JP6876608B2 - 可溶性生体分子の生物学的活性を阻害するための組成物及び方法 - Google Patents
可溶性生体分子の生物学的活性を阻害するための組成物及び方法 Download PDFInfo
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Description
本特許出願は、2014年10月3日に出願された米国仮出願第62/059,628号、2015年7月29日に出願された米国仮特許出願第62/198,519号及び2015年7月29日に出願された米国仮特許出願第62/198,541号に対する優先権を主張するものであり、それらの各々がその全体において参照により本明細書に組み込まれる。
本発明は以下の実施形態も提供する。
[1]少なくとも1つの表面及び前記表面に固定された薬剤を有する粒子であって、
前記薬剤は、特異的結合ペアの第1のメンバーである標的と選択的に結合し、
前記標的の前記粒子との結合は、前記標的と前記特異的結合ペアの第2のメンバーとの相互作用を阻害する、粒子。
[2]表面及び前記表面に固定された薬剤を含む粒子であって、
前記薬剤は、標的と選択的に結合することができ、
薬剤と前記標的との結合は、前記標的と細胞との間の相互作用を阻害する、粒子。
[3]前記薬剤は、細胞の表面にある分子と結合する前記薬剤の能力が低減するよう前記粒子上で配向される、上記[1]又は[2]に記載の粒子。
[4]前記薬剤は、細胞の表面に発現する標的と結合する前記薬剤の能力が低減するよう前記粒子上で配向される、上記[3]に記載の粒子。
[5]前記薬剤は、細胞の表面にある分子との前記薬剤の結合が立体的に阻害されるよう前記粒子上で配向される、上記[1]〜[4]のいずれかに記載の粒子。
[6]前記薬剤は、細胞の表面にある標的との前記薬剤の結合が立体的に阻害されるよう前記粒子上で配向される、上記[5]に記載の粒子。
[7]前記表面は、細胞の表面にある分子と結合する前記薬剤の能力が低減するよう配向される、上記[1]〜[6]のいずれかに記載の粒子。
[8]前記細胞はヒト細胞である、上記[2]〜[7]のいずれかに記載の粒子。
[9]前記標的の最大寸法は、500nmを超えない、上記[1]〜[8]のいずれかに記載の粒子。
[10]前記標的の最大寸法は、200nmを超えない、上記[9]に記載の粒子。
[11]前記標的の最大寸法は、100nmを超えない、上記[10]に記載の粒子。
[12]前記標的の最大寸法は、50nmを超えない、上記[11]に記載の粒子。
[13]前記標的の最大寸法は、5nmを超えない、上記[12]に記載の粒子。
[14]前記標的の最大寸法は、1nmを超えない、上記[13]に記載の粒子。
[15]前記標的は、可溶性生体分子である、上記[1]〜[14]のいずれかに記載の粒子。
[16]前記標的は、小分子、タンパク質又は核酸である、上記[1]〜[15]のいずれかに記載の粒子。
[17]前記標的は、ウイルスタンパク質である、上記[1]〜[16]のいずれかに記載の粒子。
[18]前記ウイルスタンパク質は、構造タンパク質である、上記[17]に記載の粒子。
[19]前記ウイルスタンパク質は、ウイルスカプシドタンパク質又はウイルスエンベロープタンパク質である、上記[17]又は[18]に記載の粒子。
[20]前記標的は毒素である、上記[1]〜[19]のいずれかに記載の粒子。
[21]前記毒素は、細菌毒素、植物毒素又は動物毒素である、上記[20]に記載の粒子。
[22]前記標的は、可溶型の細胞膜結合タンパク質である、上記[16]に記載の粒子。
[23]前記細胞膜結合タンパク質は、細胞表面受容体タンパク質である、上記[22]に記載の粒子。
[24]前記標的は、細胞表面受容体に対するリガンドである、上記[1]〜[23]のいずれかに記載の粒子。
[25]前記リガンドは、サイトカイン、ケモカイン又はリンホカインである、上記[24]に記載の粒子。
[26]前記リガンドは、インターロイキンタンパク質である、上記[25]に記載の粒子。
[27]前記リガンドは、腫瘍壊死因子(TNF)ファミリーリガンド又はその変異体である、上記[24]に記載の粒子。
[28]前記TNFファミリーリガンドは、TNFα又はその変異体である、上記[27]に記載の粒子。
[29]前記TNFファミリーリガンドは、Fasリガンド、リンホトキシン、リンホトキシンアルファ、リンホトキシンベータ、4-1BBリガンド、CD30リガンド、EDA-A1、LIGHT、TLA1、TWEAK、TNFβ、TRAIL又は前述のいずれかの変異体である、上記[27]に記載の粒子。
[30]前記リガンドは、ケモカインである、上記[25]に記載の粒子。
[31]前記標的は、サイトゾル受容体又は核受容体に対するリガンドである、上記[1]〜[21]のいずれかに記載の粒子。
[32]前記薬剤は、細胞表面受容体タンパク質のリガンドである、上記[1]〜[31]のいずれかに記載の粒子。
[33]前記薬剤は、細胞表面受容体タンパク質の天然のリガンドである、上記[32]に記載の粒子。
[34]前記薬剤は、前記薬剤の前記細胞表面受容体タンパク質との結合又は前記薬剤による前記細胞表面受容体タンパク質の活性化が立体的に阻害されるよう前記粒子上で配向される、上記[32]又は[33]に記載の粒子。
[35]少なくとも1つの表面及び前記表面に固定された薬剤を有する粒子であって、
前記薬剤は、可溶性生体分子と選択的に結合し、
前記可溶性生体分子は、細胞表面受容体タンパク質の形態であり、
前記薬剤は、前記薬剤による前記細胞表面受容体タンパク質との結合又は前記細胞表面受容体タンパク質の活性化が立体的に阻害されるよう前記粒子上で配向される、粒子。
[36]前記細胞表面受容体タンパク質は、がん細胞によって発現される、上記[32]〜[35]のいずれかに記載の粒子。
[37]前記細胞表面受容体タンパク質は、がん細胞によって可溶型の細胞表面受容体タンパク質として脱離されるタンパク質である、上記[36]に記載の粒子。
[38]前記細胞表面受容体タンパク質は、活性化されると、アポトーシスを誘導する、上記[32]〜[37]のいずれかに記載の粒子。
[39]前記細胞表面受容体タンパク質は、腫瘍壊死因子受容体(TNFR)タンパク質である、上記[38]に記載の粒子。
[40]前記細胞表面受容体タンパク質は、Fas受容体タンパク質である、上記[38]に記載の粒子。
[41]前記細胞表面受容体タンパク質は、TNF関連アポトーシス誘導リガンド受容体(TRAILR)タンパク質、4-1BB受容体タンパク質、CD30タンパク質、EDA受容体タンパク質、HVEMタンパク質、リンホトキシンベータ受容体タンパク質、DR3タンパク質又はTWEAK受容体タンパク質である、上記[38]に記載の粒子。
[42]前記細胞表面受容体タンパク質は、インターロイキン受容体タンパク質である、上記[32]〜[38]のいずれかに記載の粒子。
[43]前記インターロイキン受容体タンパク質は、IL-2受容体タンパク質である、上記[42]に記載の粒子。
[44]前記薬剤は、小分子、大員環化合物、ポリペプチド、タンパク質、ペプチド、ペプチド模倣化合物、核酸又は核酸類似体である、上記[1]〜[43]のいずれかに記載の粒子。
[45]前記薬剤は、抗体又は抗体の生体分子結合フラグメントである、上記[44]に記載の粒子。
[46]前記薬剤は、抗体の生体分子結合フラグメントであり、前記生体分子結合フラグメントは、Fabフラグメント、F(ab) 2 フラグメント、scFvフラグメント及びドメイン抗体から選択される、上記[45]に記載の粒子。
[47]前記薬剤は、非抗体足場タンパク質である、上記[44]に記載の粒子。
[48]前記薬剤は、インターロイキンタンパク質又はその変異体である、上記[44]に記載の粒子。
[49]前記インターロイキンタンパク質は、IL-2タンパク質又はその変異体である、上記[48]に記載の粒子。
[50]前記薬剤は、腫瘍壊死因子(TNF)ファミリーリガンド又はその変異体を含む、上記[44]に記載の粒子。
[51]前記TNFファミリーリガンドは、TNFα又はその変異体である、上記[50]に記載の粒子。
[52]前記TNFファミリーリガンドは、Fasリガンド、リンホトキシン、リンホトキシンアルファ、リンホトキシンベータ、4-1BBリガンド、CD30リガンド、EDA-A1、LIGHT、TLA1、TWEAK、TNFβ、TRAIL及び前述のいずれかの変異体から選択される、上記[50]に記載の粒子。
[53]前記細胞表面受容体タンパク質を活性化する前記薬剤の能力が、前記細胞表面受容体タンパク質の天然のリガンドの前記能力と比較して低減されている、上記[32]〜[52]のいずれかに記載の粒子。
[54]前記薬剤は、前記細胞表面受容体タンパク質を活性化しない、上記[53]に記載の粒子。
[55]前記粒子は、立方体又は球状である、上記[1]〜[54]のいずれかに記載の粒子。
[56]前記粒子は多孔質であり、前記粒子の外側表面及び前記孔の内側表面を含む、上記[1]〜[55]のいずれかに記載の粒子。
[57]前記薬剤は、前記内側表面に固定される、上記[56]に記載の粒子。
[58]複数の孔は、少なくとも50nmの断面寸法を有する、上記[56]又は[57]に記載の粒子。
[59]複数の孔は、少なくとも100nmの断面寸法を有する、上記[58]に記載の粒子。
[60]前記粒子は球状であり、前記粒子は前記粒子の球面から延びる2つの交差する隆線部をさらに含み、前記隆線部は、(i)前記球状粒子の表面に固定された薬剤の、細胞表面受容体タンパク質との結合、若しくは該薬剤の細胞表面受容体タンパク質の活性化、を阻害する、及び/又は(ii)前記標的が前記薬剤と結合したとき、前記標的と、前記標的が前記第1のメンバーである特異的結合ペアの第2のメンバーとの相互作用を阻害する大きさにされ、配向される、上記[55]に記載の粒子。
[61]前記粒子は、環状(toroidal)である、上記[1]〜[54]のいずれかに記載の粒子。
[62]前記薬剤は、前記粒子の内側円周表面に固定されている、上記[61]に記載の粒子。
[63]前記粒子の直径は、300nmを超えない、上記[1]〜[62]のいずれかに記載の粒子。
[64]前記粒子の直径は、250nmを超えない、上記[63]に記載の粒子。
[65]前記粒子は、角錐、四面体、六面体、八面体、十二面体又は二十面体である、上記[1]〜[64]のいずれかに記載の粒子。
[66]前記粒子は、その頂点の少なくとも1つから外側へ向かう少なくとも1つの突起物を含む、上記[55]〜[65]のいずれかに記載の粒子。
[67]前記粒子は、その頂点から外側へ向かう2つ以上の突起物を含む、上記[66]に記載の粒子。
[68]1つ以上の突起物は、(i)前記球状粒子の表面に固定された前記薬剤の、細胞表面受容体タンパク質との結合、若しくは前記薬剤による細胞表面受容体タンパク質の活性化、を阻害する及び/又は(ii)前記標的が前記薬剤と結合したとき、前記標的と、前記標的が前記第1のメンバーである特異的結合ペアの第2のメンバーとの相互作用を阻害する大きさにされ、配向される、上記[66]又は[67]に記載の粒子。
[69]前記粒子は、対象の脈管構造中を循環する形状及び大きさにされる、上記[1]〜[68]のいずれかに記載の粒子。
[70]前記粒子の最大寸法は、約1μmを超えない、上記[1]〜[69]のいずれかに記載の粒子。
[71]前記粒子の最大寸法は、750nmを超えない、上記[70]に記載の粒子。
[72]前記粒子の最大寸法は、500nmを超えない、上記[71]に記載の粒子。
[73]前記粒子の最小寸法は、少なくとも約300nmである、上記[1]〜[72]のいずれかに記載の粒子。
[74]複数の薬剤を含み、その複数の薬剤は、約10〜約10 9 の薬剤からなる、上記[1]〜[73]のいずれかに記載の粒子。
[75]前記複数の薬剤は、約10 3 〜約10 7 の薬剤からなる、上記[74]に記載の粒子。
[76]前記複数の薬剤は、約10 4 〜約10 6 の薬剤からなる、上記[75]に記載の粒子。
[77]前記粒子は、2つ以上の薬剤を含む、上記[1]〜[76]のいずれかに記載の粒子。
[78]前記粒子は、少なくとも2つの薬剤を含み、各薬剤は、異なる標的に選択的に結合することができる、上記[1]〜[77]のいずれかに記載の粒子。
[79]前記粒子の表面は、それぞれが異なる薬剤を含む複数の番地(address)を含む、上記[78]に記載の粒子。
[80]前記粒子の表面は、排出誘発因子化合物(excretion inducer compound)を含む、上記[1]〜[79]のいずれかに記載の粒子。
[81]前記粒子は環状形状を有し、前記排出誘発因子は環の外側円周表面と結合している、上記[80]に記載の粒子。
[82]前記粒子の本体は、アルミナ、金属、ガラス、シリカ、ラテックス、プラスチック、アガロース、ポリアクリルアミド、メタアクリレート又はポリマーを含む、上記[1]〜[81]のいずれかに記載の粒子。
[83]前記粒子は、シリコンを含む、上記[1]〜[82]のいずれかに記載の粒子。
[84]前記シリコンは、多孔質シリコンである、上記[83]に記載の粒子。
[85]複数のコーティング分子をさらに含む、上記[1]〜[84]のいずれかに記載の粒子。
[86]前記複数のコーティング分子の少なくとも1つの分子は、前記表面と結合している、上記[85]に記載の粒子。
[87]第2の表面をさらに含み、前記複数のコーティング分子の少なくとも1つの分子は前記第2の表面と結合している、上記[85]又は[86]に記載の粒子。
[88]リザーバーをさらに含み、前記リザーバーの壁は前記第2の表面を含む、上記[87]に記載の粒子。
[89]部材をさらに含み、前記部材は、前記リザーバーへの開口部を覆う、上記[88]に記載の粒子。
[90]前記部材は、生分解性である、上記[89]に記載の粒子。
[91]前記部材は、生分解性ポリマーである、上記[90]に記載の粒子。
[92]前記部材は、生体液に約1日〜約4年間曝露された後、生物分解するよう構成される、上記[90]又は[91]に記載の粒子。
[93]前記部材は、生体液に約1日〜約1年間曝露された後、生物分解するよう構成される、上記[92]に記載の粒子。
[94]前記表面は前記粒子の内部表面であり、前記第2の表面は前記粒子の外部表面である、上記[87]に記載の粒子。
[95]第2の複数のコーティング分子をさらに含み、
前記第2の複数のコーティング分子の少なくとも1つの分子は、前記第2の表面と結合しており、
前記第2の複数のコーティング分子は、インビボにおける前記粒子のクリアランスを低下させる、上記[94]に記載の粒子。
[96]前記第2の複数のコーティング分子は、前記複数のコーティング分子と細胞及び/又は細胞外タンパク質との間の相互作用を阻害し、それによりインビボにおける前記粒子のクリアランスを低下させる、上記[95]に記載の粒子。
[97]前記第2の複数のコーティング分子は、生分解性である、上記[95]又は[96]に記載の粒子。
[98]前記第2の複数のコーティング分子は、生分解性ポリマーを含む、上記[97]に記載の粒子。
[99]前記第2の複数のコーティング分子は、生体液に約1日〜約4年間曝露された後、生物分解するよう構成される、上記[97]又は[98]に記載の粒子。
[100]前記第2の複数のコーティング分子は、生体液に約1日〜約1年間曝露された後、生物分解するよう構成される、上記[99]に記載の粒子。
[101]前記第2の複数のコーティング分子は、CD47を含む、上記[95]〜[100]のいずれかに記載の粒子。
[102]前記複数のコーティング分子は、インビボにおける前記粒子のクリアランスを増加させる、上記[85]〜[101]のいずれかに記載の粒子。
[103]前記複数のコーティング分子は、病原体関連分子パターンを含む、上記[85]〜[102]のいずれかに記載の粒子。
[104]前記病原体関連分子パターンは、非メチル化CpG DNA、二本鎖RNA、リポ多糖、ペプチドグリカン、リポアラビノマンナン、ザイモサン、マイコプラズマリポタンパク質、フラジェリン、ポリ(イノシン-シチジル)酸、リポテイコ酸又はイミダゾキノリンである、上記[103]に記載の粒子。
[105]前記複数のコーティング分子は、カルレティキュリンを含む、上記[102]に記載の粒子。
[106]前記複数のコーティング分子は、ファゴサイトーシスによる前記粒子のクリアランスを増加させる、上記[102]〜[105]のいずれかに記載の粒子。
[107]前記複数のコーティング分子は、前記粒子の腎クリアランスを増加させる、上記[102]に記載の粒子。
[108]前記複数のコーティング分子は、前記粒子の胆肝道クリアランスを増加させる、上記[102]に記載の粒子。
[109]前記複数のコーティング分子は、疎水性分子を含む、上記[108]に記載の粒子。
[110]前記複数のコーティング分子は、インビボにおける前記粒子のクリアランスを低下させる、上記[85]に記載の粒子。
[111]前記複数のコーティング分子は、生分解性である、上記[110]に記載の粒子。
[112]前記複数のコーティング分子は、生分解性ポリマーを含む、上記[111]に記載の粒子。
[113]上記[1]〜[112]のいずれかに記載の複数の粒子を含む組成物。
[114]薬学的に許容される担体及び上記[1]〜[112]のいずれかに記載の粒子又は上記[113]に記載の組成物を含む医薬組成物。
[115]上記[114]に記載の医薬組成物を含む充填されたシリンジ。
[116]対象中の可溶性生体分子の生物学的活性を阻害するための方法であって、前記対象に上記[113]に記載の組成物又は上記[114]に記載の医薬組成物を、前記可溶性生体分子の生物学的活性を阻害するのに十分な量で投与することを含む、方法。
[117]可溶型の少なくとも1つのサイトカイン受容体を脱離するがん細胞を含むがんに罹患している対象を治療するための方法であって、前記対象に上記[1]〜[112]のいずれかに記載の複数の粒子を、前記脱離した可溶型の前記少なくとも1つのサイトカイン受容体の生物学的活性を阻害するのに有効な量で投与し、それにより前記がんを治療することを含む、方法。
[118]前記がん細胞は、可溶型のTNF受容体を脱離する、上記[117]に記載の方法。
[119]前記複数の粒子は、TNFαポリペプチド又はその変異体を含む薬剤を含む、上記[118]に記載の方法。
[120]前記がん細胞は、可溶型のIL-2受容体を脱離する、上記[117]に記載の方法。
[121]前記複数の粒子は、IL-2ポリペプチド又はその変異体を含む薬剤を含む、上記[120]に記載の方法。
[122]前記対象は、哺乳動物である、上記[116]〜[121]のいずれかに記載の方法。
[123]前記哺乳動物は、ヒトである、上記[122]に記載の方法。
[124]前記対象は、がん又は自己免疫疾患を有する、上記[116]〜[123]のいずれかに記載の方法。
可溶性生体分子は、一般に特異的結合ペアの第1のメンバーである。本明細書中で使用される場合、「結合パートナー」、「特異的結合パートナー」又は「特異的結合ペアのメンバー」は、一般に実質的な親和性及び特異性により互いに結合する結合メンバーのペアの任意のメンバーを含む。結合パートナーのペアは、サンプルのその他の構成成分の少なくとも大半又は少なくとも実質的にすべてを、実質的に排除して互いに結合することができ、及び/又はとりわけ約10-4、10-5、10-6、10-7又は10-8M未満の解離定数を有してもよい。結合パートナーのペアは、協調して特異性及び親和性を増加させるために複数の原子相互作用に依存する予め定義された様式で組み合わさる(fit together)ことができる。結合パートナーは、とりわけ生物系(例えば、受容体-リガンド相互作用)、化学的相互作用及び/又は分子インプリンティング技術に由来するものであってもよい。特異的な結合ペアとも称される、結合パートナーの例となる対応するペアを表1に提示する。表記「第1の」及び「第2の」は、任意であり、互換性がある。
本明細書中で使用される場合、「粒子」という用語は、アルミナ、金属(例えば、金若しくはプラチナ)、ガラス、シリカ、ラテックス、プラスチック、アガロース、ポリアクリルアミド、メタクリレート又は任意の高分子材料などの任意の材料を含んでもよく、かつ任意の大きさ及び形状であってもよい小さな塊を指す。一部の実施形態において、粒子(複数可)は、シリコンを含む。例えば、それぞれの開示の全体が参照により組み込まれる、国際特許出願公開第WO2013/011764号、同第WO2013/029278号及び同第WO2014/151381号並びに米国特許出願公開第2014/0271886号を参照のこと。一部の実施形態において、粒子は、デンプンを含んでもよく、又はデンプンからなるものでもよい(例えば、国際特許出願公開第WO2010/084088号を参照のこと)。
一部の実施形態において、粒子を作製するために使用した材料(例えば、シリコン)は、約40%〜約95%、例えば、約60%〜約80%の多孔度を有してもよい。多孔度とは、本明細書中で使用される場合、材料中の空隙の尺度であり、材料の全体積に対する空間の体積の割合である。特定の実施形態において、担体材料は、少なくとも約10%、少なくとも約20%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%又はさらに少なくとも約90%の多孔度を有する。特定の実施形態において、多孔度は、約40%超、例えば、約50%超、約60%超又はさらに約70%超である。
一部の実施形態において、粒子の形状は、固定された薬剤の、細胞の表面にある生体分子と相互に作用する能力が低減されるか、又は実質的に低減されるようなものである。例えば、一部の実施形態において、本明細書に記載されている粒子の表面に固定されたTNFα又はIL-2は、遊離TNFα又はIL-2が細胞の表面にあるTNFα受容体又はIL-2受容体と結合する能力の50%未満(例えば、45、40、35、30、25、20、15、10、9、8、7、6、5、4、3、2又は1%)の能力を有する。一部の実施形態において、粒子と結合した可溶性生体分子の、その同種のリガンド(特異的結合ペアの第2のメンバー)と相互作用する能力は、低減されているか、又は実質的に低減されている。例えば、本明細書に記載されている粒子と結合した可溶性TNFRは、遊離した可溶性TNFRが遊離TNFαと相互作用する能力の50%未満(例えば、45、40、35、30、25、20、15、10、9、8、7、6、5、4、3、2又は1%)の能力を有する。別の例において、本明細書に記載されている粒子と結合した可溶性ビリオンは、遊離ビリオンがその同種の細胞表面受容体(複数可)と相互作用し、細胞に感染する能力の50%未満(例えば、45、40、35、30、25、20、15、10、9、8、7、6、5、4、3、2又は1%)の能力を有する。薬剤と細胞表面にある生体分子との相互作用又は粒子と結合した生体分子とその同種のリガンドとの間の相互作用を低減するか、又は実質的に低減することができる例示的な粒子形状が図1〜3に示され、本明細書に記載されている。
上述のとおり、一部の実施形態において、粒子(複数可)の表面に固定された薬剤は、抗体又はその抗原結合フラグメントである。抗体は、当該技術分野において既知の方法によって誘発されてもよい。例えば、マウス、ハムスター又はウサギなどの哺乳動物が、可溶性生体分子(例えば、可溶性TNFR、毒素又はウイルスタンパク質)の免疫原性形態により免疫されてもよい。或いは、免疫化は、観察される免疫原性応答を生じる反応を引き起こす生体分子(例えば、可溶性タンパク質)をインビボで発現する核酸を使用することによって行われてもよい。タンパク質又はペプチドに免疫原性を与えるための技術としては、担体との結合又は当該技術分野において周知のその他の技術が挙げられる。例えば、本発明のポリペプチドのペプチジル部分が、アジュバントの存在下において投与されてもよい。免疫化の進行は、血漿又は血清中の抗体価の検出によって監視することができる。標準的なELISA又はその他のイムノアッセイは、抗体のレベルを評価するために抗原としての免疫原とともに使用することができる。
一部の実施形態において、粒子は、排出剤(clearance agent)を含む。排出剤は、尿への排出、分解、胆肝道経路による排出及び/又はファゴサイトーシスによるなどの生物学的経路による粒子のクリアランスを促進することができる。
本開示は、本明細書に記載されている組成物(例えば、概して若しくは具体的に記載されている粒子のいずれか又は本明細書に記載されている複数の粒子)が、インビトロ及び/又はインビボで細胞及び組織に投与されてもよいことを意図する。インビボでの投与としては、がんの動物モデルなどの疾患の動物モデルへの投与又はそれを必要とする対象への投与が挙げられる。適した細胞、組織又は対象は、愛玩用動物、家畜、動物園の動物、絶滅の危機に瀕している種、希少動物、非ヒト霊長類及びヒトなどの動物を含む。例となる愛玩用動物は、イヌ及びネコを含む。
特定の実施形態において、本開示の対象粒子(複数可)は、薬学的に許容される担体とともに製剤化される。(例えば、本明細書に記載されている粒子又は複数の粒子を含む)1つ以上の組成物は、単独で、又は医薬製剤(組成物)の構成成分として投与することができる。本明細書において概して又は具体的に記載されている本開示のあらゆる組成物は、本明細書に記載されているとおり製剤化されてもよい。特定の実施形態において、本組成物は、第2の治療剤とともに製剤化された本開示の2つ以上の粒子又は本開示の粒子を含む。
本明細書に記載されている組成物(例えば、粒子及びその医薬組成物)は、さまざまな診断及び治療的適用において有用である。例えば、本明細書に記載されている粒子は、がんを治療する、対象から毒を除去する又はウイルス若しくは細菌感染症を治療するために使用することができる。
一部の実施形態において、本明細書に記載されている粒子は、がんのある対象を治療するのに有用な場合がある。本明細書に記載されている粒子組成物に有用な例となる薬剤及び/又はそのような粒子によって捕捉され得る可溶性生体分子は、本明細書に記載されており(例えば、表2)、当該技術分野において知られている。例えば、sTNFR、MMP2、MMP9、sIL-2R、sIL-1受容体及び同種のものを捕捉することができる粒子は、がんを治療するのに及び/又は免疫脱抑制(immune dis-inhibition)を軽減することによってがんに対する免疫応答を向上させるのに有用である。
一部の実施形態において、本明細書に記載されている粒子は、炎症性障害及び/又は自己免疫障害を治療するために使用することができる。本明細書に記載されている粒子組成物に有用な例となる薬剤及び/又はそのような粒子によって捕捉され得る可溶性生体分子は、本明細書に記載されており(例えば、表2)、当該技術分野において知られている。例えば、サイトカイン(例えば、TNFα又はIL-2、IL-6若しくはIL-1などインターロイキン)或いはケモカイン(例えば、CXCL8又はCXCL1)を捕捉することができる粒子は、さまざまな自己免疫障害及び/又は炎症性障害を治療するのに有用な場合がある。
一部の実施形態において、本明細書に記載されている粒子は、微生物(例えば、ウイルス若しくは細菌)又はエンドトキシンなどの微生物の構成成分と結合するよう設計されてもよい。それゆえに、本明細書に記載されている粒子は、例えば、感染性疾患を治療するのに有用な場合がある(例えば、HPV、HBV、C型肝炎ウイルス(HCV)、レトロウイルス、例えば、ヒト免疫不全ウイルス(HIV-1及びHIV-2)、ヘルペスウイルス、例えば、エプスタインバーウイルス(EBV)、サイトメガロウイルス(CMV)、HSV-1及びHSV-2並びにインフルエンザウイルスを含むウイルス感染性疾患。さらに、アスペルギルス(Aspergillus)、ブルギア(Brugia)、カンジダ(Candida)、クラミジア(Chlamydia)、コクシジウム(Coccidia)、クリプトコッカス(Cryptococcus)、ディロフィラリア(Dirofilaria)、淋菌(Gonococcus)、ヒストプラズマ(Histoplasma)、リーシュマニア(Leishmania)、マイコバクテリウム(Mycobacterium)、マイコプラズマ(Mycoplasma)、ゾウリムシ(Paramecium)、百日咳(Pertussis)、プラスモジウム(Plasmodium)、肺炎球菌(Pneumococcus)、ニューモシスチス(Pneumocystis)、リケッチア(Rickettsia)、サルモネラ(Salmonella)、シゲラ(Shigella)、ブドウ球菌(Staphylococcus)、連鎖球菌(Streptococcus)、トキソプラズマ(Toxoplasma)及びコレラ菌(Vibriocholerae)などの細菌、真菌及びその他の病原性感染症が含まれる。例となる種としては、淋菌(Neisseria gonorrhea)、結核菌(Mycobacterium tuberculosis)、カンジダ・アルビカンス(Candida albicans)、カンジダ・トロピカリス(Candida tropicalis)、膣トリコモナス(Trichomonas vaginalis)、ヘモフィルス・バギナリス((Haemophilus vaginalis)、B群連鎖球菌(Group B Streptococcus)種、マイクロプラズマ・ホミニス(Microplasma hominis)、軟性下疳菌(Hemophilus ducreyi)、鼡径肉芽腫(Granuloma inguinale)、性病性リンパ肉芽腫(Lymphopathia venereum)、梅毒トレポネーマ(Treponema pallidum)、ウシ流産菌(Brucella abortus)。ヤギ流産菌(Brucella melitensis)、ブタ流産菌(Brucella suis)、イヌ流産菌(Brucella canis)、カンピロバクター・フィータス(Campylobacter fetus)、カンピロバクター・フィータス・インテスティナリス(Campylobacter fetus intestinalis)、レプトスピラ・ポモナ(Leptospira pomona)、リステリア菌(Listeria monocytogenes)、ヒツジ流産菌(Brucella ovis)、オウム病クラミジア(Chlamydia psittaci)、トリトリコモナス・フィータス(Trichomonas foetus)、トキソプラズマ・ゴンディ(Toxoplasma gondii)、大腸菌(Escherichia coli)、アクチノバチルス・エクーリ(Actinobacillus equuli)、サルモネラ・アボルトゥス・オヴィス(Salmonella abortus ovis)、サルモネラ・アボルトゥス・エクイ(Salmonella abortus equi)、緑膿菌(Pseudomonas aeruginosa)、コリネバクテリウム・エクイ(Corynebacterium equi)、コリネバクテリウム・ピオゲネス(Corynebacterium pyogenes)、アクチノバチルス・セミニス(Actinobaccilus seminis)、マイコプラズマ・ボヴィゲニタリウム(Mycoplasma bovigenitalium)、アスペルギルス・フミガツス(Aspergillus fumigatus)、アブシディア・ラモサ(Absidia ramosa)、媾疫トリパノソーマ(Trypanosoma equiperdum)、大形馬バベシア(Babesia caballi)、破傷風菌(Clostridium tetani)、クロストリジウム・ボツリヌム(Clostridium botulinum);又は例えば、パラコクシディオイデス・ブラジリエンシス(Paracoccidioides brasiliensis)などの真菌;又はその他の病原体、例えば、熱帯熱マラリア原虫(Plasmodium falciparum)が挙げられる。米国国立アレルギー感染症研究所(NIAID)優先病原体(priority pathogen)も含まれる。これらとしては、カテゴリーA病原体、例えば、大痘瘡(痘瘡)、炭疽菌(Bacillus anthracis)(炭疽)、ペスト菌(Yersinia pestis)(ペスト)、クロストリジウム・ボツリヌム毒素(ボツリヌス中毒)、野兎病菌(Francisella tularensis)(野兎病)、フィロウイルス(エボラ出血熱、マールブルグ出血熱)、アレナウイルス(ラッサ(ラッサ熱)、フニン(アルゼンチン出血熱)及び関連ウイルス);カテゴリーB病原体、例えば、コクシエラ・バーネッティ(Coxiella burnetti)(Q発熱)、ブルセラ(Brucella)属種(ブルセラ症)、鼻疽菌(鼻疽)、アルファウイルス(ベネズエラ馬脳脊髄炎ウイルス(Venezuelan encephalomyelitis)、東部及び西部馬脳脊髄炎)、トウゴマ(Ricinus communis)のリシン毒素(ヒマシマメ)、ウェルシュ菌(Clostridium perfringens)のイプシロン毒素;ブドウ球菌(Staphylococcus)エンテロトキシンB、サルモネラ種、志賀赤痢菌(Shigella dysenteriae)、大腸菌O157株:H7、コレラ菌(Vibrio cholerae)、クリプトスポリジウム・パルバム(Cryptosporidium parvum);カテゴリーC病原体、例えば、ニパウイルス、ハンタウイルス、ダニ媒介性出血熱ウイルス、ダニ媒介性脳炎ウイルス、黄熱及び多剤耐性結核菌;蠕虫、例えば、住血吸虫及びサナダムシ;及び原虫、例えば、リーシュマニア(Leishmania)(例えば、メキシコリーシュマニア(L. mexicana))、及びマラリア原虫(Plasmodium)が挙げられる。
特定の実施形態において、本開示はまた、本開示の少なくとも1つの組成物(例えば、粒子(複数可))が充填された1つ以上の容器を含む薬学的パッケージ又はキットを提供する。そのような容器(複数可)に任意に関連づけられた、医薬品若しくは生物学的製品の製造、使用若しくは販売を規制する政府機関によって指示される形態の表示であってもよく、その表示は、(a)ヒト投与のための製造、使用若しくは販売の機関による承認、(b)使用のための説明書又はその両方を示す。
がんを治療するための方法
ヒト患者は、可溶性TNFR又は可溶性IL-2Rを脱離するがん(例えば、肺がん、結腸がん、乳がん、脳腫瘍、肝がん、膵がん、皮膚がん若しくは血液がん)を有すると医療従事者によって特定されている。その患者に、可溶性TNFR又はIL-2Rと結合し、それを隔離する(本明細書に記載されている)粒子を含む組成物を、がんを治療するのに有効な量で投与する。任意に、患者に、可溶性TNFR又はIL-2Rの作用の阻害を維持するために「維持用量」の組成物を投与し、それにより患者のがんに対する免疫監視を強化し続ける。
ヒトを解毒するための方法
ヒト患者は、ボツリヌス毒素に関連する毒性の症状を示している。その患者に、可溶性ボツリヌス毒素と結合し、それを隔離する(本明細書に記載されている)粒子を含む組成物を、毒性に関連する1つ以上の症状を改善するのに有効な量で投与する。
ウイルス感染症を治療するための方法
ヒト患者は、HIV-1感染を有すると医療従事者によって特定されている。その患者に、可溶性HIV-1ビリオンと結合し、それを隔離する(本明細書に記載されている)粒子を含む組成物を患者の血液循環中のウイルスの力価を低下させるのに有効な量で投与する。患者に、HIV-1ビリオン力価の低下を維持するために「維持用量」の組成物を投与し、それにより患者の感染を抑制するとともに、他者へのウイルスの伝染の可能性を低減する。
シリコン粒子を製造するための方法
多様な孔サイズを有する1000nm×400nm及び1000nm×800nmのサイズの多孔質シリコンディスクを製造する。ディスクのサイズ及び形態並びに孔径は、走査電子顕微鏡法によって特性解析される。金(Au)ナノ粒子を多孔質シリコンディスクの孔に蒸着する。腫瘍壊死因子(TNF)は、配位結合(dative covalent bond)により金ナノ粒子の表面に結合している。リガンド密度及びTNF-Au結合の安定性を評価する。
ポリマー粒子を製造するための方法
ポリ(ラクチド-co-グリコリド)(PLGA)粒子をエマルジョンにより作製する。PLGA粒子のサイズ及び形態を走査電子顕微鏡法、原子間力顕微鏡法及び透過型電子顕微鏡法によって特性解析される。その粒子を、マクロファージ動員(すなわち、ファゴサイトーシス)のために四級アンモニウムベータサイクロデキストリンでコーティングする。コーティングを原子間力顕微鏡法及び透過型電子顕微鏡法によって確認する。コーティング密度及び均一性を、透過型電子顕微鏡法及び動的光散乱によって特性解析する。
ポリマーベースの粒子の薬物動態
実施例5のスポンジ(すなわち、実施例5の「スポンジ」、例えば、103〜1012のスポンジを含む組成物)を原発性及び転移性がんのマウスモデル並びに健康な対照の静脈内又は腫瘍内のいずれかに投与する。各投与経路に対するLD50を特定することによってスポンジの毒性を判定する。スポンジの半減期は、各投与経路に関するスポンジの血漿中濃度をLC/MS及びICPによりモニタリングすることによって決定する。マウスの生検材料を採取し、LC/MS、ICP及び共焦点顕微鏡法によりスポンジ及びその構成成分に関して組織を分析することによってスポンジの体内分布を確認する。
ポリマーベースの粒子の有効性
実施例5のスポンジ(すなわち、実施例5の「スポンジ」、例えば、103〜1012のスポンジを含む組成物)を、MDA-MB-231又は4T1異種移植片(xenograph)を含むマウスに投与する。腫瘍サイズの縮小及び増大を評価するためにMDA-MB-231モデルを使用し、転移の抑制を評価するために4T1モデルを使用する。スポンジを週に1回6週間にわたりMDA-MB-231マウスの腫瘍内に投与し、体重及び腫瘍サイズを定期的にモニタリングする。スポンジを週に1回6週間にわたり4T1マウスの静脈内に投与し、転移の数をモニタリングする。
シリコン/金ベースの粒子の薬物動態及び有効性
実施例6及び7の実験を、実施例5の多孔質シリコン粒子を用いて繰り返す。
Claims (42)
- 少なくとも1つの表面及び前記表面に固定された薬剤を有する粒子であって、
前記薬剤は、可溶性生体分子である標的と選択的に結合し、ここで前記可溶性生体分子は、がん細胞により脱離される細胞表面タンパク質であり、
前記標的の前記粒子との結合は、前記標的とその天然のリガンドとの相互作用を阻害し、
前記薬剤は、細胞の表面にある細胞表面タンパク質と結合する前記薬剤の能力が低減するように前記粒子上で配向されており、
前記粒子はコーティングを含み、そのコーティングは前記薬剤と細胞の表面にある細胞表面タンパク質との相互作用を阻害する、粒子。 - 前記薬剤は、細胞の表面にある前記細胞表面タンパク質との前記薬剤の結合が立体的に阻害されるように前記粒子上で配向されている、請求項1に記載の粒子。
- 前記薬剤は、細胞表面受容体タンパク質のリガンドである、請求項1又は2に記載の粒子。
- 細胞表面受容体タンパク質のリガンドは、インターロイキンタンパク質又はケモカインである、請求項3に記載の粒子。
- 細胞表面受容体タンパク質のリガンドは、Fasリガンド、リンホトキシン、リンホトキシンアルファ、リンホトキシンベータ、4-1BBリガンド、CD30リガンド、EDA-A1、LIGHT、TLA1、TWEAK、TNF、TRAIL、又は前述のいずれかの変異体である、請求項3に記載の粒子。
- 前記細胞表面受容体タンパク質は、活性化されると、アポトーシスを誘導し、かつ、前記細胞表面受容体タンパク質は:
(i) 腫瘍壊死因子受容体(TNFR)タンパク質、
(ii) Fas受容体タンパク質、又は
(iii) TNF関連アポトーシス誘導リガンド受容体(TRAILR)タンパク質、4-1BB受容体タンパク質、CD30タンパク質、EDA受容体タンパク質、HVEMタンパク質、リンホトキシンベータ受容体タンパク質、DR3タンパク質、若しくはTWEAK受容体タンパク質
である、請求項3〜5のいずれか一項に記載の粒子。 - 前記細胞表面受容体タンパク質は、インターロイキン受容体タンパク質である、請求項3〜5のいずれか一項に記載の粒子。
- インターロイキン受容体タンパク質は、IL-2受容体タンパク質である、請求項7に記載の粒子。
- 細胞の表面にある前記細胞表面受容体タンパク質と前記薬剤との結合又は細胞の表面にある前記細胞表面受容体タンパク質の前記薬剤による活性化が立体的に阻害されるように、前記薬剤は前記粒子上で配向されている、請求項3〜8のいずれか一項に記載の粒子。
- 前記薬剤は、細胞表面受容体タンパク質を活性化しない、請求項9に記載の粒子。
- 少なくとも1つの表面とその表面に固定された薬剤とを有する粒子であって、
前記薬剤は可溶性生体分子に選択的に結合し、
前記可溶性生体分子は、細胞表面受容体タンパク質の形態であり、そして
前記薬剤は、細胞の表面にある前記細胞表面受容体タンパク質と前記薬剤との結合又は細胞の表面にある前記細胞表面受容体タンパク質の前記薬剤による活性化が立体的に阻害されるように、前記粒子上で配向されており、
前記粒子はコーティングを含み、そのコーティングは前記薬剤と細胞の表面にある細胞表面タンパク質との相互作用を阻害する、粒子。 - 前記細胞表面受容体タンパク質は、がん細胞によって発現される、請求項3〜11のいずれか一項に記載の粒子。
- 前記細胞表面受容体タンパク質は、活性化されると、アポトーシスを誘導する、請求項3〜12のいずれか一項に記載の粒子。
- 前記細胞表面受容体タンパク質は、インターロイキン受容体タンパク質である、請求項11〜13のいずれか一項に記載の粒子。
- 前記薬剤は、小分子、大員環化合物、ポリペプチド、タンパク質、ペプチド、ペプチド模倣化合物、核酸又は核酸類似体である、請求項1〜14のいずれか一項に記載の粒子。
- 前記薬剤は、前記の標的生体分子の天然のリガンドの変異体である、請求項11〜15のいずれか一項に記載の粒子。
- 前記薬剤は、
(i) 抗体若しくは抗体の生体分子結合フラグメントであるか、
(ii) 非抗体足場タンパク質であるか、
(iii) インターロイキンタンパク質若しくはその変異体であるか、又は
(iv) 腫瘍壊死因子(TNF)ファミリーリガンド若しくはその変異体を含む、
請求項11〜15のいずれか一項に記載の粒子。 - 前記薬剤は抗体又は抗体の生体分子結合フラグメントであり、そしてさらに生体分子結合フラグメントはFabフラグメント、F(ab)2フラグメント、scFvフラグメント及びドメイン抗体から選択される、請求項17に記載の粒子。
- 前記TNFファミリーリガンドは、TNFα若しくはその変異体であるか、又はFasリガンド、リンホトキシン、リンホトキシンアルファ、リンホトキシンベータ、4-1BBリガンド、CD30リガンド、EDA-A1、LIGHT、TLA1、TWEAK、TNF、TRAIL、及び前述のいずれかの変異体から選択される、請求項17に記載の粒子。
- 前記細胞表面受容体タンパク質を活性化する前記薬剤の能力が、前記細胞表面受容体タンパク質の天然のリガンドの前記能力と比較して低減されている、請求項3〜19のいずれか一項に記載の粒子。
- 前記粒子は、対象の脈管構造中を循環する形状及び大きさにされる、請求項1〜20のいずれか一項に記載の粒子。
- 前記粒子の最大寸法は、約1μmを超えない、請求項1〜21のいずれか一項に記載の粒子。
- 前記粒子の最小寸法は、少なくとも約300nmである、請求項1〜22のいずれか一項に記載の粒子。
- 複数の薬剤を含み、その複数の薬剤は、約10〜約109個の薬剤からなる、請求項1〜23のいずれか一項に記載の粒子。
- 複数のコーティング成分又はコーティング分子を含む、請求項1〜24のいずれか一項に記載の粒子。
- 前記複数のコーティング成分又はコーティング分子は、前記薬剤と細胞の表面にある前記細胞表面タンパク質との間の相互作用を阻害する、請求項25に記載の粒子。
- 第2の表面をさらに含み、前記複数のコーティング成分又はコーティング分子のうち少なくとも1つの成分又は分子は前記第2の表面と結合している、請求項25又は26に記載の粒子。
- 前記複数のコーティング成分又はコーティング分子のうち少なくとも1つの成分又は分子は、前記粒子の前記表面と結合している、請求項25又は26に記載の粒子。
- 前記複数のコーティング成分又はコーティング分子が、ポリエチレングリコール(PEG)、ポリラクテート、ポリ乳酸、糖、脂質、ポリグルタミン酸、ポリグリコール酸(PGA)、ポリ乳酸(PLA)、ポリ(乳酸-co-グリコール酸)(PLGA)、又はポリ酢酸ビニル(PVA)を含み、好ましくは前記複数のコーティング成分又はコーティング分子がPEGを含む、請求項25〜28のいずれか一項に記載の粒子。
- 前記表面は前記粒子の内部表面であり、前記第2の表面は前記粒子の外部表面である、請求項27に記載の粒子。
- 第2の複数のコーティング成分又はコーティング分子をさらに含み、
前記第2の複数のコーティング成分又はコーティング分子のうち少なくとも1つの成分又は分子は、前記第2の表面と結合しており、
前記第2の複数のコーティング成分又はコーティング分子は、インビボにおける前記粒子のクリアランスを低下させる、請求項30に記載の粒子。 - 前記第2の複数のコーティング成分又はコーティング分子は、前記複数のコーティング成分又はコーティング分子と細胞及び/又は細胞外タンパク質との間の相互作用を阻害し、それによりインビボにおける前記粒子のクリアランスを低下させる、請求項31に記載の粒子。
- 前記複数のコーティング成分又はコーティング分子は、インビボにおける前記粒子のクリアランスを増加させる、請求項25〜32のいずれか一項に記載の粒子。
- 前記複数のコーティング成分又はコーティング分子は、インビボにおける前記粒子のクリアランスを低下させる、請求項25〜32のいずれか一項に記載の粒子。
- 前記細胞はヒト細胞である、請求項1〜34のいずれか一項に記載の粒子。
- 請求項1〜35のいずれか一項に記載の複数の粒子を含む組成物。
- 薬学的に許容される担体及び請求項36に記載の組成物を含む医薬組成物。
- 対象中の可溶性生体分子の生物学的活性を阻害するための、請求項37に記載の医薬組成物。
- 可溶型の少なくとも1つのサイトカイン受容体を脱離するがん細胞を含むがんに罹患している対象を治療するための、請求項37に記載の医薬組成物。
- 前記がん細胞は、以下:
(i) 可溶型のTNF受容体、又は
(ii) 可溶型のIL-2受容体
を脱離する、請求項39に記載の医薬組成物。 - 前記対象は、哺乳動物であり、好ましくはヒトである、請求項37〜40のいずれか一項に記載の医薬組成物。
- 前記対象は、がん又は自己免疫疾患を有する、請求項38又は41記載の医薬組成物。
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