JP2017533256A - 療法用ナノ粒子および関連する組成物、方法、およびシステム - Google Patents
療法用ナノ粒子および関連する組成物、方法、およびシステム Download PDFInfo
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Abstract
Description
[0001] 本発明は、国立衛生研究所により裁定された契約番号HHSN261201300030Cの下での政府支援によりなされた。従って、政府は、本発明において一定の権利を有する。
[0002] 本出願は、配列リストを含み、それは、ASCIIフォーマットで電子的に提出されており、本明細書に参照によりそのまま援用される。2015年9月1日に作成された前記のASCIIコピーは、0269.13PCT_SL.txtと名付けられており、大きさは9,822バイトである。
[0028] 一側面において、本発明は、生理活性薬剤の特定の組織および細胞への標的化された送達のための安定なナノ粒子を提供する。本発明のナノ粒子は、リガンドコーティングまたはシェルおよび50ナノメートル未満の平均直径を有し、生理活性薬剤カーゴの体の生物学的障壁を通した送達および/または対象の細胞もしくは組織中への送達を可能にする。
[0040] さらに別の態様において、リガンドは、ヒアルロナンである。
[0044] 本発明のCs処理されたナノ粒子は、生理活性薬剤を担持して標的とされる組織および細胞に送達するために用いられることができる。句“生理活性薬剤(単数または複数)”は、本明細書で用いられる際、細胞、組織、または器官に投与または送達された際に、その細胞、組織、または器官の1以上の生理学的、生化学的、または病理学的プロセスを真似る、変化させる、または調節する1種類以上の薬剤を指す。好ましくは、その変化または調節は、医学的に望ましい変化または調節である。より具体的には、生理活性薬剤は、オリゴヌクレオチド、ポリヌクレオチド、プラスミドDNA、DNA、RNA、siRNA、mRNA、miRNA、shRNA、アプタマー、アンチセンス分子、またはリボザイムを含むがそれらに限定されないあらゆる核酸ベースの分子、ならびにタンパク質、ポリペプチド、ペプチド、炭水化物、抗体または小分子のような生理活性薬剤を含むがそれらに限定されないイメージングまたはモニタリングまたは療法的もしくは予防的使用を含む目的のためのいくつかの異なる化合物または分子のあらゆる1以上であることができる。
[0075] 一側面において、本発明は、固形腫瘍におけるカゼインキナーゼ2の発現を阻害する方法を提供する。本発明の方法は、ポリヌクレオチドを腫瘍に送達する標的化されたナノ粒子を投与することを含み、ここで、ポリヌクレオチドは、カゼインキナーゼ2核酸配列にハイブリダイズしてその発現を低減または阻害する。
[0089] 本発明の療法組成物の配合およびそれらのその後の投与は、本明細書において記載されており、当業者により実施されることができる。一般に、療法に関して、療法を必要とする患者は、本発明に従う組成物を、本明細書の他の箇所において記載されているような投与量および新規の投与戦略において提供される。本発明のある態様において、投与は、患者の体重または体表面積、年齢、および処置されている疾患または障害の重症度の1以上に基づいて決定される。
[00100] 標的化されたサブ−50ナノ粒子を作製するために用いられることができる方法の以下の記載は、代表的なものであることのみが意図されており、限定することは意図されていない。本明細書に参照により援用される米国特許第6,632,671号、米国特許第7,741,304号、および米国特許公開第2013/0267577号は、未改変のナノ粒子の調製を開示している。簡潔には、例えば腫瘍細胞に対して標的化および送達されるべき負に荷電した生理活性薬剤、例えば核酸は、凝縮させてその大きさを約50nm以下に低減するためにポリカチオン性ポリマーと複合体形成させることができる。いくつかの異なるポリカチオン性ポリマー(“凝縮”剤または“凝縮性”タンパク質としても知られている)が、用いられることができ、当該技術で周知である(Rolland 1998, Crit. Rev. Therapeutic Drug Carr. Syst., 15:143-198)。例えば、十分なポリカチオン性凝縮性タンパク質が、負に荷電したカーゴ部分と複合体形成して、負に荷電したカーゴ部分の少なくとも約75%(例えば、約80%、85%、90%、95%、99%または100%)を中和することができ、それは、核酸に関して、エチジウム色素排除により測定されることができる(例えば、(1998, J. Controlled Release, 53:289-99)を参照)。単に例として、125μgの10kDポリオルニチンが、500μgの20塩基長オリゴヌクレオチドを凝縮させるために用いられることができ、または87.5μgのスペルミンが、250μgの14kD siRNAオリゴを凝縮させるために用いられることができる。負電荷を欠く、または正電荷を有するカーゴ部分に関しては、凝縮性ポリカチオン性ポリマーは、必要ではない可能性がある。
[00118] 別の態様において、Cs多形ナノ粒子のリガンドシェルは、テンフィブゲンを含む。さらに別の態様において、Cs多形ナノ粒子のリガンドシェルは、ヒアルロナンを含む。
[00127] 多様なカーゴおよび標的化部分を含む典型的なナノ粒子は、以下のように生成された。
[00138] 配合物F:TBGでコートされたサブ−50nm対照ナノ粒子を、6.3mcgのTBGを500mcgの2R−改変キメラオリゴ(抗凝固因子VII、Akinc, et al. 2008 Nat Biotechnol 26:5(561-9)において報告されている通りのもの)に添加し、125mcgの10kDポリオルニチン(Sigma)を用いて凝縮させ、5ugのTM−ジオールを用いてミセル化したことを除いて、配合物Aにおいて記載されたように生成した。これらのナノ粒子を精製する際に、TBGコートされたミセルを、以下の濃度:1.17nM Sr2+、4.68nM Mg2+に関して改変された配合物Aの塩を受け入れる溶液中に噴霧した。平均粒径は、炭素格子上にスポットされた1ng/mlの試料の楕円径を用いるネガティブ染色TEMにより測定した際に、50nm未満(24.7±3nm)であり、Zetasizer 4動的光散乱デバイスにより測定の間20ボルトの電位において2分間のパルスを用いて1mM KCl中で2μg/mlで測定した際に、−7.6±2.4mevの表面電荷を有していた。
[00144] 有効である他にも、ナノ粒子剤形は、規制および他の実体からの医薬製造の要求および製品の要求に従わなければならず、例えば、ナノ粒子の物理的安定性は、その規制上の認可、衝撃配合(impacting formulation)、製造、および貯蔵プロトコルの重要な構成要素である。セシウムのナノ粒子合成への微量の添加は、滅菌水中で実施された場合、驚くべきことに、高められた輸送性能およびバートン由来安定性尺度により示されるように、結果として向上した物理的安定性をもたらすことがわかっている。
[00155] 実施例3−改変されたキメラポリヌクレオチド混合物は、マウス腫瘍モデルにおいて驚くべき有効性を示す。
[00158]
特に、実験群のオリゴヌクレオチド構成要素間の限られた違いにもかかわらず、TBGでナノ封入された(encapsulated)2R huMixオリゴは、処置の開始の30日後に対照に対して腫瘍重量、細胞増殖(Ki−67)および炎症指数(NF−κB)の3つのカテゴリー全てにおいて有意な低減をもたらした唯一のアプローチであった(表2、E3実験、配合物E)。封入された単一ヌクレオチド2R改変(E1実験、配合物B)も、封入されたhuMixアプローチ(E2実験、配合物C)も、処置の30日後に腫瘍重量における有意な低下を示さなかった。実際、huMix処置群(配合物C)は、腫瘍重量において対照と比較して34%の有意な増大を示した。逆に、ナノ封入された2RhuMix(配合物E)で処置されたマウスからの腫瘍は、プールされたBN対照腫瘍に対して腫瘍重量における有意な56%の低減を示し、それは、細胞増殖および炎症指数における大きく劇的な低減と一致していた(−73% Ki−67指数、−99.7% p65 NF−kB信号割合、p<0.05)。他の処置群は、細胞増殖指数およびp65 NF−kB信号の両方において対照に対して有意な低減を示さず、それらの2つの尺度および腫瘍重量における有意な低減を示した処置群はなおさらなかった。E2実験におけるmuMix処置は、NF−kB信号面積割合における対照に対する有意な59.7%の低減を示したが、これは、腫瘍重量における対照に対する26.2%の増大を伴っており、明らかに望ましくない結果であった。さらに特筆すると、E3実験において、2R huMixコホートにおいて対照に対してp65 NF−kB信号における有意な低減(99.7%)があり、一方で、マウス配列に対するミスマッチが2R huMixのミスマッチと等しかったE2実験においては、huMixコホートにおけるp65 NF−kB信号における変化はほとんどなかった(表2、上記)。
[00166] ナノ粒子のCs改変と一緒でのオリゴヌクレオチド主鎖および配列における限られた改変の作用を、別のモデルにおいて研究するため、ヒト腫瘍株(UM−SCC−47、HPV−(+)舌組織由来)およびNIH非近交系無胸腺ヌードマウスを含む異種移植腫瘍モデルを試験した。この実験において、ヌードマウスに2e6個の細胞を皮下接種し、腫瘍が60〜80cu.mmまで成長する間、2週間維持した後、100μg/kgでの毎日のSQ処置を開始した。腫瘍を14日間の処置後に回収し、上記のFaDu実験と同様に試験した。結果が、下記で表4において要約されている。
[00170] CK2アルファ(ホモ・サピエンス20番染色体、GRCh38 Primary Assembly; NCBI参照配列: NC_000020.11; 塩基473322〜543838の70.52kbの領域; Intl Hu Genome Seq Consort; 2004 Nature 431(7011):931-945)
[00171] CK2アルファプライム(ホモ・サピエンス16番染色体、GRCh38 Primary Assembly; NCBI参照配列: NC_000016.10; 塩基58157907〜58197878の39.97kbの領域; Martin, et al. 2004 Nature 432(7011):988-994)
[00172] NM_001896; CK2アルファプライムのmRNA配列に関するcDNA配列; ホモ・サピエンスカゼインキナーゼ2、アルファプライムポリペプチド(CSNK2A2)、mRNA (17-March-2008) (SEQ ID NO:11)
[00173] NM_177560; CK2アルファのmRNA配列に関するcDNA配列; ホモ・サピエンスカゼインキナーゼ2、アルファ1ポリペプチド(CSNK2A1)、転写産物バリアント3、mRNA (12-March-2008) (SEQ ID NO:12)
Claims (8)
- ナノ粒子を含む組成物であって、該ナノ粒子が、以下:
少なくとも1種類の生理活性薬剤、6.0単位未満のHLB値を有する界面活性剤、リガンド、ならびにLi+およびCs+を含み、ここで:
i)該少なくとも1種類の生理活性薬剤および界面活性剤が、界面活性剤ミセルコアを形成し;
ii)該リガンドが、シェルを形成し;
iii)該Li+が、Cs+で前処理されており;そして
iv)該ナノ粒子が、約50ナノメートル未満の平均直径を有する組成物。 - 請求項1に記載の組成物であって、該ナノ粒子が、滅菌水を用いて調製される組成物。
- 請求項1に記載の組成物であって、該少なくとも1種類の生理活性薬剤が、ポリヌクレオチドまたはプラスミドDNAである組成物。
- 請求項1に記載の組成物であって、ここで:
i)該少なくとも1種類の生理活性薬剤が、複数のポリヌクレオチドを含み、それぞれが、3’RNA部分および5’の主にDNAの部分を含み、それぞれのポリヌクレオチドの5’末端から第2位が、2’−OMe修飾RNAであり、該複数のポリヌクレオチドの平均で約40%より多く約60%未満の配列が、SEQ ID NO:8を含み、かつ該複数のポリヌクレオチドの平均で残りの割合の配列が、SEQ ID NO:9を含み、そして
ii)該リガンドが、テネイシン受容体を標的化するタンパク質である組成物。 - 請求項4に記載の組成物であって、該タンパク質が、テンフィブゲンである組成物。
- 少なくとも1種類の生理活性薬剤を対象に投与する方法であって、該方法が、該対象に請求項1に記載の組成物を投与することを含む方法。
- 固形腫瘍癌を有する患者を処置するための方法であって、該患者に療法上有効量の請求項1に記載の組成物を投与することを含み、ここで
i)該少なくとも1種類の生理活性薬剤が、複数のポリヌクレオチドを含み、それぞれが、3’RNA部分および5’の主にDNAの部分を含み、それぞれのポリヌクレオチドの5’末端から第2位が、2’−OMe修飾RNAであり、該複数のポリヌクレオチドの平均で約40%より多く約60%未満の配列が、SEQ ID NO:8を含み、かつ該複数のポリヌクレオチドの平均で残りの割合の配列が、SEQ ID NO:9を含み、そして
ii)該リガンドが、テネイシン受容体を標的化するタンパク質である方法。 - 請求項1に記載の組成物を調製するための方法であって、該方法が、以下の工程:
i)少なくとも1種類の生理活性薬剤を凝縮剤と複合体化させて凝縮した生理活性薬剤を形成し;
ii)該凝縮した生理活性薬剤を、6.0未満のHLBを有する界面活性剤を含む水混和性溶媒中に分散させて界面活性剤ミセルを形成し;
iii)リガンドを該界面活性剤ミセルの外部表面に吸着させて、リガンド粒子を形成し;そして
iv)該リガンド粒子をCs+で前処理されたLi+および滅菌水と混合してインキュベートして該組成物を形成する;
を含む方法。
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US201462045519P | 2014-09-03 | 2014-09-03 | |
US62/045,519 | 2014-09-03 | ||
PCT/US2015/048371 WO2016036960A1 (en) | 2014-09-03 | 2015-09-03 | Therapeutic nanoparticles and related compositions, methods and systems |
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JP6679593B2 (ja) | 2020-04-15 |
WO2016036960A1 (en) | 2016-03-10 |
AU2015311857A1 (en) | 2017-03-23 |
CA2959660A1 (en) | 2016-03-10 |
EP3188716A1 (en) | 2017-07-12 |
CN107072963A (zh) | 2017-08-18 |
US20210267897A1 (en) | 2021-09-02 |
WO2016036960A8 (en) | 2016-09-29 |
US10987308B2 (en) | 2021-04-27 |
SG10201902499VA (en) | 2019-04-29 |
IL250844A0 (en) | 2017-04-30 |
CN107072963B (zh) | 2020-07-07 |
KR20170054429A (ko) | 2017-05-17 |
JP2020114835A (ja) | 2020-07-30 |
US20160058706A1 (en) | 2016-03-03 |
EP3188716B1 (en) | 2022-10-26 |
AU2015311857A2 (en) | 2017-05-18 |
SG11201701571UA (en) | 2017-03-30 |
CN111700877A (zh) | 2020-09-25 |
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