JP6371058B2 - 結合していないアジュバントを有するナノキャリア組成物 - Google Patents
結合していないアジュバントを有するナノキャリア組成物 Download PDFInfo
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- JP6371058B2 JP6371058B2 JP2013512250A JP2013512250A JP6371058B2 JP 6371058 B2 JP6371058 B2 JP 6371058B2 JP 2013512250 A JP2013512250 A JP 2013512250A JP 2013512250 A JP2013512250 A JP 2013512250A JP 6371058 B2 JP6371058 B2 JP 6371058B2
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- adjuvant
- nanocarrier
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Description
本出願は、米国特許法第119条に基づき、2010年5月26日に出願された米国仮特許出願第61/348713号、2010年5月26日に出願された同第61/348717号、2010年5月26日に出願された同第61/348728号、および2010年6月25日に出願された同第61/358635号の優先権の利益を主張するものであり、その内容全体を本明細書に援用する。
本願発明者らは、想定外かつ驚くべきことに、本明細書に開示の本発明を実施することで、上述した課題および制約を回避できることを見出した。本願発明者らは、想定外かつ驚くべきことに、合成ナノキャリアの集合と、どの合成ナノキャリアにも結合していないアジュバントとを投与すると、そうでない場合よりも強く迅速な免疫反応が得られることを発見した。特に、本願発明者らは、(1)合成ナノキャリアの集合と、(2)どの合成ナノキャリアとも結合されていない第1のアジュバントと、(3)薬学的に許容可能な賦形剤を含む剤形を含む組成物と関連した組成物および方法を提供可能であることを想定外に発見した。
「アジュバント」とは、特定の抗原を構成しないが、同時に投与された抗原に対する免疫反応の強度と、もちとをブーストする因子を意味する。このようなアジュバントは、Toll様受容体、RIG−1およびNOD様受容体(NLR)などのパターン認識受容体の刺激物質、ミョウバンなどの鉱物塩、エシェリキア・コリ(Escherihia coli)、サルモネラ・ミネソタ(Salmonella minnesota)、サルモネラ・チフィリウム(Salmonella typhimurium)またはシゲラ・フレックスネリ(Shigella flexneri)などの腸内細菌のモノホスホリルリピド(MPL)Aと組み合わせたミョウバン、あるいは特にMPL(登録商標)(AS04)すなわち上述した細菌のMPL Aと別々に組み合わせたミョウバン、QS−21、Quil−A、ISCOMs、ISCOMATRIX(商標)などのサポニン、MF59(商標)、Montanide(登録商標) ISA 51およびISA 720などのエマルション、AS02(QS21+スクワレン+MPL(登録商標))、AS15、AS01などのリポソームおよびリポソーム製剤、ナイセリア・ゴノレー(N. gonorrheae)、クラミジア・トラコマチス(Chlamydia trachomatis)といった細菌由来の外膜小胞(OMV)などの合成または特異的に調製した微粒子およびマイクロキャリア、あるいはキトサン粒子、Pluronic(登録商標)ブロックコポリマーなどのデポを形成する作用剤、ムラミルジペプチドなどの特異的に修飾または調製されたペプチド、RC529などのアミノアルキルグルコサミニド4−ホスフェート、あるいは細菌トキソイドまたは毒素フラグメントなどのタンパク質を含むものであってもよいが、これに限定されるものではない。
多岐にわたる合成ナノキャリアを、本発明に従って使用可能である。いくつかの実施形態では、合成ナノキャリアが、球形または回転楕円形である。いくつかの実施形態では、合成ナノキャリアが、平坦または板状である。いくつかの実施形態では、合成ナノキャリアが立方体形、直方体形または立方体である。いくつかの実施形態では、合成ナノキャリアが、卵形または長円形である。いくつかの実施形態では、合成ナノキャリアが、円柱形、錐形または角錐形である。
合成ナノキャリアについては、従来技術において知られている多岐にわたる方法で調製すればよい。たとえば、合成ナノキャリアは、ナノ沈殿、流体用の流路を用いるフローフォーカシング、噴霧乾燥、シングルおよびダブルエマルション溶媒蒸発、溶媒抽出、相分離、ミリング、マイクロエマルション法、マイクロファブリケーション、ナノファブリケーション、犠牲層、単純コアセルベーションおよび複合コアセルベーション、当業者間で周知の他の方法などの方法で形成可能なものである。上記に代えてまたは上記に加えて、単分散半導体、導電性ナノ材料、磁性ナノ材料、有機ナノ材料、その他のナノ材料用の水性溶媒および有機溶媒の合成について、記載されている(Pellegrino et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13:3843)。別の方法が、文献に記載されている(たとえば、Doubrow, Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992;Mathiowitz et al., 1987, J. Control. Release, 5:13;Mathiowitz et al., 1987, Reactive Polymers, 6:275;およびMathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755、米国特許第5578325号明細書および同第6007845号明細書;P. Paolicelli et al., “Surface−modified PLGA−based Nanoparticles that can Efficiently Associate and Deliver Virus−like Particles” Nanomedicine. 5(6):843〜853 (2010)を参照のこと)。
実施例1:ナノキャリアおよび混合R848アジュバントを投与すると、炎症誘発性サイトカインが全身で強く産生される
NC−R848−1ナノキャリア配合物の材料
オボアルブミンペプチド323−339アミド酢酸塩を、Bachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505. 商品コード4065609)。75/25ラクチド/グリコライドモノマー組成物と分子量約4100DaでR848含有量5.2%w/wのPLGA−R848コンジュゲートを合成した。約3,500Daのニコチン末端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)を購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGA−R848を100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA−R848溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせる。PLGA−R848@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4065609)。75/25ラクチド/グリコライドモノマー組成物と分子量約4100DaでR848含有量5.2%w/wのPLGA−R848コンジュゲートを合成した。約5,000Daのニコチン終端PEGブロックと約17,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGA−R848を100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA−R848溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA−R848@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミド酢酸塩を、Bachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505. 製品コード4065609)。ラクチド含有量73%、グリコライド含有量27%で固有粘度が0.12dL/gのPLGAを、SurModics Pharmaceuticalsから購入した(756 Tom Martin Drive, Birmingham, AL 35211.製品コード7525 DLG 1A)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGAを100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
マウスの群に対して、小分子ヌクレオチド類似物に結合した、結合していない、またはこれと混合した100μgのナノキャリア(NC)、既知のTLR7/8アゴニストおよびアジュバントR848を、後肢に皮下注射した。ナノキャリア中のR848量は2〜3%で、注射1回あたり結合されたR848の2〜3μgにつながった;使用する遊離R848の量は注射1回あたり20μgであった。全血採血からマウス血清を採取し、全身の血清サイトカイン産生量をELISAによって異なる時点で測定した(BD Biosciences)。図1A〜図1Cに示すように、混合R848(NC+R848)を用いた場合に、主要な炎症誘発性サイトカインTNF−α、IL−6およびIL−12の全身での強い産生が観察されたのに対し、R848(NC−R848−1およびNC−R848−2)と結合したNCの別々の調製物を用いる場合に、TNF−α、IL−6およびIL−12の発現は検出されなかった。ピークサイトカイン発現レベルの差は、TNF−αおよびIL−6で>100倍、IL−12で>50倍であった。R848に結合していないNC(NCのみと表示)は、混合R848なしで用いると全身のサイトカインを誘発しなかった。
NC−R848ナノキャリア配合物の材料
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4065609)。75/25ラクチド/グリコライドモノマー組成物と分子量約4100DaでR848含有量5.2%w/wのPLGA−R848コンジュゲートを合成した。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGA−R848を100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA−R848溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA−R848@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4065609)。ラクチド含有量73%、グリコライド含有量27%で固有粘度が0.12dL/gのPLGAを、SurModics Pharmaceuticalsから購入した(756 Tom Martin Drive, Birmingham, AL 35211.製品コード7525 DLG 1A)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGAを100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
免疫IFN−γなどの初期の炎症誘発性サイトカインは、ほとんどが免疫誘導時の副作用と関連しているが、他のサイトカインの産生が、効果的な免疫反応の誘発に関与していることが知られている。したがって、NCの注射後の免疫サイトカインIFN−γの全身での産生を、接種0〜24時間後に測定した。簡単に説明すると、マウスの群に対して、小分子ヌクレオチド類似物に結合またはこれと混合した100μgのNC、TLR7/8アゴニストおよびアジュバントR848を、後肢に皮下注射した。ナノキャリア中のR848量は2%で、注射1回あたり結合されたR848の2μgにつながった;使用する遊離R848の量は注射1回あたり20μgであった。全血採血からマウス血清を採取し、全身の血清サイトカイン産生量をELISAによって異なる時点で測定した(BD Biosciences)。Th1免疫反応に重要なIFN−γが、NC−R848(R848を2μg含有)とR848(20μg)を混合したNCのどちらにも求められた(図2)。さらに、混合したR848を含むNCによる高いレベルのIFN−γが早期に発生する。
NC−Nic w/o R848ナノキャリア配合物用の材料
オボアルブミンペプチド323−339アミドTFA塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4064565)。固有粘度0.19dL/gのPLAを、Boehringer Ingelheimから購入した(Ingelheim Germany.製品コードR202H)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(MW=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@69mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLA@100mg/mLをジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせ、PLA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミドTFA塩を、Bachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505。パーツ番号4064565)。純度約98〜99%のR848(レシキモド)を合成し、精製した。固有粘度0.19dL/gのPLAを、Boehringer Ingelheimから購入した(Ingelheim Germany.製品コードR202H)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@69mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLA@100mg/mLをジクロロメタンに溶解し、R848を10mg/mLで加え、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLA/R848溶液3部とPLA−PEG−ニコチン1部とを組み合わせて、PLA@75mg/mL、R848@7.5mg/mL、PLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
第2のアジュバントを使用するあるいは使用せずに、捕捉(非コンジュゲート)R848を有するNC−Nic(外面にニコチンを提示するナノキャリア)でマウスを免疫した。100μgのNC−Nicを使用して、マウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫した(皮下、後肢)。次に、26日目と40日目に血清抗ニコチン抗体を測定した。抗ニコチン抗体のEC50は、標準的なポリリジン−ニコチン(図3)に対するELISA(群1:NC−Nic w/o捕捉R848;群2:1.5%のNC−Nic w。捕捉R848;群3:NC−Nic w。捕捉R848が1.5%+80μgのミョウバン;群4:NC−Nic w。CpG−1826の1.5%の捕捉R84+25μg)。これは、ナノキャリア(NC)中に捕捉R848(Th1アジュバント、TLR7/8アゴニスト)を用いると、免疫反応が生じ、これはR848なしでNCによって誘発される免疫反応より優れている(群2>群1)。さらに、R848と一緒に遊離Th2アジュバント(ミョウバン)をNC−Nicに加えると、体液性免疫反応がさらに増大する(群3>群2)。同時に、もうひとつの遊離Th1アジュバント(CpG、TLR9アゴニスト;群4)を加えても免疫反応が増大するが、この組み合わせではミョウバンほど強力ではない(群4>群2vs.4<群3)。
NC−Nicナノキャリア配合物の材料
オボアルブミンペプチド323−339アミドTFA塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4064565)。固有粘度0.19dL/gのPLAを、Boehringer Ingelheimから購入した(Ingelheim Germany.製品コードR202H)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@69mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLA@100mg/mLをジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせ、PLA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミドTFA塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4064565)。純度約98〜99%のR848(レシキモド)を合成し、精製した。固有粘度0.19dL/gのPLAを、Boehringer Ingelheimから購入した(Ingelheim Germany.製品コードR202H)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@69mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLA@100mg/mLをジクロロメタンに溶解し、R848を10mg/mLで加え、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLA/R848溶液3部とPLA−PEG−ニコチン1部とを組み合わせ、PLA@75mg/mL、R848@7.5mg/mL、PLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
混合R848を使用して、あるいは使用せずに、NC中にアジュバントを持たないNC−Nic(外面にニコチンを提示するナノキャリア)でマウスを免疫した。100μgのNC−Nicを使用して、マウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫した(皮下、後肢)。次に、26日目と40日目に血清抗ニコチン抗体を測定した。抗ニコチン抗体のEC50を、ポリリジン−ニコチン(図4)に対する標準的なELISAで測定した(群1:NC−Nic w/o捕捉R848;群2:NC−Nic w/o捕捉R848+20μgの遊離R848)。このことから、遊離R848(Th1アジュバント、TLR7/8アゴニスト)を抗原保持NCに混合すると、免疫反応が生じて、混合R848なしでNCによって誘発される免疫反応より優れている(群2>群1)ことがわかる。
ナノキャリア配合物用の材料
オボアルブミンペプチド323−339アミド酢酸塩を、Bachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505. 製品コード4065609)。純度約98〜99%のR848(レシキモド)を合成し、精製した。開環プロセスで分子量約1300Da、R848含有量が約9重量%のPLA−R848コンジュゲートを合成した。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:ポリマーを100mg/mLで溶解し、R848をPLA−PEG−ニコチン溶液に加えた後、PLA−R848溶液3部とPLA−PEG−ニコチン/R848溶液1部とを組み合わせ、PLA−R848@75mg/mL、PLA−PEG−ニコチン@25mg/mL、R848@1.9mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
混合ミョウバンを使用して、あるいは使用せずに、R848およびOP−IIヘルパーペプチドを有するナノキャリア、NC−Nic(外面にニコチンを提示するナノキャリア)でマウスを免疫した。100μgのNC[Nic,R848,OP−II]+/−80μgの混合ミョウバン(Pierce)を使用して、マウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫した(皮下、後肢)。次に、血清抗ニコチン抗体を40日目と70日目に測定した。抗ニコチン抗体のEC50を、ポリリジン−ニコチンに対する標準的なELISAで測定した(図6)(群1:NC[Nic,R848,OP−II];群2:NC[Nic,R848,OP−II]+80μgの混合ミョウバン)。このことから、遊離ミョウバン(Th2アジュバント)を抗原保持アジュバント含有NCと混合すると免疫反応が生じ、これは、混合ミョウバンなしで同一NCによって誘発される免疫反応より優れている(群2>群1)ことがわかる。
オボアルブミンタンパク質をWorthington Biochemical Corporationから購入した(730 Vassar Avenue,Lakewood,NJ 08701.製品コード3048)。固有粘度0.21dL/gのPLAを、SurModics Pharmaceuticalsから購入した(756 Tom Martin Drive, Birmingham, AL 35211. 製品コード100 DL 2A)。約2,000Daのメチルエーテル終端PEGブロックと約19,000DaのPLAブロックとを有するPLA−PEG−OMeブロックコポリマーを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンタンパク質@20mg/mLをリン酸緩衝生理食塩水中、室温にて調製した。
溶液2:PLAを100mg/mLでジクロロメタンに溶解し、PLA−PEG−OMeを100mg/mLでジクロロメタンに溶解した後、PLA溶液3部とPLA−PEG−OMe溶液1部とを組み合わせて、PLA@75mg/mLおよびPLA−PEG−OMe@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
遊離アジュバントを混合した状態で、ナノキャリア、NC−OVA(カプセル化したオボアルブミンタンパク質を有するナノキャリア)または遊離オボアルブミン(OVA)のいずれかで、マウスを免疫した。マウス3匹の群を、10μgの遊離1826−CpG(TLR9アゴニスト)を混合した2.5μgの遊離OVAまたは100μgのNC−OVA(2.8%OVA)で1回免疫(皮下、後肢)した。免疫後4日目に流入領域膝窩リンパ節を採取し、メッシュで漉し、10単位/mlのIL−2を加えた完全RPMI培地にてin vitroで4日間インキュベートし、異なるエフェクター/ターゲット(E:T)比(図7)で特異的CTL(細胞傷害性T細胞)活性を求めた(オボアルブミン発現細胞系統EG.7−OVAの溶解%−親細胞系統EL−4の溶解%)。ここから、NC−カプセル化抗原を利用すると、遊離抗原で免役するよりも強い局所細胞免疫反応が生じることがわかる。
ナノキャリア配合物用の材料
オボアルブミンペプチド323−339アミド酢酸塩を、Bachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505. 製品コード4065609)。固有粘度0.19dL/gのPLAを、Boehringer Ingelheimから購入した(Ingelheim Germany.製品コードR202H)。約5,000Daのニコチン終端PEGブロックと約17,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@17.5mg/mLの希塩酸水溶液。オボアルブミンペプチドを0.13Nの塩酸溶液に入れて室温にて溶液を調製した。
溶液2:0.19−IV PLA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mlのジクロロメタン溶液。別々に、PLA@100mg/mLをジクロロメタンに溶解し、PLA−PEG−ニコチン@100mg/mLをジクロロメタンに溶解した上で、PLA−PEG−ニコチン溶液の各部についてPLA溶液3部を加えてこれらの溶液を混合して、溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMのリン酸緩衝液(pH8)に入れた溶液。
リン酸ジエステル(PO)またはホスホロチオエート(PS)形態のいずれかでCpGと混合したNC−Nic(外面にニコチンを提示し、NCにOP−IIヘルパーペプチドを含有し、アジュバントを含有しないナノキャリア)でマウスを免疫した。PO形態は、ヌクレアーゼで分解されるため、マウスに注射すると安定しない。PS形態は、ヌクレアーゼ耐性であり、したがって、マウスに注射しても安定する。陰性対照として、マウスをPBSだけで免疫した。100μgのNC−Nic+20μgのCpG(PSまたはPO)またはPBSを使用して、マウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫した(皮下、後肢)。26日目と40日目に血清抗ニコチン抗体価を測定した。ポリリジン−ニコチン(図8)(群1:NC−Nic(アジュバントなし)+遊離CpG(PS);群2:NC−Nic(アジュバントなし)+遊離CpG(PO);群3:PBSのみ)に対するELISAで、抗ニコチン抗体価(EC50)を測定した。このことから、抗原保持NCに遊離CpG(PS)(Th1アジュバント、TLR9アゴニスト)を混合すると、混合CpG(PO)またはPBSを含むNCによって誘発されるものより優れた免疫反応が生じることがわかる(群1>群2>群3)。
ナノキャリア配合物用の材料
オボアルブミンタンパク質をWorthington Biochemical Corporationから購入した(730 Vassar Avenue,Lakewood,NJ 08701.製品コード3048)。固有粘度0.21dL/gのPLAを、SurModics Pharmaceuticalsから購入した(756 Tom Martin Drive, Birmingham, AL 35211. 製品コード100 DL 2A)。約2,000Daのメチルエーテル終端PEGブロックと約19,000DaのPLAブロックとを有するPLA−PEG−OMeブロックコポリマーを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンタンパク質@20mg/mLをリン酸緩衝生理食塩水中、室温にて調製した。
溶液2:PLAを100mg/mLでジクロロメタンに溶解し、PLA−PEG−OMeを100mg/mLでジクロロメタンに溶解した後、PLA溶液3部とPLA−PEG−OMe溶液1部とを組み合わせて、PLA@75mg/mLおよびPLA−PEG−OMe@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
20μgのR848またはCpG(PS;ヌクレアーゼ耐性)と混合したNC−OVA(外面にオボアルブミン(OVA)提示しているナノキャリア、NCにアジュバントなし)でマウスを免疫した。対照マウスには、20μgのCpG(PS)と混合した2.5μgの可溶性抗原(OVA)を与えた。100μgのNC−OVA+20μgのR848またはCpG(PS)または2.5μgの可溶性OVA+20μgのCpG(PS)を使用して、マウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫した(皮下、後肢)。26日目と44日目に血清抗OVA抗体価を測定した。OVAタンパク質(図9)(群1:NC−OVA(アジュバントなし)+遊離R848;群2:NC−OVA(アジュバントなし)+遊離CpG(PS);群3:可溶性OVA+CpG(PS))に対するELISAで抗OVA抗体価(EC50)を測定した。このことから、遊離R848(Th1アジュバント、TLR7/8アゴニスト)またはCpG(PS)(Th1アジュバント、TLR9アゴニスト)を抗原保持NCと混合すると、免疫反応が生じ、これはアジュバント(CpG(PS))と混合した可溶性抗原によって誘発されるものより優れていることがわかる(群1および2>群3)。
群1のナノキャリア配合物用の材料
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4065609)。75/25ラクチド/グリコライドモノマー組成物と分子量約4100DaでR848含有量5.2%w/wのPLGA−R848コンジュゲートを合成した。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGA−R848を100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA−R848溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA−R848@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.から購入した(3132 Kashiwa Street,Torrance CA 90505.パーツ番号4065609)。ラクチド含有量73%、グリコライド含有量27%で固有粘度が0.12dL/gのPLGAを、SurModics Pharmaceuticalsから購入した(756 Tom Martin Drive, Birmingham, AL 35211.製品コード7525 DLG 1A)。約3,500Daのニコチン終端PEGブロックと、約15,000DaのDL−PLAブロックとを有するPLA−PEG−ニコチンを合成した。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入した(パーツ番号U232−08)。
溶液を以下のようにして調製した。
溶液1:オボアルブミンペプチド323−339@70mg/mLを0.13Nの塩酸で室温にて調製した。
溶液2:PLGAを100mg/mLでジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLGA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLGA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製した。
溶液3:ポリビニルアルコール@50mg/mLを100mMで100mMのリン酸緩衝液(pH8)に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
NC−Nicナノキャリア配合物用の材料
オボアルブミンペプチド323−339アミド酢酸塩をBachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505から購入する。パーツ番号4064565)。固有粘度0.19dL/gのPLAをSurModics Pharmaceuticalsから購入する(756 Tom Martin Drive, Birmingham, AL 35211(製品コード100 DL 2A)。約5,000Daのニコチン終端PEGブロックと、約20,000DaのDL−PLAブロックを有するPLA−PEG−ニコチンを、合成する。ポリビニルアルコール(Mw=11,000〜31,000、87〜89%加水分解)をJ.T.Bakerから購入する(パーツ番号U232−08)。
溶液を以下のようにして調製する。
溶液1:オボアルブミンペプチド323−339@20mg/mLを0.13Nの塩酸で室温にて調製する。
溶液2:PLA@100mg/mLをジクロロメタンに溶解し、PLA−PEG−ニコチンを100mg/mLでジクロロメタンに溶解した後、PLA溶液3部とPLA−PEG−ニコチン溶液1部とを組み合わせて、PLA@75mg/mLおよびPLA−PEG−ニコチン@25mg/mLのジクロロメタン溶液を調製する。
溶液3:ポリビニルアルコール@50mg/mLを100mMの脱イオン水に入れた溶液。
溶液4:70mMのリン酸緩衝液(pH8)。
第1(R848)および第2のアジュバント(ミョウバン)と混合したNC−Nic(外面にニコチンを提示するナノキャリア)でマウスを免疫する。100μgのNC−Nicを用いてマウス5匹の群を2週間間隔で(0日目、14日目、28日目)3回免疫する(皮下、後肢)。その後、26日目と40日目に血清抗ニコチン抗体を測定する。ポリリジン−ニコチンに対する標準的なELISAで、抗ニコチン抗体のEC50を測定する。
Claims (25)
- (1)ポリマー合成ナノキャリアの集合;
(2)どのポリマー合成ナノキャリアとも結合されていない第1のアジュバント、ここで第1のアジュバントが、炎症誘発性サイトカインの全身での誘発を高める投与量で存在する;
(3)(1)のポリマー合成ナノキャリアの集合に結合される第2のアジュバント;および
(4)薬学的に許容可能な賦形剤
を含み、任意に
(5)1種類以上の抗原
を含む、免疫反応を高めることを必要とする被検体へ投与するための組成物。 - 被検体が、0〜24時間以内の炎症誘発性サイトカイン産生を必要とする、請求項1に記載の組成物。
- 前記第1のアジュバントと第2のアジュバントとが異なる、請求項1または2に記載の組成物。
- 前記組成物が、全身投与量の前記第1のアジュバントおよび/または第2のアジュバントを含み、ここで任意に前記全身投与量が、(a)TNF−α、IL−6および/またはIL−12、または(b)IFN−γ、IL−12および/またはIL−18の全身での放出につながる、請求項1〜3のいずれか一項に記載の組成物。
- 前記1種類以上の抗原が、(a)前記ポリマー合成ナノキャリアに結合される、(b)もうひとつの集合のポリマー合成ナノキャリアに結合される、(c)どのポリマー合成ナノキャリアにも結合されない、および/または(d)B細胞抗原および/またはT細胞抗原を含む、および/または(e)B細胞抗原および/またはT細胞抗原およびヘルパーT細胞抗原を含む、請求項1〜4のいずれか一項に記載の組成物。
- (d)において、T細胞抗原がヘルパーT細胞抗原である、請求項5に記載の組成物。
- 前記組成物が、抗原を含まない、請求項1〜4のいずれか一項に記載の組成物。
- 前記第1のアジュバントおよび/または第2のアジュバントが、鉱物塩、ゲルタイプのアジュバント、微生物アジュバント、オイルエマルションまたは乳化剤ベースのアジュバント、粒子状アジュバント、合成アジュバント、ホスフェートアジュバント、ポリマー、リポソーム、マイクロキャリア、免疫刺激性核酸、ミョウバン、サポニン、インターロイキン、インターフェロン、サイトカイン、toll様受容体(TLR)アゴニスト、イミダゾキノリン、サイトカイン受容体アゴニスト、CD40アゴニスト、Fc受容体アゴニスト、補体受容体アゴニスト、QS21(登録商標)、ビタミンE、スクアレン、トコフェロール、Quil A(登録商標)、ISCOMs(登録商標)、ISCOMATRIX(登録商標)、Ribi Detox(登録商標)、CRL−1005(登録商標)、L−121(登録商標)、テトラクロロデカオキシド、ミョウバン、MF59(登録商標)、AS02(登録商標)、AS15(登録商標)、コレラ毒素、モノホスホリルリピドA、フロイント不完全アジュバント、フロイント完全アジュバント、ムラミルジペプチドまたはmontanide(登録商標)を含み、ここで任意に、(a)前記免疫刺激性核酸がCpG含有核酸を含む場合、前記第2のアジュバントはイミダゾキノリンまたはミョウバンを含む、または(b)前記イミダゾキノリンがレシキモドまたはイミキモドを含む、または(c)前記第1のアジュバントおよび/または前記第2のアジュバントがミョウバンを含む場合、前記第2のアジュバントはイミダゾキノリンまたはCpG含有核酸を含む、または(d)前記第1のアジュバントがイミダゾキノリンを含む場合、前記第2のアジュバントはCpG含有核酸またはミョウバンを含む、または(e)前記TLRアゴニストが、TLR−1アゴニスト、TLR−2アゴニスト、TLR−3アゴニスト、TLR−4アゴニスト、TLR−5アゴニスト、TLR−6アゴニスト、TLR−7アゴニスト、TLR−8アゴニスト、TLR−9アゴニスト、TLR−10アゴニスト、TLR−11アゴニストまたはこれらの組み合わせを含む、請求項1〜7のいずれか一項に記載の組成物。
- (a)において、免疫刺激性核酸が第1のアジュバントである、および(c)において、第1のアジュバントがミョウバンを含む、請求項8に記載の組成物。
- イミダゾキノリンがレシキモドである、請求項8または9に記載の組成物。
- 前記第1のアジュバントおよび/または第2のアジュバントが、(a)TLRアゴニスト、または(b)TLR−3アゴニスト、TLR−7アゴニスト、TLR−8アゴニストまたはTLR−9アゴニストを含まない、請求項1〜7のいずれか一項に記載の組成物。
- 前記第2のアジュバントが、レシキモドを含み、ここで任意に、前記組成物がニコチンおよびヘルパーT細胞抗原を含む1種類以上の抗原を含み、その各々が前記ポリマー合成ナノキャリアに結合される、請求項5または6に記載の組成物。
- ヘルパーT細胞抗原が、オボアルブミンから得られるまたは誘導されるペプチドを含む、請求項12に記載の組成物。
- オボアルブミンから得られるまたは誘導されるペプチドが、配列番号1に示す配列を含む、請求項13に記載の組成物。
- 前記ヘルパーT細胞抗原が、カプセル化によって結合される、請求項5、6および12〜14のいずれか一項に記載の組成物。
- 前記ポリマー合成ナノキャリアが1種類以上のポリマーを含み、ここで任意に、前記1種類以上のポリマーが(a)ポリエステルを含む、または(b)親水性ポリマーに結合したポリエステルを含むまたはさらに含む、請求項1〜15のいずれか一項に記載の組成物。
- ポリエステルが、ポリ(乳酸)、ポリ(グリコール酸)、ポリ(乳酸−co−グリコール酸)またはポリカプロラクトンである、請求項16に記載の組成物。
- 親水性ポリマーがポリエーテルを含む、請求項16または17に記載の組成物。
- ポリエーテルがポリエチレングリコールを含む、請求項18に記載の組成物。
- 治療または予防に用いられる、請求項1〜19のいずれか一項に記載の組成物。
- (a)被検体において炎症反応を誘発する、(b)被検体においてTh1免疫反応を誘発する、(c)被検体において体液性免疫反応を誘発する、(d)被検体において特異的な局所細胞傷害性Tリンパ球反応を誘発する、(e)がんを治療または予防する、(f)感染症または感染性の疾患を治療または予防する、または(g)アトピー症状、喘息、COPDまたは慢性感染症を治療または予防する方法に用いられる、請求項20に記載の組成物。
- 前記方法が、1種類以上の抗原を投与することをさらに含む、請求項21に記載の組成物。
- 1種類以上の抗原をさらに含む、請求項22に記載の組成物。
- (a)前記1種類以上の抗原が前記ポリマー合成ナノキャリアに結合される、(b)前記1種類以上の抗原がもうひとつの集合のポリマー合成ナノキャリアに結合される、(c)前記1種類以上の抗原が、どのポリマー合成ナノキャリアにも結合されない、(d)前記1種類以上の抗原が同時投与される、(e)前記1種類以上の抗原が、B細胞抗原および/またはT細胞抗原を含む、(f)前記1種類以上の抗原が、B細胞抗原および/またはT細胞抗原およびヘルパーT細胞抗原を含む、および/または(g)前記被検体が、ヒトである、請求項22または23に記載の組成物。
- (e)において、T細胞抗原がヘルパーT細胞抗原である、および/または前記B細胞抗原がニコチンである、ならびに/または(f)において、B細胞抗原がニコチンである、請求項24に記載の組成物。
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