 2017-04-11 |
BR112014007927B1 (pt) | 2021-04-13 |
JP6240077B2 (ja) | 2017-11-29 |
EP2763698A4 (en) | 2015-08-05 |
CA2850857C (en) | 2022-07-26 |
AU2012321022B2 (en) | 2017-03-23 |
IN2014CN02581A (ja) | 2015-08-07 |
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