JP2021165273A - ペプチドコンジュゲート粒子 - Google Patents
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Abstract
【解決手段】本発明は、ペプチドを結合させた生分解性ポリ(ラクチド−co−グリコリド)(PLG)粒子を含む組成物を提供する。特に、粒子の表面にペプチド分子を結合させるためにPLG粒子が表面官能化される(例えば、免疫学的寛容の誘発において使用するため)。
【選択図】なし
Description
本出願は、2012年6月21日出願の米国仮特許出願第61/662,687号の利益を主張するものであり、参照により、その全体が本明細書に組み込まれる。
本発明は、米国国立衛生研究所(National Institutes of Health)から授与されたR01 EB013198の下、政府の支援を受けてなされたものである。米国政府は、本発明において一定の権利を有する。
キメラマウスの生成
6〜8週齢のB6.SJL−PtprcaPep3b/BoyJ(CD45.1)マウスを950ラドの1回線量で照射した。12時間後、C57BL/6−7.2fms−EGFPドナーからの107骨髄細胞でマウスを再構成した。照射後10日間は、飲料水中のスルファメトキサゾール(Sigma Aldrich)およびトリメトプリム(Sigma Aldrich)をマウスに与えた。上述のように、照射の6週間後にマウスをWNVに感染させた。フローサイトメトリーを使用してキメラ化を確認したところ、以前に実証されたように、常にドナー起源の96〜99%であることが分かった。(Getts et al.,J Neurochem.103:1019,2007)。
マウスを麻酔し、50mLの滅菌PBSで灌流した。パラフィンブロックに処理した心臓を除いて(Getts et al.,J.Neurochem 103:10919−1030,2007)、全ての臓器を単離し、Optimum Cutting Temperatureコンパウンド(OCT;Tissue−Tek、日本、東京都)中で瞬間凍結させた。8ミクロンの組織切片を、クリオスタットミクロトーム上で切断し、一晩空気乾燥させた後、必要になるまで−80℃で保存した。凍結切片を解凍し、組織学的検査(標準的なヘマトキシリン およびエオシン染色)または免疫組織化学的検査を行った(Getts et al.,J.Exp Med 205:2319−2337,2008)。MARCO、SIGN−R1およびSIGLEC−1(R&D Systems,MN,USA)、CD68(Abcam,MA,USA)、ならびにKi67(Abcam)に対する抗体を示される通りに使用した。DP−70カメラおよびDPマネージャー2.2.1ソフトウェア(Olympus、日本、東京)を使用して、Olympus BX−51顕微鏡上で画像を取得した。
DP−70カメラおよびDPマネージャー2.2.1ソフトウェア(Olympus)を使用して、Olympus BX−51顕微鏡(Olympus、日本)上で画像を取得した。
以前に記載されているように(Getts et al,J Exp Med.29:2319,2007)、デオキシ−リボヌクレアーゼ(0.005 g/ml;Sigma Aldrich)およびコラゲナーゼ IV(0.05 g/ml;Sigma Aldrich)を含むPBS中、37℃で60分間脳を消化することにより、PBSで灌流したマウスの脳から白血球を得た。10%FCSで消化を停止し、70μmナイロン製細胞濾過器にホモジネートを通過させた(Becton Dickinson、NJ,USA)。340xgで10分間遠心分離した後に得られたペレットを、30% Percoll(Amersham,Norway)中に再懸濁し、80% Percollに重層した。1140xgで25分間室温で遠心分離した後、30%/80% 界面から白血球を回収した。同じプロトコルは、肝臓から白血球を得るためにも用いられ、処理前に組織の重量が計測される。
フローサイトメトリー分析のために、右大腿を切除し、PBSを充填した注射器を使用して骨髄細胞を洗い流した。骨髄前駆体の単離のために、少なくとも4匹のマウスからの大腿および脛骨を用いた。洗い流した後に得られた細胞懸濁液を、70μmの細胞濾過器を通して濾過し、340gで5分間遠心分離した。得られたペレット中の赤血球を、NH4Clベースの赤血球溶解緩衝剤(BD Pharm Lyse(商標);BD Pharmingen)中に溶解した後、340xgで5分間遠心分離した。末梢血の場合、心穿刺により血液を採取し、直ちにクエン酸緩衝液(mMol、Sigma Alrich)中に移した。得られた懸濁液を70% Percoll に重層し、ブレーキをオフにして、室温で20分間1140xgで遠心分離した。界面を回収し、PBS中で細胞を1回洗浄し、340xgで遠心分離した。脾臓の白血球を単離するために、7070μm細胞濾過機に脾臓を通過させ、340gで5分間遠心分離した。得られたペレット中の赤血球を、NH4Clベースの赤血球溶解緩衝剤(BD Pharm Lyse(商標);BD Pharmingen)中に溶解した後、340xgで5分間遠心分離した。
脳、肝臓、血液、および骨髄から(上述のように)採取した細胞を、PBSで洗浄し、抗CD16/CD32 抗体(Biolegend)でブロックした。トリパンブルー排除法を用いて生存細胞を計数したところ、常に>95%の細胞生存率を示していた。
養子移入と称される活性疾患の第2のモデルを調査するために、本発明の実施形態の開発中に実験を行った。動物をペプチドで免疫する代わりに、活性疾患を有するマウスの脾臓からのリンパ球をレシピエントに移植し、その後疾患を発症させた。PLGナノ粒子が、養子性に移植した活性化エフェクター細胞を不活性化する能力を特徴づけるために、本発明の実施形態の開発中に実験を行った。対照ペプチドと結合した粒子または脾細胞で処理したマウスには、4日目に始まって臨床スコアの増加が見られた。PLG−PLP139〜151粒子で処理したマウスは、2日目に、2つの時点を除く全ての時点で40日目までずっと平均臨床スコア0を有し、それらの他の時点での平均臨床スコアは0.25であった。
製造者の指示(Quansys Biosciences、Logan,Utah,USA)に従って多重化プレートELISAを行った。端的に述べると、脳、脾臓、および肝臓組織をPBS中でホモジナイズし、1000xgで回転させて清澄させ、アッセイを行うまで−20℃で保存した。血清試料も使用した。提供された緩衝液中で解凍した試料および標準物質を希釈し、各々30μlを、それぞれが特定の可溶性タンパク質に対する捕捉抗体を含有する16個のスポットを含む各ウェルに播種した。次いで、軌道振盪器上で、プレートを120rpmで1時間インキュベートした。プレートを3回洗浄し、30μlの検出抗体を各ウェルに加え、さらに1時間インキュベートした。3回洗浄した後、ストレプアビジン−HRPを加え、さらに15分間インキュベートした。次いで、プレートを6回洗浄し、基質混合物を加えた。CCDイメージャ(Kodak、Rochester NY,USA)上でプレートを直ちに読み取った。Quansys Q−viewソフトウェア(Quansys Biosciences)を使用してプレートの画像を分析した。
0.1mgのMOGペプチド(MEVGWYRSPFSRVVHLYRNGK(配列番号1);Auspep、Parkville,Victoria,Australia;>95%HPLC精製)を含有するエマルション、および2mg/mLの結核菌(Sigma Aldrich)を含有するフロイント完全アジュバントをマウスに皮下注射した。2日後、マウスに、500μlの百日咳毒素(Sigma Aldrich)を腹腔内投与した。マウスを疾患進行について監視し、以下のスケールで等級分けした:1、尾の弛緩および/または片後肢の脱力;2、複数肢の脱力、歩行障害;3、単一肢の麻痺;4、複数肢の麻痺、失禁;5、瀕死。
グラフを作成し、GraphPad PrismおよびInStatにおいてそれぞれコンピュータ統計的分析を行った(どちらのプログラムもGraphPad software、San Diego,CA,USAから)。データに応じて、対応のない両側スチューデントt検定、またはTukey−Kramerの事後検定を用いた一元配置ANOVA ANOVAを行い、P<0.05を有意と見なした。
負電荷を帯びた免疫修飾性粒子(IMP)の調製
D2O中のポリ(エチレン−無水マレイン酸)(PEMA)の溶液(4mL、1% w/v)に、ジクロロメタン(DCM)中のポリ(ラクチド−co−グリコール酸)(PLG)の溶液(2mL、20% w/v)を滴下で加えた。VC 30 Ultrasonic Processorを使用して、氷上で30秒間16ワットで混合物を超音波処理した。得られたホモジナイズされた粗生成物を、次いで、D2Oの溶液(0.5% w/vのPEMAを含有する200mL)に注ぎ入れた。Bellco Glass,Inc.のBellstir Multi−stir 9 磁気攪拌機を使用して、3.5の速度設定で、ホモジナイズされたスラリを一晩撹拌させた(10Wで10秒間、16Wで10秒間、16Wで30秒間)。
3時間の撹拌後、使い捨てポリスチレン製キュベット中で動的光散乱法を用いて粒径分析を行った。
a.10W、10秒−Z−平均=499.9nm−PdI=0.23、ピーク=634.5nm
b.16W、10秒−Z−平均=528.9nm−PdI=0.227、ピーク=657.5nm
c.16W、30秒−Z−平均=471.6nm−PdI=0.228、ピーク=580.5nm
d.16W、60秒−Z−平均=491.1nm−PdI=0.275、ピーク=600.8nm
新しいD2Oおよび10x炭酸水素ナトリウム緩衝液を一晩4℃で冷却した。40μm細胞濾過器を使用して、各バッチから36mLの粒子懸濁液を濾過し、冷10x炭酸水素ナトリウム緩衝液4mLを含む適切に標示した50mL遠心管内に入れた。各ビーカーから、そのような管を約6本作り出した。全ての管を4℃で15分間7000gで遠心分離し、上清を吸引した。上記手順を用いて懸濁液の調製を繰り返し、できる限り多くの粒子ペレットを1mLの冷D2Oに懸濁した。
抗原を結合させたPLGAビーズの投与は、再発性実験的自己免疫性脳炎を予防する
再発性実験的自己免疫性脳炎(R−EAE)の予防のための寛容を誘導するために、免疫優性プロテオリピドタンパク質PLP139〜151エピトープ(PLG−PLP139〜151)を用いてPLGナノ粒子を調べた。上述のようにR−EAEマウスを作製した。
抗原を結合させたPLG粒子の静脈内注入は、OVA/ミョウバンで事前に感作させた動物においてアナフィラキシー誘導性の体温低下を誘発しない
活性疾患の存在のために、抗原に対するアナフィラキシーが懸念される:これは、即死を引き起こす可能性があり、ポリスチレン結合粒子とともに記載されている。アナフィラキシーは、体温の著しい低下と関連している。OVA−PLGの静脈内投与が、事前に感作させた動物においてアナフィラキシー誘導性の体温低下を誘導するかどうかを調べるために、0日目に、腹腔内注射により10μgのOVA/ミョウバンでマウスを免疫した。14日目に、腹腔内注射により10μgのOVA/ミョウバンでマウスを再び免疫し、次いで、21日目に静脈内投与したOVA−PLGで寛容化した。次いで、28日目に、静脈内投与によりOVA−PLG粒子またはOVAのいずれかでマウスを寛容化した。
PLP−PLG粒子による予防的投与は、長期の抗原特異的寛容を誘導する
疾患誘発の7日前に、濃度を上昇させたPLP139〜151−PLGの静脈内投与によって最適用量を決定し、OVA323〜339−PLGで処理したSJL/Jマウスと比較して臨床疾患の発症について監視した(図6A)。6〜8週齢のメスSJL/Jマウスに、PLP139〜151(四角)またはOVA323〜339(丸)のいずれかを結合させたPLGナノ粒子を静脈内注射した。7日後(図6B)、25日後(図6C)、または50日後(図6D)に、CFA中のPLP139〜151の皮下注射によりEAEを誘導した。パネルBの動物を臨床疾患について100日間追跡した。図6Eは、疾患誘導から8日目に、パネルBに示すマウスのサブセットにおいて遅延型過敏反応(DTH)を行ったことを示す。パネルBのPLP139〜151/CFA予備刺激群から選択された代表の動物(OVA323〜339−PLGおよびPLP139〜151−PLG)の耳を、予備刺激用のPLP139〜151エピトープおよびOVA323〜339対照ペプチドに曝露した。24時間後にDTHの尺度として耳の腫脹を判定し、曝露前の応答を差し引いた。図6Fは、6〜8週齢のメスSJL/Jマウスに、PLP178〜191(三角)、OVA323〜339(丸)、もしくはPLP139〜151(四角)を結合させたPLGナノ粒子、または未結合粒子のみ(縁取りのある丸)を静脈内注射したことを示す。7日後、CFA中のPLP178〜191の皮下注射によりEAEを誘導し、示される時点で疾患を監視した。
抗原結合粒子を用いた再発性実験的自己免疫性脳炎の治療
PLG−PLP139〜151粒子が、疾患を予防するのではなく、むしろ疾患を治療する能力を調査するために、かつ、投与経路が疾患の発症に影響を及ぼしたかどうかを判定するために、本発明の実施形態の開発中に実験を行った。0日目に、PLP139〜151およびアジュバントでマウスを免疫した。マウスは、通常、12〜14日目に最大臨床スコアを有する。このモデルでは、10日目に、静脈内(iv)投与、腹腔内(ip)投与、皮下(sc)投与、または経口的のいずれかにより、PLG−PLP139〜151粒子または対照PLG−OVA323〜339粒子のいずれかでマウスを処理した。図7に示すように、予防的寛容は、PLG−PLP139〜151粒子が静脈内または腹腔内のいずれかで投与された場合に最も効率的である。静脈内投与したPLP139〜151−PLGで処理した動物は、疾患を発症せず、ほとんどの時点で平均臨床スコア0を有していた。これは、70%を超える動物がアナフィラキシーによって死亡したことが観察された、PLP139〜151ポリスチレン粒子を用いて処理した動物とは対称的である。
抗原結合粒子の寛容は、活性な再発性実験的自己免疫性脳炎における抗原特異的Th1およびTh17応答の誘導を阻害する
抗原結合粒子の投与がTヘルパー細胞の誘導を阻害するかどうかを判定するために、−7日目に、MOG35〜55−PLGまたはOVA323〜339−PLG粒子のいずれかをBALB/cマウスに静脈内投与した。0日目に、OVA323〜339−PLG粒子およびフロイント完全アジュバント(CFA)をマウスに皮下投与した。10日目に、MOG35〜55−PLGまたはOVA323〜339−PLG粒子のいずれかで動物を再刺激し、流入領域リンパ節細胞を単離した。10日目に、CPM、ならびにIL−17、GM−CSF、IFN−γ、IL−10、およびIL−4のレベルを測定した。図8に示すように、OVA323〜339−PLG粒子の投与は、処理した動物においてTh1およびTh17応答を阻害した。
PLP−139〜151を結合させたPLGA粒子により寛容を誘導した。
PLP139〜151−PLGまたはOVA323〜339PLGをマウスに送達することにより、さらなる治療的寛容戦略を行った。組織学的分析は、PLP139〜151−PLG粒子の投与が頸髄の炎症および脱髄を阻害することを示した。マウスをPLP−PLGまたはOVA323〜339−PLGで処理し、40日目に組織を回収した。頸髄を単離し、切片化して、R−EAEおよび多発性硬化症の病態の根底にあるCNSにおける免疫応答を調査した。図9は、OVA323〜339−PLGで処理した動物の組織よりも天然組織に類似するPLP139〜151−PLGで処理した動物の脊髄内の免疫細胞浸潤の低下を示す。OVA323〜339−PLGで処理した動物は、CD45、CD4、およびCD11bに陽性染色を示したのに対し、PLP139〜151−PLGで処理した動物は、これらの因子に最小限の染色を示した。
PLP−139〜151を結合させたPLGA粒子によって誘導される寛容は、制御性T細胞の増加/活性化に一部依存する。
−9日目に、制御性T細胞の一般的なマーカーである抗CD25抗体(Tregs)でSJL/Jマウスを処理し、次いで、−7日目に、OVA323〜339PLG粒子および抗CD25抗体、OVA323〜339PLG粒子および対照IgG抗体、PLP139〜151−PLG粒子および抗CD25抗体、またはPLP139〜151−PLG粒子および対照IgG抗体のいずれかで処理した。図13に示すように、PLP139〜151−PLG粒子および抗CD25抗体で処理した動物は、時折、PLP139〜151−PLG粒子および対照IgG抗体で処理した動物よりも高い平均臨床スコアを示した。これは、Treg、または少なくともCD25を発現するT細胞が、寛容の誘導において役割を果たすことを裏付けるものである。
活性および養子性EAEにおいて、PLP139〜151−PLG粒子によって治療的寛容を誘導した。
PLP139〜151−PLG粒子によって誘導された治療的寛容を、活性および養子性EAEにおいて比較した。2.5×106 PLP139〜151で活性化した芽球の養子移入により、6〜8週齢のメスSJL/Jマウスに養子性EAEを誘導した。疾患誘導から2日後(図14A)および14日後(図14C)に、500nmのPLGナノ粒子に結合したPLP139〜151(四角)またはOVA323〜339(丸)ペプチドをマウスに腹腔内注射した。臨床疾患スコアを、抗原を結合させた脾細胞による処理後のスコアと比較した(図14A)。42日目に、PLP139〜151またはOVA323〜339寛容化マウスから、組織学的分析のために脳および脊髄を採取した。パネルAのマウスの切片を、PLPタンパク質およびCD45について染色した(図14B)。パネル(C)のマウスの脊髄切片をLuxol Fast Blueで染色した(図14D)。脱髄および細胞浸潤の領域を矢印で示す。結果は、養子性EAEを有するマウスにおいて、PLP139〜151−PLG粒子によって寛容が誘導されることを示す。
養子移入EAEにおいて、抗PD−1モノクローナル抗体を用いた処理は、PLP139〜151を封入したPLGナノ粒子による寛容誘導を抑制する
養子性EAEを有するマウスにおいて、抗PD−1抗体を用いた処理がPLP139〜151が誘導した寛容に及ぼす影響を調べるために、0日目に、3×106 PLP139〜151で活性化したT細胞芽球を静脈内投与によりマウスに投与した。2日目に、PLG粒子中に封入されたPLP139〜151またはOVA323〜339を、PBSまたは抗PD−1抗体のいずれかとともに静脈内投与により投与した。4日目、6日目、8日目、10日目、および12日目に、全ての動物に250μgの抗PD−1抗体またはPBSを投与した。
養子移入EAEにおいて、作動性抗CD40モノクローナル抗体を用いた処理は、PLP139〜151が封入されたPLGナノ粒子による寛容誘導をIL−12依存性様式で抑制する
養子性EAEを有するマウスにおいて、作動性抗CD40抗体がPLP139〜151が誘導した寛容に及ぼす影響を調べるために、0日目に、3×106 PLP139〜151で活性化したT細胞芽球を静脈内投与によりマウスに投与した。2日目に、PLG粒子内に封入されたPLP139〜151またはOVA323〜339を静脈内投与によりマウスに投与した。3日目に、対照IgG2a抗体、抗CD40抗体、または抗CD40抗体のいずれか、および抗Il−12抗体を動物に投与した。
PLG粒子内に封入されたOVAは、アレルギー性気道炎症および生体内OVA特異的Th2応答を予防的に阻害する。
PLG粒子内に封入されたOVAが気道炎症に及ぼす予防効果を調べるために、−7日目に、マウスをOVA−PLGで静脈内処理した。0日目に、10μg/マウスの用量のOVA/ミョウバンをマウスに腹腔内注射した。7日目に、マウスを再びOVA−PLGで静脈内処理し、14日目に、さらに10μg/マウスのOVA/ミョウバンを腹腔内注射した。28日目〜30日目に、エアロゾル化したOVAでマウスを3回処理した。
PLG粒子内に封入されたOVAは、アレルギー性気道炎症および生体内OVA特異的Th2応答を治療的に阻害する
PLG粒子内に封入されたOVAが気道炎症に及ぼす治療効果を調べるために、0日目および14日目に、10μg/マウスの用量のOVA/ミョウバンでマウスを腹腔内処理した。28日目および42日目に、OVA−PLGをマウスに静脈内投与した。56日目〜58日目に、エアロゾル化したOVAでマウスを3回処理した。
クロモグラニンA p31ペプチド−PLG粒子によって誘導される寛容は、1型糖尿病を阻害する
3週齢マウスから脾臓、腋窩、上腕、鼠径部、および膵臓のリンパ節細胞を単離することにより、BDC2.5マウスにおいて1型糖尿病を誘導した。単離細胞を培養し、2×106細胞/mLを0.5μMのp31ペプチドとともに96時間インキュベートすることにより生体外で活性化した。0時に、静脈内投与により、5×106細胞をNOD.SCIDマウス(6〜8週)に移入した。3日後、SPまたはPLG2に結合したp31またはMOG35〜55ペプチドの静脈内投与によりマウスを寛容化した。
インスリンを結合させたPLG粒子によって誘導される寛容は、NODマウスにおける自然発症性1型糖尿病の発症を阻害する
NODマウスを、6、8、および10週齢で、静脈内投与によりBSA(N=22)またはインスリン(N=23)を結合させたPLG粒子のいずれかで処理した。次いで、>250mg/dLの血糖として定義される糖尿病の発症についてマウスをアッセイした。図25に示すように、インスリンを結合させたPLG粒子の投与は、300日にわたって糖尿病を発症しなかったマウスの割合を有意に増加させた(22.7%と比較して69.6%;p=0.0027)。
生着動態
−7日目に、OVA−PLGまたは対照ペプチドDby−PLG(オスC57BL/6マウスによって発現される主要なH−Y抗原)のいずれかでメスCD45.2マウスを寛容化した。−1日目に、マウスを200ラドで照射し、次いで、0日目に、オスCD45.1マウスの1×106、5×106、または1×107骨髄細胞を移植した。次いで、1日目に、OVA−PLG、Dby−SP、またはDby−PLGのいずれかでレシピエントマウスを寛容化し、キメラ化のFACS分析のために血液を採取した。図26は、レシピエントマウスに観察されたCD45.1ドナー細胞の割合を示す。
クマリン−6 PLGA粒子は、投与の24時間後には検出不可能である。
抗原に結合しているかまたは抗原を含まないかのいずれかであるクマリン−6 PLGA粒子でマウスを処理した。図29に示すように、粒子は、投与後3時間には検出可能であったが、投与後24時間には検出不可能であった。DAPIで対比染色した、注射後3時間(中央の行)および注射後24時間(下の行)の、腹腔内蛍光PLGA/PEMA微粒子を注射したマウス脾臓(左の列)、肝臓(中央の列)、および肺(左の列)切片と比較した非注射ナイーブマウス(上の行)。
ナノ粒子は生体内でマクロファージと会合する
投与後6時間および15時間の肝臓の分析は、PLGA粒子が肝臓内でF4/80+細胞と共局在化していたことを示す(図30)。
コア内に可溶性PLP139〜151を含有する表面官能化ポリ(ラクチド−co−グリコリド)粒子を使用したSJL/JマウスにおけるR−EAEの阻害
0日目のPLP139〜151/CFAによる予備刺激前の−7日目および−1日目に、コア内に可溶性PLP139〜151ペプチドを含む2.5mgの500nm〜700nm表面官能化ポリ(ラクチド−co−グリコリド)粒子をSJL/Jマウスの群に腹腔内注射した。0日目に対照マウスを予備刺激したが、−7日目または−1日目には粒子処理を行わなかった。さらに20日間、R−EAEの臨床徴候についてマウスを観察した。
可溶性卵白アルブミンを含有する表面官能化ポリ(ラクチド−co−グリコリド)粒子によるアレルギー性気道炎症の阻害
マウスにアレルギー性気道炎症(AIA)を誘導した。0日目および+14日目の卵白アルブミン/ミョウバンによる予備刺激前の−7日目および+7日目に、コア内に可溶性卵白アルブミンまたは可溶性ウシ血清アルブミン(対照)を含む2.5mgの500nm〜700nm表面官能化ポリ(ラクチド−co−グリコリド)粒子をBalb/cマウスの群に静脈内注射した。+28−30日目に、エアロゾル化した卵白アルブミンにマウスを曝露した。次いで、マウスを屠殺し、気管支肺胞洗浄液を得た。卵白アルブミン特異的IgEの血清レベルも測定した。
抗原が封入された表面官能化ポリ(ラクチド−co−グリコリド)粒子の合成
本実施例は、自己免疫疾患における免疫誘導およびアレルギーの治療のための、ポリ(ラクチド−co−グリコリド)のシェルに取り囲まれた、高密度のカルボキシレート基で表面官能化され、コア内に可溶性抗原を含有する生分解性ポリ(ラクチド−co−グリコリド)粒子の製剤化および部分的特徴について詳述する。
1.エンドトキシン不含水中の150μLの200mg/mL卵白アルブミンまたはウシ血清アルブミンを、20mLシンチレーションバイアル中のジクロロメタン中の2mLの20% w/vポリ(ラクチド−co−グリコリド)に滴下で加えた。
2.得られた混合物を氷上に置き、プローブ超音波処理器を使用して10ワットで30秒間超音波処理した。
3.10mLの水中1% w/v ポリ(エチレン−alt−無水マレイン酸)を加えた。
4.得られた混合物を氷上に置き、プローブ超音波処理器を使用して16ワットで30秒間超音波処理した。
5.得られた混合物を600mLビーカー中の200mLの0.5% w/v ポリ(エチレン−alt−無水マレイン酸に注ぎ入れ、一晩撹拌して粒子を硬化させた。
6.次いで、硬化した粒子を遠心分離して精製し、炭酸水素緩衝液pH9.6で3回洗浄した。
7.精製した粒子を、水中4% w/vスクロースおよび3% w/v D−マンニトールに再懸濁し、液体窒素中で瞬間凍結し、凍結乾燥させた。
コア内に可溶性PLP139〜151を含有する表面官能化リポソームは、多発性硬化症のマウスR−EAEモデルにおいて免疫学的寛容を誘導する
本発明はまた、高密度の負電荷を帯びた基で表面官能化され、コア内に可溶性抗原を含有する生分解性リポソーム送達ビヒクルが、多発性硬化症のR−EAEマウスモデルにおいて免疫学的寛容を誘導することも発見した。
1)生分解性粒子は、体内に長時間残留せず、完全分解の時間を制御することができる。
2)粒子およびリポソームは、細胞を活性化せずに内部移行を促進するように官能化することができる。この目的のために、我々は、PLGミクロスフェアにホスファチジルセリンを充填した。
3)粒子およびリポソームは、特定の細胞集団のための標的リガンドを組み込むように設計することもできる。
4)粒子内に内部移行する細胞型の活性化を制限し、アネルギーならびに/または制御性T細胞の欠失および活性化を介して寛容の誘発を促進するように、IL−10およびTGF−β等の抗炎症性サイトカインも誘導することができる。
(1)T細胞および抗体媒介性の自己免疫疾患(多発性硬化症、1型糖尿病、関節リウマチ、全身性エリテマトーデス等)−寛容は、特定の自己免疫疾患を駆動する関連自己抗原と複合化させた粒子を用いて誘導される。
(2)食物および肺アレルギー、皮膚アレルギー、ならびに喘息−寛容は、アレルギー反応を誘発する特定の食物(例えば、ピーナツタンパク質等)、注入される物質(ハチ毒タンパク質等)、または吸入される物質(例えば、ブタクサ花粉タンパク質、ペットのフケタンパク質等)と複合化させた粒子を用いて誘導される。
(3)移植拒絶反応−寛容は、レシピエントによる拒絶反応を予防するために、臓器移植の前にドナー臓器またはドナー細胞上の移植抗原に対して誘導される。
(4)酵素補充療法−患者が、特定の欠陥を治療するために投与される組み換え的に生成された酵素に対する中和抗体応答を形成するのを防止するために、遺伝的欠陥を有する患者が産生することができない酵素に対して寛容が誘導される。
Claims (36)
- 負のゼータ電位を有する担体粒子に結合した抗原を含む、組成物。
- 前記粒子の前記ゼータ電位は、約−100mV〜約0mVである、請求項1に記載の組成物。
- 前記粒子の前記ゼータ電位は、約−50mV〜約−40mVである、請求項2に記載の組成物。
- 前記粒子は、約80:20〜約100:0のモル比を有するコポリマーである、請求項1に記載の組成物。
- 前記粒子は、ポリスチレン粒子、カルボキシル化ポリスチレン粒子、またはポリ(乳酸−co−グリコール酸)粒子である、請求項1に記載の組成物。
- 前記粒子は、約0.1μm〜約10μmの直径を有する、請求項1に記載の組成物。
- 前記粒子は、約0.3μm〜約5μmの直径を有する、請求項6に記載の組成物。
- 前記粒子は、約0.5μm〜約3μmの直径を有する、請求項7に記載の組成物。
- 前記粒子は、約0.5μm〜約1μmの直径を有する、請求項8に記載の組成物。
- 前記粒子は、約0.5μmの直径を有する、請求項9に記載の組成物。
- 前記抗原は、前記担体粒子の表面に結合する、請求項1に記載の組成物。
- 前記抗原は、前記担体粒子内に封入される、請求項1に記載の組成物。
- 前記抗原は、自己免疫抗原、対象に移植される組織上に発現される抗原、またはアレルゲンを含む、請求項1に記載の組成物。
- 前記抗原は、ミエリン塩基性タンパク質、アセチルコリン受容体、内在性抗原、ミエリンオリゴデンドロサイト糖タンパク質、膵β細胞抗原、インスリン、グルタミン酸デカルボキシラーゼ(GAD)、11型コラーゲン、ヒト軟骨gp39、fp130−RAPS、プロテオリピドタンパク質、フィブリラリン、低分子核小体タンパク質、甲状腺刺激因子受容体、ヒストン、糖タンパク質gp70、ピルビン酸脱水素酵素ジヒドロリポアミドアセチルトランスフェラーゼ(PCD−E2)、毛包抗原、A−グリアジン、およびヒトトロポミオシンアイソフォーム5、バヒアグラス花粉(BaGP)、モモアレルゲンPru p 3、αs−1カゼイン牛乳アレルゲン、Apig1セロリアレルゲン、Bere1ブラジルナッツアレルゲン、B−ラクトグロブリン牛乳アレルゲン、ウシ血清アルブミン、Cor a 1.04ヘーゼルナッツアレルゲン、または卵白アルブミン卵アレルゲンからなる群から選択されるタンパク質の少なくとも一部を含む、請求項13に記載の組成物。
- 前記抗原は、ミエリン塩基性タンパク質、アセチルコリン受容体、内在性抗原、ミエリンオリゴデンドロサイト糖タンパク質、膵β細胞抗原、インスリン、グルタミン酸デカルボキシラーゼ(GAD)、11型コラーゲン、ヒト軟骨gp39、fp130−RAPS、プロテオリピドタンパク質、フィブリラリン、低分子核小体タンパク質、甲状腺刺激因子受容体、ヒストン、糖タンパク質gp70、ピルビン酸脱水素酵素ジヒドロリポアミドアセチルトランスフェラーゼ(PCD−E2)、毛包抗原,A−グリアジン、またはヒトトロポミオシンアイソフォーム5、バヒアグラス花粉(BaGP)、モモアレルゲンPru p 3、αs−1カゼイン牛乳アレルゲン、Apig1セロリアレルゲン、Bere1ブラジルナッツアレルゲン、B−ラクトグロブリン牛乳アレルゲン、ウシ血清アルブミン、Cor a 1.04ヘーゼルナッツアレルゲン、または卵白アルブミン卵アレルゲンを含む、請求項13に記載の組成物。
- 前記抗原は、コンジュゲート分子によって前記粒子に結合される、請求項1に記載の組
成物。 - 前記コンジュゲート分子は、エチレンカルボジイミド(ECDI)である、請求項16に記載の組成物。
- 前記粒子は、生分解性である、請求項1に記載の組成物。
- 前記粒子は、表面官能化される、請求項1に記載の組成物。
- 前記粒子は、カルボン酸で表面官能化される、請求項19に記載の組成物。
- 薬学的に許容される担体をさらに含む、請求項1〜20のいずれか1項に記載の組成物。
- 対象において抗原特異的寛容を誘導する方法であって、前記対象に抗原結合粒子を含む有効量の組成物を前記対象に投与することを含み、前記粒子は、負のゼータ電位を有する、方法。
- 前記投与は、疾患または状態を治療または予防するために行われる、請求項22に記載の方法。
- 前記疾患または状態は、自己免疫疾患、炎症性疾患、アレルギー、移植拒絶反応、および過免疫応答からなる群から選択される、請求項23に記載の方法。
- 前記疾患または状態は、多発性硬化症、1型糖尿病、喘息、食物アレルギー、環境アレルギー、セリアック病、および前記抗原に対する過剰反応を低減するために前記対象において前記抗原によって引き起こされる状態からなる群から選択される、請求項24に記載の方法。
- 前記粒子は、ポリスチレン粒子、カルボキシル化ポリスチレン粒子、またはポリ(乳酸−co−グリコール酸)粒子である、請求項22に記載の方法。
- 前記粒子は、ポリ(乳酸−co−グリコール酸)粒子である、請求項26に記載の方法。
- 前記ポリ(乳酸−co−グリコール酸)粒子の投与は、ポリスチレン粒子の投与と比較して少ないアナフィラキシーをもたらす、請求項27に記載の方法。
- 前記組成物は、静脈内投与される、請求項22に記載の方法。
- 負のゼータ電位を有する免疫修飾粒子を調製するためのプロセスであって、
前記プロセスは、前記負のゼータ電位を有する免疫修飾粒子を形成するのに有効な条件下で免疫修飾粒子前駆体と緩衝液とを接触させることを含む、プロセス。 - 前記免疫修飾粒子前駆体は、共重合によって形成される、請求項30に記載のプロセス。
- 前記緩衝液は、塩基性pHを有する、請求項30に記載のプロセス。
- 前記緩衝液は、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム、リン酸二水素カリウム、リン酸二水素ナトリウム、またはリン酸二水素リチウムである、請求項30に記載のプロセス。
- 表面官能化リポソームのコア内に封入された抗原を含む、組成物。
- リポソームは、30:30:40の比率のホスファチジルコリン:ホスファチジルグリセロール:コレステロールからなる、請求項34に記載の組成物。
- 前記抗原は、自己免疫抗原、対象に移植される組織上に発現される抗原、またはアレルゲンを含む、請求項34に記載の組成物。
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