JP2021183612A - 細胞傷害性tリンパ球応答を低下させる寛容原性合成ナノキャリア - Google Patents
細胞傷害性tリンパ球応答を低下させる寛容原性合成ナノキャリア Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条の下で、2011年4月29日に出願された米国仮特許出願第61/480,946号、2011年7月29日に出願された同第61/513,514号、2011年9月6日に出願された同第61/531,147号、2011年9月6日に出願された同第61/531,153号、2011年9月6日に出願された同第61/531,164号、2011年9月6日に出願された同第61/531,168号、2011年9月6日に出願された同第61/531,175号、2011年9月6日に出願された同第61/531,180号、2011年9月6日に出願された同第61/531,194号、2011年9月6日に出願された同第61/531,204号、2011年9月6日に出願された同第61/531,209号、2011年9月6日に出願された同第61/531,215号の利益を主張するものであり、これらの仮特許出願のそれぞれの内容全体が、参照により本明細書に援用される。
免疫抑制薬と、望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープとを、目的の細胞、特にAPCの作用点に一層直接的に送達することにより、CD8+ T細胞増殖および/または活性が低下し得ることが分かっている。CD8+ T細胞は細胞傷害性であり、タンパク質を発現する細胞上の「外来」タンパク質を認識してそれらを死滅させ得る。しかしながら、場合によっては細胞傷害性は望ましくない。従ってこの機序を、例えばCD8+ T細胞増殖および/または活性を下方制御し、および/またはCD8+ T細胞を調節性CD8+ T細胞に変換することにより、寛容化する方法が有益であり得る。
「投与する(administering)」または「投与(administration)」は、薬理学的に有用な方法で被験体に材料を提供することを意味する。
本明細書には、免疫抑制薬と、望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープとを含む寛容原性合成ナノキャリア組成物、および関連する方法が提供される。かかる組成物および方法は、抗原特異的CD8+ T細胞免疫応答、例えば増殖および/または活性を低下させることにより、望ましくない免疫応答の発生を低下させ、および寛容原性免疫応答の発生を促進するのに有用である。本組成物は、寛容原性免疫応答が望ましい対象に投与され得る。かかる対象には、炎症性疾患、自己免疫疾患、アレルギー、臓器若しくは組織拒絶反応または移植片対宿主病を有するか、またはそれを有するリスクがある対象が含まれる。かかる対象にはまた、その対象に望ましくない免疫応答を引き起こしたことがあるか、またはそれを引き起こすと予想される治療用タンパク質を投与されたことがあるか、それを投与されているか、またはそれを投与されることになる対象も含まれる。かかる対象にはまた、移植を受けたことがあるか、または移植を受けることになる対象も含まれる。
合成ナノキャリアは、当該技術分野において公知の様々な方法を用いて調製され得る。例えば、合成ナノキャリアは、ナノ析出(nanoprecipitation)、流体チャネルを用いたフローフォーカシング(flow focusing)、噴霧乾燥、単一および二重乳化溶媒蒸発、溶媒抽出、相分離、ミリング、マイクロエマルジョン法、マイクロ加工、ナノ加工(nanofabrication)、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、並びに当業者に周知の他の方法のような方法によって形成され得る。その代わりにまたはそれに加えて、単分散半導体ナノ材料、伝導性ナノ材料、磁性ナノ材料、有機ナノ材料、および他のナノ材料のための水性および有機溶媒合成が、記載されている(Pellegrino et al.,2005,Small,1:48;Murray et al.,2000,Ann.Rev.Mat.Sci.,30:545;およびTrindade et al.,2001,Chem.Mat.,13:3843)。更なる方法が、文献に記載されている(例えば、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)を参照されたい)。
材料
オボアルブミンタンパク質のT細胞およびB細胞エピトープであることが分かっている17アミノ酸ペプチドであるオボアルブミンペプチド323−339を、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505;品番4065609)から購入した。ラパマイシンは、TSZ CHEM(185 Wilson Street,Framingham,MA 01702;製品カタログ番号R1017)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
初めに一次油中水型エマルションを調製した。W1/O1は、小型圧力管において溶液1(0.2mL)、溶液2(0.2mL)、および溶液3(1.0mL)を合わせ、且つBranson Digital Sonifier 250を使用して50%振幅で40秒間超音波処理することにより調製した。次に、溶液4(3.0mL)を一次W1/O1エマルションと合わせ、10秒間ボルテックスし、且つBranson Digital Sonifier 250を使用して30%振幅で60秒間超音波処理することにより、二次エマルション(W1/O1/W2)を調製した。
初めに一次油中水型エマルションを調製した。W1/O1は、小型圧力管において0.13M塩酸溶液(0.2mL)、溶液2(0.2mL)、および溶液3(1.0mL)を合わせ、且つBranson Digital Sonifier 250を使用して50%振幅で40秒間超音波処理することにより調製した。次に、溶液4(3.0mL)を一次W1/O1エマルションと合わせ、10秒間ボルテックスし、且つBranson Digital Sonifier 250を使用して30%振幅で60秒間超音波処理することにより、二次エマルション(W1/O1/W2)を調製した。
約3mgの合成ナノキャリアを回収し、遠心して上清を合成ナノキャリアペレットと分離した。ペレットにアセトニトリルを添加し、試料を超音波処理して遠心することにより、不溶性材料を全て除去した。上清およびペレットをRP−HPLCに注入し、278nmで吸光度を読み取った。ペレットに見出されたμg数を使用して%取込み(負荷)を計算し、上清およびペレット中のμg数を使用して総回収μg数を計算した。
約3mgの合成ナノキャリアを回収し、遠心して上清を合成ナノキャリアペレットと分離した。ペレットにトリフルオロエタノールを添加し、試料を超音波処理してポリマーを溶解し、0.2%トリフルオロ酢酸を添加して試料を超音波処理した後、遠心により不溶性材料を全て除去した。上清およびペレットをRP−HPLCに注入し、215nmで吸光度を読み取った。ペレットに見出されたμg数を使用して%取込み(負荷)を計算し、上清およびペレット中のμg数を使用して総回収μg数を計算した。
このアッセイは、免疫優性オボアルブミン(323−339)に特異的なトランスジェニックT細胞受容体を有するOTIIマウスの使用を含んだ。抗原特異的tDCを作るため、CD11c+脾細胞を単離し、インビトロで1μg/mlのオボアルブミン(323−339)ペプチドを添加し、または抗原を添加しなかった。次に可溶性のまたはナノキャリアに封入されたラパマイシンをDCに2時間添加し、次にそれを十分に洗浄して、培養物から遊離ラパマイシンを除去した。OTIIマウスから精製レスポンダーCD4+CD25−細胞を単離し、10:1のT対DC比でtDCに添加した。次にtDCおよびOTII T細胞混合物を4〜5日間培養し、図1に示されるとおりフローサイトメトリーによりTreg細胞(CD4+CD25highFoxP3+)の頻度を分析した。領域はアイソタイプ対照に基づき選択した。
メソ多孔質SiO2ナノ粒子コアを、ゾル・ゲル法によって生成する。ヘキサデシルトリメチルアンモニウムブロミド(CTAB)(0.5g)を、脱イオン水(500mL)に溶解させ、次に、2MのNaOH水溶液(3.5mL)を、CTAB溶液に加える。溶液を30分間撹拌し、次に、テトラエトキシシラン(TEOS)(2.5mL)を溶液に加える。得られたゲルを、80℃の温度で3時間撹拌する。生じる白色の沈殿物を、ろ過によって捕捉した後、脱イオン水で洗浄し、室温で乾燥させる。次に、残っている界面活性剤を、HClのエタノール溶液中で一晩懸濁させることによって粒子から抽出する。粒子を、エタノールで洗浄し、遠心分離し、超音波処理により再分散させる。この洗浄手順を更に2回繰り返す。
リポソームを、薄膜水和(thin film hydration)を用いて形成する。1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン(DPPC)(32μmol)、コレステロール(32μmol)、およびシクロスポリンA(6.4μmol)を、純粋なクロロホルム(3mL)に溶解させる。この脂質溶液を、50mLの丸底フラスコに加え、溶媒を、60℃の温度でロータリーエバポレータにおいて蒸発させる。次に、フラスコを、窒素ガスでフラッシュして、残りの溶媒を除去する。リン酸緩衝生理食塩水(2mL)および5つのガラスビーズをフラスコに加え、60℃で1時間振とうすることによって脂質膜を水和して、懸濁液を形成する。懸濁液を小型の圧力管に移し、各パルス間に30秒の遅延を伴う30秒のパルスの4回のサイクルにわたって、60℃で、超音波で分解する。次に、懸濁液を室温で2時間そのままにしておき、完全に水和させる。リポソームを、遠心分離によって洗浄した後、新鮮なリン酸緩衝生理食塩水に再懸濁させる。
PLGA−ラパマイシンコンジュゲートの調製:
酸性末端基を有するPLGAポリマー(7525 DLG1A、酸価0.46mmol/g、Lakeshore Biomaterials;5g、2.3mmol、1.0当量)を、30mLのジクロロメタン(DCM)に溶解させる。N,N−ジシクロヘキシルカルボジイミド(1.2当量、2.8mmol、0.57g)を加えた後、ラパマイシン(1.0当量、2.3mmol、2.1g)および4−ジメチルアミノピリジン(DMAP)(2.0当量、4.6mmol、0.56g)を加える。混合物を室温で2日間撹拌する。次に、混合物をろ過して、不溶性ジシクロヘキシル尿素を除去する。ろ液を、約10mLの体積に濃縮し、100mLのイソプロピルアルコール(IPA)に加えて、PLGA−ラパマイシンコンジュゲートを析出させる。IPA層を除去し、次に、ポリマーを、50mLのIPAおよび50mLのメチルt−ブチルエーテル(MTBE)で洗浄する。次に、ポリマーを、35Cで2日間、真空下で乾燥させて、白色の固体としてPLGA−ラパマイシン(約6.5g)を得る。
溶液1:希塩酸水溶液中20mg/mLのオボアルブミンペプチド323−339。オボアルブミンペプチドを0.13Mの塩酸溶液に室温で溶解させることによって溶液を調製する。溶液2:塩化メチレン中100mg/mLのPLGA−ラパマイシン。LGA−ラパマイシンを純粋な塩化メチレンに溶解させることによって溶液を調製する。溶液3:塩化メチレン中100mg/mLのPLA−PEG。PLA−PEGを純粋な塩化メチレンに溶解させることによって溶液を調製する。溶液4:100mMのpH8のリン酸緩衝液中50mg/mLのポリビニルアルコール。
HS−PEG−ラパマイシンの調製:
乾燥DMF中のPEG酸ジスルフィド(1.0当量)、ラパマイシン(2.0〜2.5当量)、DCC(2.5当量)およびDMAP(3.0当量)の溶液を、室温で一晩撹拌する。不溶性ジシクロヘキシル尿素を、ろ過によって除去し、ろ液をイソプロピルアルコール(IPA)に加えて、PEG−ジスルフィド−ジ−ラパマイシンエステルを析出させ、IPAで洗浄し、乾燥させる。次に、ポリマーを、DMF中のトリス(2−カルボキシエチル)ホスフィン塩酸塩で処理して、PEGジスルフィドを還元して、チオールPEGラパマイシンエステル(HS−PEG−ラパマイシン)にする。得られたポリマーを、IPAからの沈殿によって回収し、上述されるように乾燥させ、H NMRおよびGPCによって分析する。
500mLの1mMのHAuCl4の水溶液を、凝縮器を備えた1Lの丸底フラスコ中で激しく撹拌しながら、10分間加熱還流させる。次に、50mLの40mMのクエン酸三ナトリウムの溶液を、撹拌溶液に素早く加える。得られた濃いワインレッドの溶液を、25〜30分間還流状態に保ち、熱を取り除いて、溶液を室温に冷ます。次に、溶液を、0.8μmの薄膜フィルタを通してろ過して、AuNC溶液を得る。AuNCを、可視分光法および透過電子顕微鏡法を用いて特性評価する。AuNCは、直径が約20nmであり、クエン酸塩でキャッピングされ、520nmでピーク吸収を有する。
150μlのHS−PEG−ラパマイシン(10mMのpH9.0の炭酸緩衝液中10μΜ)の溶液を、1mLの20nmの直径のクエン酸塩でキャッピングされた金ナノキャリア(1.16nM)に加えて、2500:1のチオール対金のモル比を得る。混合物を、アルゴン下で、室温で1時間撹拌して、金ナノキャリア上でチオールとクエン酸塩との完全な交換を可能にする。次に、表面におけるPEG−ラパマイシンと複合したAuNCを、12,000gで30分間の遠心分離によって精製する。上清をデカントし、次に、AuNC−S−PEG−ラパマイシンを含有するペレットを、1×PBS緩衝液で洗浄する。次に、精製された金−PEG−ラパマイシンナノキャリアを、更なる分析およびバイオアッセイのために、好適な緩衝液に再懸濁させる。
メソ多孔質SiO2ナノ粒子コアを、ゾル・ゲル法によって生成する。ヘキサデシルトリメチルアンモニウムブロミド(CTAB)(0.5g)を、脱イオン水(500mL)に溶解させ、次に、2MのNaOH水溶液(3.5mL)を、CTAB溶液に加える。溶液を30分間撹拌し、次に、テトラエトキシシラン(TEOS)(2.5mL)を溶液に加える。得られたゲルを、80℃の温度で3時間撹拌する。生じる白色の沈殿物を、ろ過によって捕捉した後、脱イオン水で洗浄し、室温で乾燥させる。次に、残っている界面活性剤を、HClのエタノール溶液中で一晩懸濁させることによって粒子から抽出する。粒子を、エタノールで洗浄し、遠心分離し、超音波処理により再分散させる。この洗浄手順を更に2回繰り返す。
リポソームを、薄膜水和によって形成する。1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン(DPPC)(32μmol)、コレステロール(32μmol)、およびラパマイシン(6.4μmol)を、純粋なクロロホルム(3mL)に溶解させる。この脂質溶液を、10mLのガラス管に加え、溶媒を窒素ガス流下で除去し、真空下で6時間乾燥させる。過剰量のオボアルブミンを含有する2.0mlの25mMのMOPS緩衝液(pH8.5)による薄膜の水和によって、多重膜ベシクルを得る。脂質薄膜が管表面から剥がれるまで、管をボルテックスする。多重膜ベシクルを単層膜へと分解するために、10回のサイクルの凍結(液体窒素)および解凍(30℃の水浴)を行う。次に、試料を25mMのMOPS緩衝液(pH8.5)中で1mlまで希釈する。200nmの細孔のポリカーボネートフィルタに試料を10回通すことによって、得られたリポソームのサイズを、押出しによって均一にする。次に、得られたリポソームを、更なる分析およびバイオアッセイのために使用する。
工程1。L−フェニルアラニンエチルエステル(L−PAE)で修飾されたポリ(γ−グルタミン酸)(γ−PGA)の調製:4.7mmol単位のγ−PGA(Mn=300kD)を、0.3NのNaHCO3水溶液(50mL)に溶解させる。L−PAE(4.7mmol)およびEDC.HCl(4.7mmol)を溶液に加え、4Cで30分間撹拌する。次に、溶液を24時間撹拌しながら室温に維持する。低分子量の化学物質を、50kDのMWCOを有する透析膜を用いて透析によって除去する。得られたγ−PGA−グラフト−L−PAEは、凍結乾燥によって得られる。
EPO封入γ−PGAナノ粒子を調製するために、0.25〜4mgのEPOを、1mLのPBS(pH7.4)に溶解させ、1mLのγ−PGA−グラフト−L−PAE(DMSO中10mg/mL)をEPO溶液に加える。得られた溶液を、14,000×gで15分間遠心分離し、PBSで繰り返しすすぐ。次に、得られたEPO封入γ−PGAナノ粒子を、更なる分析およびバイオアッセイのためにPBS(5mg/mL)に再懸濁させる。
工程1。金NC(AuNC)の形成:500mLの1mMのHAuCl4の水溶液を、凝縮器を備えた1Lの丸底フラスコ中で激しく撹拌しながら、10分間加熱還流させる。次に、50mLの40mMのクエン酸三ナトリウムの溶液を、撹拌溶液に素早く加える。得られた濃いワインレッドの溶液を、25〜30分間還流状態に保ち、熱を取り除いて、溶液を室温に冷ます。次に、溶液を、0.8μmの薄膜フィルタを通してろ過して、AuNC溶液を得る。AuNCを、可視分光法および透過電子顕微鏡法を用いて特性評価する。AuNCは、直径が約20nmであり、クエン酸塩でキャッピングされ、520nmでピーク吸収を有する。
本発明の組成物をリン酸緩衝生理食塩水(PBS)に溶解し、500μgの組成物を含有する0.1〜0.2mlで雌ルイスラットに筋肉内注射する。対照群のラットは0.1〜0.2mlのPBSの投与を受ける。注射の9〜10日後、ラットから脾臓およびリンパ節を採取し、40μmナイロン(nyclon)細胞ストレーナで組織を解離することにより単一細胞懸濁液を得る。試料を、PBS(1%FCS)中、適切な希釈の関連モノクローナル抗体で染色する。ヨウ化プロピジウム(propidum iodide)染色細胞は分析から除外する。試料をLSR2フローサイトメーター(BD Biosciences,USA)で取り込み、FACS Divaソフトウェアを用いて分析する。細胞に関してマーカーCD4、CD8等の発現を分析する。例えば、CD8+ T細胞の存在の低下が、所望の免疫応答の誘導を示唆する。
Balb/cマウスに自己抗原を投与し、CD8+ T細胞増殖のレベルを評価する。続いて、抗原と免疫抑制薬とを含む本発明の組成物を用量依存的に皮下投与する。CD8+ T細胞増殖のレベルを再び評価し、ここでCD8+ T細胞増殖の低下が寛容原性免疫応答を示す。
免疫抑制薬と、骨髄細胞から得られるまたはそれに由来する抗原とを含む少なくとも106個の合成ナノキャリアの集団を対象に皮下投与し、その4週間後に対象は骨髄移植を受ける。対象が移植を受けた後、対象における望ましくない免疫応答の発生について、移植を受けた後の最初の1週間は1日1回評価し、その後次の3週間にわたり週1回、更に次の11ヶ月間にわたり月1回、評価する。評価の一環として、CD8+ T細胞数をとり、骨髄移植または合成ナノキャリアを対象に投与する前にとったCD8+ T細胞数と比較する。1年目は合成ナノキャリアの維持量を隔月で対象に投与する。対象は、骨髄移植に対する望ましくない免疫応答を全く示さないか、または最小限度しか示さないものと予想される。
合成ナノキャリア作成の材料および方法
ナノキャリア1
ラパマイシンは、TSZ CHEM(185 Wilson Street,Framingham,MA 01702;製品カタログ番号R1017)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
溶液1:塩化メチレン中50mg/mLのラパマイシン。この溶液は、ラパマイシンを純塩化メチレンに溶解することにより調製した。
溶液2:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。
溶液3:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。
溶液4:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコール。
オボアルブミンタンパク質のT細胞およびB細胞エピトープであることが分かっている17アミノ酸ペプチドであるオボアルブミンペプチド323−339を、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505;品番4065609)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
溶液1:希塩酸水溶液中20mg/mLのオボアルブミンペプチド323−339。この溶液は、オボアルブミンペプチドを室温で0.13M塩酸溶液に溶解することにより調製した。
溶液2:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。
溶液3:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。
溶液4:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコール。
シンバスタチンを、LKT Laboratories,Inc.(2233 University Avenue West,St.Paul,MN 55114;製品カタログ番号S3449)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
溶液1:塩化メチレン中50mg/mLのシンバスタチン。この溶液は、シンバスタチンを純塩化メチレンに溶解することにより調製した。
溶液2:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。
溶液3:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。
溶液4:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコール。
オボアルブミンタンパク質のT細胞およびB細胞エピトープであることが分かっている17アミノ酸ペプチドであるオボアルブミンペプチド323−339を、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505;品番4065609)から購入した。ラパマイシンは、TSZ CHEM(185 Wilson Street,Framingham,MA 01702;製品カタログ番号R1017)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
溶液1:希塩酸水溶液中20mg/mLのオボアルブミンペプチド323−339。この溶液は、オボアルブミンペプチドを室温で0.13M塩酸溶液に溶解することにより調製した。
溶液2:塩化メチレン中50mg/mLのラパマイシン。この溶液は、ラパマイシンを純塩化メチレンに溶解することにより調製した。
溶液3:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。
溶液4:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。
溶液5:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコール。
オボアルブミンタンパク質のT細胞およびB細胞エピトープであることが分かっている17アミノ酸ペプチドであるオボアルブミンペプチド323−339を、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505;品番4065609)から購入した。シンバスタチンを、LKT Laboratories,Inc.(2233 University Avenue West,St.Paul,MN 55114;製品カタログ番号S3449)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
溶液1:希塩酸水溶液中20mg/mLのオボアルブミンペプチド323−339。この溶液は、オボアルブミンペプチドを室温で0.13M塩酸溶液に溶解することにより調製した。
溶液2:塩化メチレン中50mg/mLのシンバスタチン。この溶液は、シンバスタチンを純塩化メチレンに溶解することにより調製した。
溶液3:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。
溶液4:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。
溶液5:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコール。
B6.Cg−Tg(TcraTcrb)425Cbn/J(OTII)マウスおよびC57BL/6(B6)マウスの脾臓を採取し、機械的に解離させ、70μM篩で個別にろ過して単一細胞懸濁液を得た。次に二段階法で精製CD4+CD25−細胞を抽出した。Miltenyi Biotec AutoMACS磁気セルソーターを使用して、初めに脾臓細胞をCD4+ T細胞単離キットIIで標識し、CD25枯渇キットで非標識画分からCD25+細胞を枯渇させた。精製B6細胞を細胞内色素カルボキシフルオレセインスクシンイミジルエステル(CFSE)で染色した後、精製OTII細胞と等濃度で混合した。次にそれをB6.SJL−Ptprca/BoyAi(CD45.1)レシピエントマウスに静脈内(i.v.)注入した。
B6.Cg−Tg(TcraTcrb)425Cbn/J(OTII)マウスおよびC57BL/6(B6)マウスの脾臓を採取し、機械的に解離させ、70μM篩で個別にろ過して単一細胞懸濁液を得た。次に、Miltenyi Biotec AutoMACS磁気セルソーターを使用して、二段階法で精製CD4+CD25−細胞を抽出した。MiltenyiのCD4+ T細胞単離キットIIを使用して脾臓細胞を標識した。次にCD25枯渇キットで非標識CD4+ T細胞画分からCD25+細胞を枯渇させた。次にB6マウスからの精製CD4細胞を細胞内色素カルボキシフルオレセインスクシンイミジルエステル(CFSE)で染色した後、精製OTII細胞と等濃度で混合した。次にそれをB6.SJL−Ptprca/BoyAi(CD45.1)レシピエントマウスに静脈内(i.v.)注入した。
結果を図2および図3に示す(免疫調節薬1:ラパマイシン;免疫調節薬2:シンバスタチン)。これらの図はインビボ効果を示し、抗原単独または免疫賦活分子と共に若しくはそれ無しに抗原を含む合成ナノキャリアと比較したときの、抗原と免疫抑制薬とを含む合成ナノキャリアによるエフェクター免疫細胞数の低下を実証する。図3はまた、抗原のみを含む合成ナノキャリアと比較したときの、抗原と免疫抑制薬とを含む合成ナノキャリアによるFoxP3を発現する割合の増加も実証する。
材料および方法
ナノキャリア1
オボアルブミンタンパク質を、Worthington Biochemical Corporation(730 Vassar Avenue,Lakewood,NJ 08701;製品コード3048)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。コール酸ナトリウム水和物を、Sigma−Aldrich Corp.(3050 Spruce Street,St.Louis,MO 63103;製品コードC6445)から購入した。
溶液1:リン酸緩衝生理食塩水溶液中50mg/mLのオボアルブミン。この溶液は、室温でオボアルブミンをリン酸緩衝生理食塩水溶液に溶解することにより調製した。溶液2:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。溶液3:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。溶液4:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコールおよび10mg/mLのコール酸ナトリウム水和物。
オボアルブミンタンパク質を、Worthington Biochemical Corporation(730 Vassar Avenue,Lakewood,NJ 08701;製品コード3048)から購入した。ラパマイシンは、TSZ CHEM(185 Wilson Street,Framingham,MA 01702;製品カタログ番号R1017)から購入した。ラクチド:グリコリド比が3:1、且つ固有粘度が0.75dL/gのPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとを含むPLA−PEGブロック共重合体を合成した。ポリビニルアルコール(85〜89%加水分解)を、EMD Chemicals(製品番号1.41350.1001)から購入した。コール酸ナトリウム水和物を、Sigma−Aldrich Corp.(3050 Spruce Street,St.Louis,MO 63103;製品コードC6445)から購入した。
溶液1:リン酸緩衝生理食塩水溶液中50mg/mLのオボアルブミン。この溶液は、室温でオボアルブミンをリン酸緩衝生理食塩水溶液に溶解することにより調製した。溶液2:塩化メチレン中50mg/mLのラパマイシン。この溶液は、ラパマイシンを純塩化メチレンに溶解することにより調製した。溶液3:塩化メチレン中100mg/mLのPLGA。この溶液は、PLGAを純塩化メチレンに溶解することにより調製した。溶液4:塩化メチレン中100mg/mLのPLA−PEG。この溶液は、PLA−PEGを純塩化メチレンに溶解することにより調製した。溶液5:100mM pH8リン酸緩衝液中50mg/mLのポリビニルアルコールおよび10mg/mLのコール酸ナトリウム水和物。
この実験の目的は、OVA発現細胞の細胞溶解に対する封入された(t2SVP)免疫抑制薬の効果を評価することであった。かかる細胞は、抗原を発現する可移植性細胞を例示する役割を果たす。1つの動物群は、対照として未免疫のままとした(しかし処置は受けた)。第2の動物群はオボアルブミンの「受身投与」を用いて免疫し、第3の群はOVAおよびCpGで肩甲下領域に免疫した。これらの群の各々は、隔週のナノキャリア注射を受けた。免疫化のため、動物には100μlのOVA+CpGを皮下投与し(肩甲下)、または100μl中25μgのOVAを静脈内投与した。寛容誘導処置は100μl t2SVPの静脈内投与を含んだ。ナノキャリアは5mg/mlで提供した。全ての群で同量のOVAが注入されるように寛容原性ナノキャリアを希釈した。注射は0日目、14日目、28日目、42日目、56日目に実施した。
OVAトランスジェニック細胞をCFSEにより5μM濃度を使用して標識した一方、対照細胞(正常、野生型)を50μM濃度で標識した。これらを洗浄し、カウントし、均等比で試験動物に移入されるように混合した。翌日、動物を犠牲にし、その脾臓を採取した。これらの臓器から単一細胞懸濁液を調製し、7AAD(細胞生存度染色)で標識してカウントした。フローサイトメトリーによる分析から、CFSEhi(対照)対CFSElow(OVA発現)の検出が可能となる。抗原特異的溶解により、非免疫天然対照と比較したときCFSElow集団において選択的損失が生じる。
図4は、抗原のみを含むナノキャリアと比較したときの、抗原と免疫抑制薬とを含むナノキャリアによる細胞溶解の減少を示す。
ナノキャリア1
オボアルブミンタンパク質のTおよびB細胞エピトープであることが知られている17アミノ酸のペプチドであるオボアルブミンペプチド323−339を、Bachem Americas Inc.(3132 Kashiwa Street,Torrance CA 90505;パーツ番号4065609)から購入した。3:1のラクチド:グリコリド比および0.75dL/gの固有粘度を有するPLGAを、SurModics Pharmaceuticals(756 Tom Martin Drive,Birmingham,AL 35211;製品コード7525 DLG 7A)から購入した。約5,000DaのPEGブロックと約20,000DaのPLAブロックとのPLA−PEGブロックコポリマーを合成した。ポリビニルアルコール(85〜89%加水分解されたもの)を、EMD Chemicals(製品番号1.41350.1001)から購入した。
ナノキャリアを解凍して平衡化させた。初期希釈物は10×ストック溶液から構成され、これをOVA323−339中100μg/mlの濃度に更に希釈し、即ち1×溶液とした。この1×溶液を、静脈内注射あたり200μlの注射に使用した。動物をOVAタンパク質(OVA)で免疫し、OVA323−339ペプチドで処置した。免疫化経路は以下のとおりであった:10μgのOVA+4mgミョウバン、腹腔内、免疫学的にナイーブな各Balb/C雌マウスあたり400μl。実験群は各5匹の動物からなった。脾臓細胞をCFSEまたはCTOを使用して抗原で再刺激し、Ag特異的増殖の量を決定した。
FlowJoソフトウェアを使用してFCSファイルを分析した。7AAD陽性細胞(死細胞を標識する核染色剤)の陽性細胞を除外し、CD4、CD8、Gr−1、F4/80、B220、TCRbおよびCD11bの発現に依存する細胞形態を定量化した。
T細胞サブセットに対するゲーティング戦略→7AAD− F4/80− GR−1− TCRb+ CD4+/− CD8+/−
図5は、動物モデルにおけるナノキャリアの有効性を実証する。具体的には、図5は、OVA323−339と免疫抑制薬とを含む合成ナノキャリアで処置した動物対象からの洗浄液試料におけるCD8+ T細胞数の低下を実証する。
ナノキャリア
上記の例(実施例16)と同様に、オボアルブミンペプチドの代わりにMHCクラスI拘束性ペプチドSINFEKL(配列番号944)を使用して、ナノキャリアを調製した。
ナノキャリアを解凍して平衡化させる。初期希釈物は10×ストック溶液から構成され、これをペプチド中100μg/mlの濃度に更に希釈し、即ち1×溶液とする。この1×溶液を、静脈内注射あたり200μlの注射に使用する。動物を、ペプチドを含むタンパク質で免疫し、ペプチドで処置する。免疫化経路は以下のとおりである:10μgのペプチド+4mgミョウバン、腹腔内、免疫学的にナイーブな各Balb/C雌マウスあたり400μl。実験群は各5匹の動物からなる。脾臓細胞をCFSEまたはCTOを使用して抗原で再刺激し、Ag特異的な増殖の量を決定する。
FlowJoソフトウェアを使用してFCSファイルを分析する。7AAD陽性細胞(死細胞を標識する核染色剤)の陽性細胞を除外し、CD4、CD8、Gr−1、F4/80、B220、TCRbおよびCD11bの発現に依存する細胞形態を定量化する。
T細胞サブセットに対するゲーティング戦略→7AAD− F4/80− GR−1− TCRb+ CD4+/− CD8+/−
Claims (83)
- (i)免疫抑制薬にカップリングされた合成ナノキャリアの第1の集団と、
(ii)望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングされた合成ナノキャリアの第2の集団と
を含む組成物。 - 前記第1の集団と前記第2の集団とが同じ集団である、請求項1に記載の組成物。
- 前記第2の集団の前記合成ナノキャリアが、前記抗原のB細胞エピトープに更にカップリングされる、請求項1または2に記載の組成物。
- 前記合成ナノキャリアが、前記抗原のB細胞エピトープを実質的に含まない、請求項1または2に記載の組成物。
- 前記免疫抑制薬が、スタチン、mTOR阻害薬、TGF−βシグナル伝達剤、コルチコステロイド、ミトコンドリア機能の阻害薬、P38阻害薬、NF−κβ阻害薬、アデノシン受容体作動薬、プロスタグランジンE2作動薬、ホスホジエステラーゼ4阻害薬、HDAC阻害薬またはプロテアソーム阻害薬を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記mTOR阻害薬がラパマイシンである、請求項5に記載の組成物。
- 前記抗原が、アレルゲン、自己抗原または治療用タンパク質であるか、または炎症性疾患、自己免疫疾患、臓器若しくは組織拒絶反応または移植片対宿主病に関連する、請求項1〜6のいずれか一項に記載の組成物。
- 前記望ましくないCD8+ T細胞免疫応答が、抗原特異的CD8+ T細胞増殖および/または活性である、請求項1〜7のいずれか一項に記載の組成物。
- 対象に投与したときの前記抗原に対する前記望ましくないCD8+ T細胞免疫応答を低下させるのに有効な量である、請求項1〜8のいずれか一項に記載の組成物。
- 前記合成ナノキャリアの第1および/または第2の集団で平均した前記免疫抑制薬および/またはエピトープの負荷が、0.0001%〜50%(重量/重量)である、請求項1〜9のいずれか一項に記載の組成物。
- 前記合成ナノキャリアの第1および/または第2の集団で平均した前記免疫抑制薬および/またはエピトープの負荷が、0.1%〜10%(重量/重量)である、請求項10に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、脂質ナノ粒子、ポリマーナノ粒子、金属ナノ粒子、界面活性剤ベースのエマルション、デンドリマー、バッキーボール、ナノワイヤ、ウイルス様粒子またはペプチド若しくはタンパク質粒子を含む、請求項1〜11のいずれか一項に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、脂質ナノ粒子を含む、請求項12に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、リポソームを含む、請求項13に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、金属ナノ粒子を含む、請求項12に記載の組成物。
- 前記金属ナノ粒子が金ナノ粒子を含む、請求項15に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、ポリマーナノ粒子を含む、請求項12に記載の組成物。
- 前記ポリマーナノ粒子が、非メトキシ末端のプルロニックポリマーであるポリマーを含む、請求項17に記載の組成物。
- 前記ポリマーナノ粒子が、ポリエステル、ポリエーテルとカップリングされたポリエステル、ポリアミノ酸、ポリカーボネート、ポリアセタール、ポリケタール、多糖、ポリエチルオキサゾリンまたはポリエチレンイミンを含む、請求項17または18に記載の組成物。
- 前記ポリエステルが、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を含む、請求項19に記載の組成物。
- 前記ポリマーナノ粒子が、ポリエステルおよびポリエーテルとカップリングされたポリエステルを含む、請求項19または20に記載の組成物。
- 前記ポリエーテルが、ポリエチレングリコールまたはポリプロピレングリコールを含む、請求項19〜21のいずれか一項に記載の組成物。
- 前記第1および/または第2の集団の前記合成ナノキャリアの動的光散乱法を用いて得られる粒度分布の平均が、100nmより大きい直径である、請求項1〜22のいずれか一項に記載の組成物。
- 前記直径が150nmより大きい、請求項23に記載の組成物。
- 前記直径が200nmより大きい、請求項24に記載の組成物。
- 前記直径が250nmより大きい、請求項25に記載の組成物。
- 前記直径が300nmより大きい、請求項26に記載の組成物。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアのアスペクト比が、1:1、1:1.2、1:1.5、1:2、1:3、1:5、1:7または1:10より大きい、請求項1〜27のいずれか一項に記載の組成物。
- 薬学的に許容可能な賦形剤を更に含む、請求項1〜28のいずれか一項に記載の組成物。
- 請求項1〜29のいずれか一項に記載の組成物を含む剤形。
- 請求項1〜29のいずれか一項に記載の組成物または請求項30に記載の剤形を対象に投与するステップを含む方法。
- 前記抗原に対する望ましくないCD8+ T細胞免疫応答が前記対象において低下する、請求項31に記載の方法。
- (i)免疫抑制薬にカップリングされた合成ナノキャリアの第1の集団と、
(ii)望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングされた合成ナノキャリアの第2の集団とを含む組成物を対象に投与するステップ
を含む方法であって、前記組成物が、前記対象における前記抗原に対する前記望ましくないCD8+ T細胞免疫応答を低下させるのに有効な量である、方法。 - 対象における抗原に対する望ましくないCD8+ T細胞免疫応答を、
(i)免疫抑制薬にカップリングされた合成ナノキャリアの第1の集団と、
(ii)前記抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングされた合成ナノキャリアの第2の集団と
を含む組成物を投与することにより低下させるステップ
を含む方法。 - 1例以上の被験対象において抗原に対する望ましくないCD8+ T細胞免疫応答を低下させることが既に示されたプロトコルに従い対象に組成物を投与するステップ
を含む方法であって、
前記組成物が、
(i)免疫抑制薬にカップリングされた合成ナノキャリアの第1の集団と、
(ii)前記抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングされた合成ナノキャリアの第2の集団と
を含む、方法。 - 前記第1の集団と前記第2の集団とが同じ集団である、請求項33〜35のいずれか一項に記載の方法。
- 前記対象を提供するステップまたはそれを同定するステップを更に含む、請求項31〜36のいずれか一項に記載の方法。
- 前記第2の集団の前記合成ナノキャリアが、前記抗原のB細胞エピトープに更にカップリングされる、請求項33〜37のいずれか一項に記載の方法。
- 前記合成ナノキャリアが、前記抗原のB細胞エピトープを実質的に含まない、請求項33〜37のいずれか一項に記載の方法。
- 前記免疫抑制薬が、スタチン、mTOR阻害薬、TGF−βシグナル伝達剤、コルチコステロイド、ミトコンドリア機能の阻害薬、P38阻害薬、NF−κβ阻害薬、アデノシン受容体作動薬、プロスタグランジンE2作動薬、ホスホジエステラーゼ4阻害薬、HDAC阻害薬またはプロテアソーム阻害薬を含む、請求項33〜39のいずれか一項に記載の方法。
- 前記mTOR阻害薬がラパマイシンである、請求項40に記載の方法。
- 前記望ましくないCD8+ T細胞免疫応答が、抗原特異的CD8+ T細胞増殖および/または活性である、請求項33〜41のいずれか一項に記載の方法。
- 前記抗原が、アレルゲン、自己抗原または治療用タンパク質であるか、または炎症性疾患、自己免疫疾患、臓器若しくは組織拒絶反応または移植片対宿主病に関連する、請求項33〜42のいずれか一項に記載の方法。
- 前記組成物が、前記対象に投与されたときの前記抗原に対する望ましくないCD8+ T細胞免疫応答を低下させるのに有効な量である、請求項33〜43のいずれか一項に記載の方法。
- 前記合成ナノキャリアの第1および/または第2の集団で平均した前記免疫抑制薬および/またはエピトープの負荷が、0.0001%〜50%(重量/重量)である、請求項33〜44のいずれか一項に記載の方法。
- 前記合成ナノキャリアの第1および/または第2の集団で平均した前記免疫抑制薬および/またはエピトープの負荷が、0.1%〜10%である、請求項45に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、脂質ナノ粒子、ポリマーナノ粒子、金属ナノ粒子、界面活性剤ベースのエマルション、デンドリマー、バッキーボール、ナノワイヤ、ウイルス様粒子またはペプチド若しくはタンパク質粒子を含む、請求項33〜46のいずれか一項に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、脂質ナノ粒子を含む、請求項47に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、リポソームを含む、請求項48に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、金属ナノ粒子を含む、請求項47に記載の方法。
- 前記金属ナノ粒子が金ナノ粒子を含む、請求項50に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアが、ポリマーナノ粒子を含む、請求項47に記載の方法。
- 前記ポリマーナノ粒子が、非メトキシ末端のプルロニックポリマーであるポリマーを含む、請求項52に記載の方法。
- 前記ポリマーナノ粒子が、ポリエステル、ポリエーテルとカップリングされたポリエステル、ポリアミノ酸、ポリカーボネート、ポリアセタール、ポリケタール、多糖、ポリエチルオキサゾリンまたはポリエチレンイミンを含む、請求項52または53に記載の方法。
- 前記ポリエステルが、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を含む、請求項54に記載の方法。
- 前記ポリマーナノ粒子が、ポリエステルおよびポリエーテルとカップリングされたポリエステルを含む、請求項54または55に記載の方法。
- 前記ポリエーテルが、ポリエチレングリコールまたはポリプロピレングリコールを含む、請求項54〜56のいずれか一項に記載の方法。
- 前記第1および/または第2の集団の前記合成ナノキャリアの動的光散乱法を用いて得られる粒度分布の平均が、100nmより大きい直径である、請求項33〜57のいずれか一項に記載の方法。
- 前記直径が150nmより大きい、請求項58に記載の方法。
- 前記直径が200nmより大きい、請求項59に記載の方法。
- 前記直径が250nmより大きい、請求項60に記載の方法。
- 前記直径が300nmより大きい、請求項61に記載の方法。
- 前記第1の集団および/または第2の集団の前記合成ナノキャリアのアスペクト比が、1:1、1:1.2、1:1.5、1:2、1:3、1:5、1:7または1:10より大きい、請求項33〜62のいずれか一項に記載の方法。
- 前記合成ナノキャリアの第1の集団および第2の集団を含む前記組成物の1つ以上の維持量が、前記対象に投与される、請求項31〜63のいずれか一項に記載の方法。
- 前記合成ナノキャリアの第1の集団および第2の集団を含む前記組成物の投与前および/または投与後に、前記対象における前記望ましくないCD8+ T細胞免疫応答を評価するステップを更に含む、請求項31〜64のいずれか一項に記載の方法。
- 前記評価するステップが、抗原特異的CD8+ T細胞増殖および/または活性のレベルを決定することを含む、請求項65に記載の方法。
- 前記対象が、炎症性疾患、自己免疫疾患、アレルギー若しくは移植片対宿主病を有するか、若しくはそれを有するリスクがあり、または移植を受けたことがあるか、若しくは移植を受けることになり、または治療用タンパク質の投与を受けたことがあるか、それを受けているか、若しくはそれを受けることになる、請求項31〜66のいずれか一項に記載の方法。
- 前記投与が、静脈内、腹腔内、経粘膜、経口、皮下、肺内、鼻腔内、皮内または筋肉内投与による、請求項31〜67のいずれか一項に記載の方法。
- (i)免疫抑制薬にカップリングされた合成ナノキャリアの第1の集団を作成するステップと、
(ii)望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングされた合成ナノキャリアの第2の集団を作成するステップと
を含む方法。 - 前記第1の集団と前記第2の集団とが同じ集団である、請求項69に記載の方法。
- 前記第2の集団の前記合成ナノキャリアが、前記抗原のB細胞エピトープに更にカップリングされること、または前記第2の集団がB細胞エピトープを実質的に含まないことを確実にするステップを更に含む、請求項69または70に記載の方法。
- 前記合成ナノキャリアの第1の集団および第2の集団を含む剤形を作製するステップを更に含む、請求項69〜71のいずれか一項に記載の方法。
- 対象が投与のために利用可能な前記合成ナノキャリアの第1の集団および第2の集団を含む組成物または前記剤形を作製するステップを更に含む、請求項69〜72のいずれか一項に記載の方法。
- 前記合成ナノキャリアの第1の集団および第2の集団を含む組成物による前記望ましくないCD8+ T細胞免疫応答を評価するステップを更に含む、請求項69〜73のいずれか一項に記載の方法。
- 前記望ましくないCD8+ T細胞免疫応答が、抗原特異的CD8+ T細胞増殖および/または活性である、請求項74に記載の方法。
- 作成される前記合成ナノキャリアの第1の集団および第2の集団が、請求項1〜29のいずれか一項に定義されるとおりである、請求項69〜75のいずれか一項に記載の方法。
- 組成物または剤形の作成プロセスであって、
(i)合成ナノキャリアの第1の集団を免疫抑制薬にカップリングするステップと、
(ii)合成ナノキャリアの第2の集団を、望ましくないCD8+ T細胞免疫応答に関連する抗原のMHCクラスI拘束性および/またはMHCクラスII拘束性エピトープにカップリングするステップと
を含むプロセス。 - 請求項69〜76のいずれか一項に記載の方法に定義されるとおりのステップを含む、請求項77に記載のプロセス。
- 請求項69〜78のいずれか一項に記載の方法またはプロセスによって得られる組成物または剤形。
- 療法または予防で用いるための、請求項1〜29および79のいずれか一項に記載の組成物または請求項30に記載の剤形。
- 対象における抗原に対する望ましくないCD8+ T細胞免疫応答を低下させる方法、アレルギー、自己免疫疾患、炎症性疾患、臓器若しくは組織拒絶反応または移植片対宿主病の治療または予防、または請求項31〜68のいずれか一項に記載の方法で用いるための、請求項1〜29および79のいずれか一項に記載の組成物または請求項30に記載の剤形。
- 対象における抗原に対する望ましくないCD8+ T細胞免疫応答を低下させる方法、アレルギー、自己免疫疾患、炎症性疾患、臓器若しくは組織拒絶反応または移植片対宿主病の治療または予防、または請求項31〜68のいずれか一項に記載の方法で用いる療法薬を製造するための、請求項1〜29および79のいずれか一項に記載の組成物または請求項30に記載の剤形の使用。
- 請求項79〜81のいずれか一項に記載の組成物を含む剤形。
Applications Claiming Priority (25)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161480946P | 2011-04-29 | 2011-04-29 | |
US61/480,946 | 2011-04-29 | ||
US201161513514P | 2011-07-29 | 2011-07-29 | |
US61/513,514 | 2011-07-29 | ||
US201161531175P | 2011-09-06 | 2011-09-06 | |
US201161531153P | 2011-09-06 | 2011-09-06 | |
US201161531194P | 2011-09-06 | 2011-09-06 | |
US201161531164P | 2011-09-06 | 2011-09-06 | |
US201161531209P | 2011-09-06 | 2011-09-06 | |
US201161531180P | 2011-09-06 | 2011-09-06 | |
US201161531147P | 2011-09-06 | 2011-09-06 | |
US201161531204P | 2011-09-06 | 2011-09-06 | |
US201161531215P | 2011-09-06 | 2011-09-06 | |
US201161531168P | 2011-09-06 | 2011-09-06 | |
US61/531,194 | 2011-09-06 | ||
US61/531,168 | 2011-09-06 | ||
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