JP6295235B2 - 生体分子を細胞へトランスフェクトするための組成物 - Google Patents
生体分子を細胞へトランスフェクトするための組成物 Download PDFInfo
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Description
したがって、本発明の一態様は、生物学的に活性なであって、
(1)以下の生物学的に活性な成分:
(a)核酸又はその誘導体、
(b)ヌクレオシド、ヌクレオチド、又はヌクレオシド若しくはヌクレオチドの誘導体、
(c)ペプチド、タンパク質、又はペプチド若しくはタンパク質の誘導体、
(d)リポ多糖又はその誘導体、
(e)ペプチドグリカン又はその誘導体、
(f)炭水化物又はその誘導体、
(g)脂質又はその誘導体、
(h)リポペプチド又はその誘導体、
(i)金属イオン、
(j)チオール、
(k)抗生物質又はその誘導体、
(l)ビタミン又はその誘導体、
(m)バイオフラボノイド又はその誘導体、
(n)抗酸化物質又はその誘導体、
(o)免疫応答修飾因子、
(p)抗体、
(q)生物学的に活性な非金属、
(r)ヒスタミン又は抗ヒスタミン剤、及び
(s)キナーゼ阻害剤
のうち少なくとも1種と、
(2)組成物を食細胞に送達し、その結果、生物学的に活性な成分が、食細胞によって取り込まれ、その生物活性に影響を及ぼすのに有効な少なくとも1種の担体と
を含む上記組成物である。
(1)アレルギー、喘息、自己免疫状態、癌及び腫瘍転移からなる群から選択される状態に感受性である動物モデルを提供するステップと、
(2)組成物中で、微粒子が、病原体と同じサイズ範囲にあり、組成物が、免疫活性抗原又は抗原性エピトープを含み、免疫活性抗原又は抗原性エピトープが、ペプチド、タンパク質、組換えペプチド若しくはマルチペプチド又は組換えタンパク質である本発明の組成物を動物モデルに投与して、この組成物の投与に起因する免疫応答によって、動物モデルにおいて感染を治療又は予防するステップと、
(3)アレルギー、喘息、自己免疫状態、癌及び腫瘍転移からなる群から選択される状態に対する、ステップ(2)において投与された組成物の効果を調べるステップと
を含む、上記方法である。
(1)核酸又はその誘導体、
(2)ヌクレオシド、ヌクレオチド、又はヌクレオシド若しくはヌクレオチドの誘導体、
(3)ペプチド、タンパク質、又はペプチド若しくはタンパク質の誘導体;
(4)リポ多糖又はその誘導体、
(5)ペプチドグリカン又はその誘導体、
(6)炭水化物又はその誘導体、
(7)脂質又はその誘導体、
(8)リポペプチド又はその誘導体、
(9)金属イオン、
(10)チオール、
(11)抗生物質又はその誘導体、
(12)ビタミン又はその誘導体、
(13)バイオフラボノイド又はその誘導体、
(14)抗酸化物質又はその誘導体、
(15)免疫応答修飾因子、
(16)抗体、
(17)生物学的に活性な非金属、
(18)ヒスタミン又は抗ヒスタミン剤、及び
(19)キナーゼ阻害剤。
ホスホロチオエート結合は、例えば、米国特許第6,031,092号、同6,001,982号、同5,684,148号によって記載されており、WO97/03211、WO96/39154;Mata(1997年)Toxicol.Appl.Pharmacol.144:189〜197頁も参照のこと。この用語によって包含される他の合成骨格として、メチルホスホネート結合又は交互のメチルホスホネート及びホスホジエステル結合(例えば、米国特許第5,962,674号、Strauss−Soukup(1997年)Biochemistry36:8692〜8698を参照のこと)及びベンジルホスホネート結合(例えば、米国特許第5,532,226号、Samstag(1996年)Antisense Nucleic Acid Drug(Dev 6:153〜156頁を参照のこと)が挙げられる。
(1)以下の生物学的に活性な成分:
(a)核酸又はその誘導体、
(b)ヌクレオシド、ヌクレオチド、又はヌクレオシド若しくはヌクレオチドの誘導体、
(c)ペプチド、タンパク質、又はペプチド若しくはタンパク質の誘導体、
(d)リポ多糖又はその誘導体、
(e)ペプチドグリカン又はその誘導体、
(f)炭水化物又はその誘導体、
(g)脂質又はその誘導体、
(h)リポペプチド又はその誘導体、
(i)金属イオン、
(j)チオール、
(k)抗生物質又はその誘導体、
(l)ビタミン又はその誘導体、
(m)バイオフラボノイド又はその誘導体、
(n)抗酸化物質又はその誘導体、
(o)免疫応答修飾因子、
(p)抗体、
(q)生物学的に活性な非金属、
(r)ヒスタミン又は抗ヒスタミン剤、及び
(s)キナーゼ阻害剤
のうち少なくとも1種と、
(2)組成物を食細胞に送達し、その結果、生物学的に活性な成分が、食細胞によって取り込まれ、その生物活性に影響を及ぼすのに有効な少なくとも1種の担体と
を含む。
(1)(i)アレルギー、喘息及び自己免疫状態からなる群から選択される慢性炎症性疾患及び(ii)癌及び腫瘍転移からなる群から選択される悪性状態からなる群から選択される状態に対して感受性である動物モデルを提供するステップと、
(2)組成物中では、微粒子が病原体と同じサイズ範囲にあり、組成物が免疫活性抗原又は抗原性エピトープを含み、免疫活性抗原又は抗原性エピトープが、ペプチド、タンパク質、組換えペプチド若しくはマルチペプチド又は組換えタンパク質である本発明の組成物を動物モデルに投与して、組成物の投与に起因する免疫応答によって動物モデルにおいて感染を治療又は予防するステップと、
(3)(i)アレルギー、喘息及び自己免疫状態からなる群から選択される慢性炎症性疾患及び(ii)癌及び腫瘍転移からなる群から選択される悪性状態からなる群から選択される状態に対する、ステップ(2)において投与された組成物の効果を調べるステップと
を含む、上記方法である。
微粒子の選択
1〜10μmの範囲のアガロース微粒子が、Sterogene Bioseparations, Inc.(Carlsbad、CA)によって製造されており、Saturn DigiSizer 5200(Micromeritis Instrument Corp)を使用して調べた。結果は、粒子分布は、75%が5μm未満であり、24%が5〜10μmであり、1%が10μmを超えることを示した。
活性化されたアガロース微粒子
粒子は、2種の異なる方法によって活性化した。活性化法は、Sterogene Bioseparations, Inc.(Carlsbad、CA)によってチオール−ジスルフィドリガンド交換化学を使用して実施された。リガンドの可逆的共有結合を提供するこの結合化学では、微粒子を、高密度のチオール基で官能化した。ペプチド及び他の生体分子は、2−チオピリジル部分又はエポキシド基のいずれかで官能化した。2−チオピリジル官能化ペプチドは、細胞内部移行後に、強い細胞内還元環境のために微粒子から放出されるであろう。この化学の別の利点は、高度に有効で、再現性のあるリガンドの固定化である。
病原体の抗原性タンパク質の生物情報科学分析はまた、高い抗原性能力のペプチドエピトープの同定につながり得る。このような分析を、M・ガリセプチカム(M.gallisepticum)MGAタンパク質について実施した。抗原性領域を、直鎖抗原性モチーフとの関連でさらに分析した。
チオール官能化微粒子でのMGペプチド免疫モジュレーターの調製 免疫調節性組成物の調製:2.5mlのチオール官能化微粒子(Sterogene Bioseparations,Inc.、Carlsbad、CA)に、エポキシ化50μg LPS、50μgペプチドグリカン(PG)及び250μg大腸菌(E.coli)DNAの混合物を加えた。4時間撹拌した後、スラリーを遠心分離し、LAL水で1回洗浄した。次いで、125μgのチオール化ポリ−I:Cを加え、カップリングを4時間継続した。その後、遠心分離し、LAL水で3回洗浄し、0.125mgの2−cys−チオピリジルB3ペプチドを加え、カップリングを4時間継続した。次いで、混合物をLAL水で1回洗浄し、0.125mgの単回の、N末端2−cys−チオピリジル部分を含有するMHC I及びMHC IIペプチドエピトープ混合物(G1/9+G2/4)を加え、カップリングを4時間継続した。(これらのペプチドは、チオール粒子とのカップリングのためのN末端2−チオピリジル反応性基を含有する)。上清においてOD343によってカップリング効率を測定した。LAL水で洗浄した後、粒子を等量のLAL水に再懸濁した。
他の生物学的に活性な分子の固定化
本発明者らは、Znキレート化微粒子に以下のさらなるアゴニストを固定化した:クルクミン及びルチンのようなキナーゼ阻害剤、ラクトフェリン、ラクトフェリシン、細胞内酸化還元電位を改善するためのグルタチオン及びN−アセチルシステイン、チムリン、抗生物質(例えば、オフロキサシン及びチアムリン)、セレン、イミキモド、ポリ−リシンのような多塩基性ペプチド、抗菌性塩基性ペプチド、プロリンリッチペプチド、抗酸化物質及びビタミン。
2mlのZnキレート化微粒子に、最初に0.5mgのオフロキサシン、0.5mgのクルクミン及び0.5mgのルチンを加え、1時間穏やかに揺り動かす。遠心分離し、上清を残し、6mlのLAL水で1回洗浄し、プールする。さらに1回洗浄し、洗浄液を廃棄する。その後、20μgのG1/9、20μgのG2/4及び20μgのB3ペプチドをこの順序で、各添加後に穏やかに手作業で混合しながら加える(2ml量)。1時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。さらに各2回洗浄を反復する。等量のLAL水に再懸濁し、次いで、等量の2つのバイアルに分ける。上清及び最初の洗浄混合物からカップリング効率を求めた。
2mlのZnキレート化微粒子に、最初に0.5mgのレチノイン酸及び0.5mgのルチンを加え、1時間穏やかに揺り動かす。遠心分離し、上清を残し、6mlのLAL水で1回洗浄し、プールする。さらに1回洗浄し、洗浄液を廃棄する。その後、20μgのG1/9、20μgのG2/4及び20μgのB3ペプチドをこの順序で、各添加後に穏やかに手作業で混合しながら加える(2ml量)。1時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。さらに各2回洗浄を反復する。等量のLAL水に再懸濁し、次いで、等量の2つのバイアルに分ける。上清及び最初の洗浄混合物からカップリング効率を求めた。
2mlのZnキレート化微粒子に、40μgのLPS、40μgのPG、200μgのDNA及び10μgのイミキモドの混合物を加え、1時間穏やかに揺り動す。その後、20μgのG1/9、20μgのG2/4及び20μgのB3ペプチドをこの順序で、各添加後に穏やかに手作業で混合しながら加える(2ml量)。1時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。次いで、0.5mgのノボビオシン、0.5mgのグルタチオン及び0.5mgのチアムリンを加える。3時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。さらに各2回洗浄を反復する。等量のLAL水に再懸濁し、次いで、等量の2つのバイアルに分ける。上清及び最初の洗浄混合物からカップリング効率を求めた。
2mlのZnキレート化微粒子に、40μgのLPS、40μgのPG、200μgのDNA及び10μgのイミキモドの混合物を加え、1時間穏やかに揺り動す。その後、20μgのG1/9、20μgのG2/4及び20μgのB3ペプチドをこの順序で、各添加後に穏やかに手作業で混合しながら加える(2ml量)。1時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。次いで、0.5mgのレチノイン酸及び0.5mgのチアムリンを加える。3時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水でさらに1回洗浄し、上清とともにプールする。さらに各2回洗浄を反復する。等量のLAL水に再懸濁し、次いで、等量の2つのバイアルに分ける。上清及び最初の洗浄混合物からカップリング効率を求めた。
2mlのZnキレート化微粒子に、40μgのLPS、40μgのPG、200μgのDNA及び10μgのイミキモドの混合物を加え、1時間穏やかに揺り動す。その後、20μgのG1/9、20μgのG2/4及び20μgのB3ペプチドをこの順序で、各添加後に穏やかに手作業で混合しながら加える(2ml量)。1時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。次いで、50μgのラクトフェリシン及び50μgのチムリンを加える。3時間穏やかに揺り動かした後、遠心分離し、上清を残しておく。6mlのLAL水で1回洗浄し、上清とともにプールする。さらに各2回洗浄を反復する。等量のLAL水に再懸濁し、次いで、等量の2つのバイアルに分ける。上清及び最初の洗浄混合物からカップリング効率を求めた。
動物研究
免疫調節性組成物を、3日齢のニワトリ(M.ガリセプチカム(MG)及びM.シノビエ(M.synoviae)(MS)を含まず、ELISAによって検出されるMG及びMS移行抗体を有さない)に経口投与した。各群に、10羽のニワトリがあった。ニワトリの個々の体重を記録した。ニワトリを、各群の平均体重が統計的な差がないよう割り当てた。各トリは、適当な形態で記録された処理及び体重に従って、有色の、番号付けされたウィングタグによって識別された。実験の14日目に、ニワトリにM.ガリセプチカムRlow株を用いて抗原投与した。研究は28日で終結させた。
−1日目:群G1〜G4の設定。ELISAアッセイ、PCR並びにM.ガリセプチカム及びM.シノビエの培養のために10羽のニワトリを屠殺し、実験ニワトリが、移行抗体並びにM.ガリセプチカム及びM.シノビエの存在について陰性であることを確認した。
実験研究の最後の28日目に、すべての群を安楽死させた。各トリを剖検し、MGと関連している肉眼的病変についてスコア化した。気管、左及び右胸部気嚢並びに腹膜中の浸出液の存在を記録した。病変を、以下のシステムに従ってスコア化した:気管中:0=浸出液なし、1=わずかに発赤及び少量の浸出液、2=粘膜の発赤、浸出液。左及び右気嚢:0=病変なし、1=漿液性浸出液、2=小片のフィブリンを含む漿液性浸出液、3=漿液性、フィブリン性浸出液、わずかに肥厚した気嚢壁、4=多量のフィブリン性浸出液、極めて肥厚した気嚢壁。腹膜:0=浸出液なし、1=漿液性浸出液、2=小片のフィブリンを含む漿液性浸出液、3=漿液性フィブリン性浸出液。
剖検検査の際に、気管、胸部気嚢、肝臓、肺、脾臓、腎臓及び心臓を、スワブを使用して無菌的に試料採取した。次いで、スワブから得た材料を、マイコプラズマ寒天(MA)上にプレーティングし、5% CO2インキュベーター中、37℃でインキュベートした。2、4及び7日目に、次いで、週間隔で最大3週間、プレートをマイコプラズマについて観察した。陽性コロニーを、PCRによって試験し、M.ガリセプチカム及びM.シノビエを同定した。
MG抗原投与に続いて、気嚢及び腹膜において、顕著な病理学的病変が認識された。しかし、免疫活性ペプチド及びアゴニストを含有する粒子で処理された群(G3、G4 p<0.001)では、対照(G2)の未処理、抗原投与群と比較して、病変スコアの顕著な低減が記録された。
マイコプラズマは、未処理の、感染対照ニワトリの内部臓器から再単離できることが多い。マイコプラズマの完全な排出(呼吸器+内部臓器からの)は、未処理の、対照(G2)群と比較して、官能化微粒子で処理された群(G3、G4)において見られた。同様の結果が、実験群の気道(気管、肺、気嚢)からの、又は他の内部臓器(肝臓、脾臓、腎臓及び心臓)からのマイコプラズマの再単離率を比較した場合に得られた。
群の血清反応は、実験の最後で異なっていた。未処理の、抗原投与群(G2)の反応は低かった。同時に、粒子及びペプチドエピトープ及びアゴニストを用いて処理された群(G3、4)において有意に強い反応が見られた(p<0.05)。
M.ガリセプチカムは、気管、気嚢及び肺への定着を伴う、気嚢及び腹膜における顕著な炎症を引き起こし得る。マイコプラズマはまた、内部臓器から検出され得ることが多い。本発明者らは、微生物のサイズ範囲にあり(<5μm)、種々のアゴニスト免疫調節性分子とともに固定化された、抗原性エピトープペプチド又は他の抗原を有する微粒子からなる、新規種類の「病原体を摸倣する」免疫学的に活性な組成物を開発した。
本発明は、食細胞への、複数の生物学的に活性な分子の制御された投与量導入のための改善された組成物及び方法を提供する。これらの組成物は、安定であり、所望の生物学的効果を引き起こすためにさまざまな濃度で調製できる。このような効果の一例として、免疫応答がある。それらは、種々の経路によるin vitro及びin vivo投与の両方に適している。それらの構造は、in vivoで、エフェクター分子の早過ぎる分解又は放出を防ぐ。粒子は、粘膜とのその相互作用を改善し、取り込みを促進し得る、固有の粘液接着性を有する。
Claims (1)
- 生物学的に活性な組成物であって、
(a)以下の生物学的に活性な成分:
(i)核酸又はその誘導体、
(ii)ヌクレオシド、ヌクレオチド、又はヌクレオシド若しくはヌクレオチドの誘導体、
(iii)ペプチド、タンパク質、又はペプチド若しくはタンパク質の誘導体、
(iv)リポ多糖又はその誘導体、
(v)ペプチドグリカン又はその誘導体、
(vi)炭水化物又はその誘導体、
(vii)脂質又はその誘導体、
(viii)リポペプチド又はその誘導体、
(ix)抗生物質又はその誘導体、
(x)ビタミン又はその誘導体、
(xi)バイオフラボノイド又はその誘導体、
(xii)抗酸化物質又はその誘導体、
(xiii)免疫応答修飾因子、
(xiv)抗体、
(xv)ヒスタミン又は抗ヒスタミン剤、及び
(xvi)キナーゼ阻害剤
のうち少なくとも1種と
(b)前記組成物を食細胞に送達し、その結果、生物学的に活性な成分が、食細胞によって取り込まれ、その生物活性に影響を及ぼすのに有効な少なくとも1種の生体高分子の担体と
を含み、
前記生体高分子の担体が、微粒子の形態にあり、
少なくとも1種の生物学的に活性な成分が、ジスルフィド結合、及び固定化金属キレートを含む結合からなる群から選択される結合によって前記担体と可逆的に結合し、
前記生体高分子微粒子担体が、アガロース微粒子である、
上記組成物。
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