JP2021518342A - インスリンの経口送達のためのウイルス様ナノカプシド - Google Patents
インスリンの経口送達のためのウイルス様ナノカプシド Download PDFInfo
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- JP2021518342A JP2021518342A JP2020548984A JP2020548984A JP2021518342A JP 2021518342 A JP2021518342 A JP 2021518342A JP 2020548984 A JP2020548984 A JP 2020548984A JP 2020548984 A JP2020548984 A JP 2020548984A JP 2021518342 A JP2021518342 A JP 2021518342A
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Abstract
Description
本発明は、2018年3月13日に出願された米国特許出願第62/642,356号に対する優先権を主張し、その内容の全体があらゆる目的で参照により本明細書に取り込まれる。
本発明は、国立衛生研究所及び米国農務省認可の国立食品農業研究所により与えられた契約番号AI095382、EB021230、及びCA198880に基づく政府支援により行われた。政府は発明において一定の権利を有する。
本明細書及び添付の特許請求の範囲で用いられる単数形「1つの(a)」、「1つの(an)」、及び「その(the)」は、文脈上明白な指示がない限り、複数への言及を含む。
本開示は、インスリンの経口送達のための、化学的に安定かつ胃腸管内の酵素活性に対して耐性を示すウイルス由来ナノカプシドに関する。患者の服薬遵守が低いことを含む糖尿病の治療における一定の制限は、インスリン投与のための針による注射の一般的な使用に関連する不快感及び弊害によるものであることはよく知られている。経口送達はインスリンの最も好ましい送達経路であるが、分子量が5.8kDaのタンパク質では、タンパク質分解酵素及び厳しい酸性の生理的条件による胃腸管における分解、並びに吸収後の送達効率及び腸上皮を通じての透過性を含む課題に直面する。インスリンの経口送達システムがいくつか開発され、臨床試験が認可されてきたが、低い生体利用効率の改善、再現可能な吸収の達成、及び食事依存的な吸収率の理解の獲得、及び経口投与インスリン送達システムの大量生産の必要性を含む、費用に関連する多数の要因に取り組む必要がある。
本発明のある態様は、カプシドタンパク質及びそれに由来するVLPの生産及び精製方法に関する(Expression and self−assembly of empty virus−like particles of hepatitis E virus.Li TC,Yamakawa Y,Suzuki K,Tatsumi M,Razak MA,Uchida T,Takeda N,Miyamura T.,J Virol.1997 Oct;71(10):7207−13.Essential elements of the capsid protein for self−assembly into empty virus−like particles of hepatitis E virus.Li TC,Takeda N,Miyamura T,Matsuura Y,Wang JC,Engvall H,Hammar L,Xing L,Cheng RH.J Virol.2005 Oct;79(20):12999−3006.Niikura M et al,Chimeric recombinant hepatitis E virus−like particles as an oral vaccine vehicle presenting foreign epitopes.Virology 2002;293:273−280参照)。ある実施形態において、カプシドタンパク質は改変されたカプシドタンパク質であり、それに由来するVLPはシステイン/リシン改変されたHEV VLPである。例えば、改変されたカプシドタンパク質は、HEV ORF2又はその一部の表面可変ループ中に、1又は複数のシステイン残基/リシン残基を含む。
本発明の他の態様は、1又は複数の生物活性剤のHEVウイルス様粒子(例えば、システイン/リシン改変されたHEV VLP)への封入に関する(DNA vaccine−encapsulated virus−like particles derived from an orally transmissible virus stimulate mucosal and systemic immune responses by oral administration,Gene Therapy 2004.11,628−635.S Takamura,M Niikura,T−C Li,N Takeda,S Kusagawa,Y Takebe,T Miyamura and Y Yasutomi参照)。当技術分野の標準的な技術を用いて、異種の核酸、タンパク質、ポリペプチド、化学療法剤、造影剤、及びナノ粒子などを本発明のVLPに封入することができる。例示的な生物活性剤は、タンパク質の形態又は核酸の形態のインスリンである。一般的な手順には、(1)本発明のカプシドタンパク質により形成されたVLPを分解すること、及び(2)生物活性剤の存在下でVLPを再構成することが含まれる。当業者には、封入手順の前にVLPを精製することが好ましいと理解されよう。封入手順の前に、任意の望ましくない物質(例えば、核酸)をVLPから除去、又は実質的に除去することが特に好ましい。
本発明はまた、タンパク質又は核酸の形態のインスリンなどの生物活性剤を封入する改変されたカプシドタンパク質により形成されるHEV VLPを含む医薬組成物又は生理的組成物を提供する。そのような医薬組成物又は生理的組成物はまた、1又は複数の医薬的に又は生理学的に許容可能な非薬効成分又は担体を含む。本発明の医薬組成物は様々な薬物送達システムでの使用に適している。本発明における使用に適した処方は、Remington’s Pharmaceutical Sciences,Mack Publishing Company,Philadelphia,PA,17th ed.(1985)に見られる。薬物送達の方法の簡潔な説明としては、Langer,Science 249:1527−1533(1990)を参照のこと。
I.背景
過去80年間、皮下(SC)注射は、糖尿病の治療としてのインスリン投与について、最適以下のインスリン分泌を補充するために用いられる主要な経路であった。この方法は効果的であるが、SC注射は痛みを伴い、不便であり、患者の服薬遵守を低下させる高い感染の恐れを有している。非感染性のE型肝炎ウイルスカプシドからなる、インスリンが封入されたE型肝炎ウイルスナノ粒子(HEVNP)は、摂取後にインスリンを胃腸(GI)管から肝臓へ送達することが期待される。HEVNPは、患者の服薬遵守が最も高く最も好ましい薬物送達の経路である、インスリン経口投与のための効果的及び効率的な手段の長期の調査の答えとなり得る。
生理学的な視点から、経口で投与されるインスリンは、内因性のインスリン分泌経路を模倣する能力により、肝臓のグルコース産生の管理において治療的な利点を有する[4]。HEVの自然感染の経路に従って、HEVNPに封入されたインスリンは胃腸管を通り、門脈を通って肝臓に移行することができる(図1)。対照的に、非経口のインスリン又は吸入されたインスリンは、肝抽出を回避することによって末梢循環へ直接吸収され、それにより門脈末梢インスリン勾配及び生理的な肝臓のインスリン処置を元の状態に戻すことができない。さらに、これらの経路により末梢の標的は肝臓と比較してより高いインスリン濃度にさらされ、患者が低血糖症となる危険性が高くなり、高インスリン血症の悪影響を受けやすくなる[4]。
ウイルス感染性が欠乏しているHEVに由来するナノカプセルであるHEVNPは、胃腸での安定性、標的細胞への結合、及び細胞への侵入を含むHEVの本質的な特徴を保持している。インビトロでの分解/再構築能力と合わせて、HEVNPは飲用での魅力的な経口送達ナノカプセルとして提案されてきた。HEVNPによる封入は、負に帯電した核酸及びナノサイズのタンパク質/小分子を治療的適用のためにパッケージングすることができるような、積載物とカプシドタンパク質との静電相互作用である。胃腸管を経由した肝臓への経口送達のためのインスリンの封入に加え、インスリン遺伝子も封入され得る。必要ならば、膵臓β細胞及び/又は肝臓を標的化する能力は、特定の細胞を標的化するリガンドを一晩の化学的結合又は時間がかかるが費用対効果の高い遺伝子操作によって、HEVNPの突起したドメインへ挿入することにより、付加することができる。よって、HEVNPは、インスリン遺伝子を膵臓へ送達し、その場でインスリンを一過性発現することができる、細胞を標的化する遺伝子送達担体となる能力が備わっている。インスリンを封入したHEVNPは、好ましい薬物投与の経路である経口投与により、胃腸管から肝臓へインスリンを送達することが期待される。
1. インスリンのHEVNP封入
1.1. HEVNPの分解
1.1.1. 20mMのDTT、10mMのEDTA中で、4℃で一晩、HEVNPを分解する。
1.1.2. 50mMのTris(pH7.5)、150mMのNaClにて、室温で1時間以上、分解されたHEVNPを透析する。
1.1.3. TEMによる検査、分光測定法によるタンパク質濃度測定。
1.2.1. 分解されたHEVNPを、50mMのTris(pH7.5)、150mMのCaCl2中でインスリンと混合し、最終濃度が2〜5mMとなるようにCaCl2を加える。4℃で一晩。
1.2.2. 遊離のインスリンを除去するため、サイズ排除カラムに通す。
1.2.3. 画分を収集し、分光光度計によりタンパク質濃度を測定する。
1.2.4. TEMによりインスリンが封入されたHEVNPを検査する。
2.1. 分光光度計を用いて、280nmの吸光度の測定値及び260nmの吸光度/280nmの吸光度の比を記録する。HEVNP ORF2のモル吸光係数は60280であり、これは280nmにおけるタンパク質の吸光度の値の1.019倍に相当する。これは1:1に近いので、HEVNPの濃度は、分光光度計による280nmの吸光度のタンパク質濃度測定により表すことができる。HEVNPの構成要素である、ORF2の分子量が53.318kDaであることを考慮すれば、以下のようである。
例:280nmでの分光光度計の測定から、1mg/mLのHEVNP濃度は18.8μMのORF2に相当する(各ORF2は化学的結合のための1つのシステイン部位及び1つのリシン部位を含む)。
2.2.1. 6μLのタンパク質試料に2μLの4×ローディングバッファーを加える。タンパク質を変性させるために、試料混合物をヒートブロックで100℃、10分間インキュベートする。タンパク質試料をNuPAGEゲルのセットアップにロードする。
2.2.2. 直流電源を100Vで10分間、その後、試料がゲルの底部から約1cm上に達するまで、150Vで45分間に設定してSDS−PAGEを泳動する。
2.2.3. SDS−PAGEゲルをクーマシーブルー(0.25%(w/v)クーマシーブリリアントブルーR250、30%(v/v)メタノール、10%(v/v)酢酸)で1時間染色する。
2.2.4. 染色操作後、クーマシーブルー染色を除去し、室温で12時間以上、脱染バッファー(30%(v/v)メタノール、10%(v/v)酢酸)をタンパク質ゲルにアプライする。
2.2.5. 52kDaのバンドにHEVNP ORF2の存在を確認するため、白色光下でゲルを記録する。
2.3.1. TEMでの画像化のために、10mMのMES(pH6.2)を用いてHEVNP試料を0.5〜2mg/mLに調製又は希釈する。
2.3.2. 40mAのグロー放電にて30秒間、炭素被覆グリッドをイオン化して親水性の炭素表面を生成する。グロー放電装置はEMSグロー放電器であってもよい。グリッドの親水性の炭素表面はグロー放電処理の後、30分間しか持続されない。
2.3.3. ピンセットで押さえ、グリッドに2μLのHEVNP試料を添加し、15〜30秒間待ち、ろ紙を用いて拭き取る。
2.3.4. 脱イオン蒸留水を用いて直ちにグリッドを洗浄し、ろ紙を用いて拭き取る。
2.3.5. 2μLの2%酢酸ウラニルを直ちにグリッドに添加し、15秒待ち、その後、ろ紙を用いて拭き取る。電子除湿乾燥キャビネット中に置くことにより、試料のグリッドを一晩乾燥する。
2.3.6. 透過型電子顕微鏡(TEM)にグリッドを移し、10Kから80Kの拡大率で撮像する。ウイルスRNAが存在しないため、HEVNPはTEM中で直径が約27nmの空の二十面体のタンパク質のように見える。
3.1. HEVNPとマレイミド結合型ビオチンの一段階結合
3.1.1. バッファー交換:HEVNPをミニ透析ユニットに入れ、製造業者の手順に従い、0.01MのPBS(pH7.4)にて室温で1時間透析する(Zeba Spin脱塩カラム、40K MWCO、0.5mL)。HEVNPを1.5mLチューブに移し、分光光度計を用いて280nmでのタンパク質濃度を測定する。
3.1.2. 18.8μMのシステイン反応部位(詳細は工程2.2.4を参照)に相当する1mg/mLのHEVNPを、等容量の0.01M PBS(pH7.4中)中のマレイミド−ビオチン(100μM)とモル比が1:5になるように混合し、4℃で一晩反応させる。製造業者の手順に従い、40K MWCO Spin脱塩カラム操作で、未結合のマレイミド−ビオチンを除去する(Zeba Spin脱塩カラム、40K MWCO、0.5mL)。
3.1.3. 標準的な還元SDS−PAGEを用いて試料を分析する(工程3.1)。
3.1.4. HRP結合型ストレプトアビジンによる化学発光法によるウェスタンブロットを用意する。X線フィルムにより化学発光シグナルを捕捉する(図2)。
3.2.1. バッファー交換:HEVNPをミニ透析ユニットにアプライし、0.01MのPBS(pH7.4)にて室温で1時間透析する。HEVNPを1.5mLチューブに移し、分光光度計を用いて280nmでのタンパク質濃度を測定する。
3.2.2. 650μMのマレイミドアジド及び650μMのアルキン化リガンドXを200μMのCuSO4及び1mMのアスコルビン酸を含む0.01MのPBS(pH7.4)に添加して、650μMのマレイミド結合型リガンドX(Mal−LigandX)を形成する。混合物を4℃で一晩インキュベートする。
3.2.3. 18.8μMのシステイン反応部位(詳細は工程2.2.4を参照)に相当する1mg/mLのHEVNPを、約10%容量の0.01M PBS(pH7.4)中のMal−LigandX(650μM)とモル比が1:3になるように混合し、4℃で一晩反応させる。比較的高濃度のマレイミド結合型LXY30に起因して、HEVNPへの損傷を避けるため、CuSO4などの反応物質の最終濃度は混合後に約10分の1低減される。他の選択肢としては、銅が含まれていない結合方法がある15。
3.2.4. 製造業者の手順に従い、40K MWCO Spin脱塩カラムを用いて、未結合のマレイミドクリックリガンドXを除去する(材料の表)。LXY30結合型HEVNP(LXY30−HEVNP)を4℃に保つ。
3.3.1. 18.8μMのシステイン反応部位(詳細は工程2.2.4を参照)に相当する1mg/mLのリガンドX結合型HEVNP(LigandX−VLP)を、等容量の0.01M PBS(pH7.4)中のCy5.5 NHSエステル(NHS−Cy5.5 100μM)とモル比が1:5になるように混合し、4℃で一晩反応させる。
3.3.2. 製造業者の手順に従い、40K MWCO Spin脱塩カラム操作で、未結合のCy5.5−NHSを除去する(Zeba Spin脱塩カラム、40K MWCO、0.5mL)。RGD、Cy5.5結合型HEVNP(RGD−HEVNP−Cy5.5)を4℃に保つ。
I.HEVNP封入デザイン
処方において、HEVNPは、錠剤、カプセル、スプリンクルパウダー(sprinkle powder)、又は飲料品に含ませる液体として処方することができる。HEVNPのサブコンポーネントはヒト及び動物にとって安全なワクチンであることが証明されてきた。他に提案されている経口インスリン投与の増進剤とは対照的に、HEVNPカプセルは、経口経路を通じたインスリンのようなタンパク質積載物に対する生体利用効率が増強された、粘膜集中的な送達システムとして使用可能である。四次構造に基づく積載物は、使用可能な保持時間を延ばすための巨大分子特性を利用するようにデザインされる。
2.サイズ排除カラム分離;HEVNP及びインスリンの共存は、(HEV及びインスリンに対する)ELISAによって示される(図6)。
緩衝液の最適化において、塩化セシウム勾配は、HEVNP中へのインスリン封入の効率を説明するためのELISA測定値の単一のピーク内にインスリン及びHEVNPの共存を明確に示す。「+」はELISAからの陽性の計測値及び画分6〜13におけるHEVとインスリンの共存を示している。
効果的な薬物送達システムのために、製品の高い安定性及び保存期間は重要な意味を持つ。HEVNP−インスリン試料を4℃で1年以上保存し、低温電子顕微鏡で観察した。顕微鏡写真は、保存条件に対して高い安定性を示す損傷のない粒子を示している。図8に示すように、低温電子顕微鏡法は、封入されたインスリンデテミルを有するHEVNP粒子を観察するために用いられた。
電子顕微鏡法によりインスリンの封入を示す結果が得られてきた。しかしながら、これらのナノ粒子の2次元の分布及び3次元の構造的な特徴は未だ十分に特性評価がなされていない。自社の手順と市販の画像処理パッケージを併用して、1)粒子分布を統計的に分析、及び2)インスリンが封入されたHEVNPの高解像度3D構造を判断するために、大規模データセットが収集及び分析されてきた。
マウスは2つの治療群のうちの1つに無作為に割り当てられ、インスリン耐性試験を以下のように行った。
A.マウスあたり(HEVNPで封入された)インスリン0.1Uを経口投与
B.マウスあたり(HEVNPで封入された)インスリン1Uを経口投与
シアニン5.5(Cy5.5)で標識されたHEVNPを用いたインビボでのマウスの光学的撮像は、Chenらの“Chemically activatable viral capsid functionalized for cancer targeting.” Nanomedicine 11,no.4(2016):377−390で以前に実証されており、ここでは、乳癌標的化分子(LXY30)が、改変されたシステインアーム及び露出したリシン残基に連結されたCy5.5に結合された。動物全体の撮像により、LXY30を有するHEVNPが腫瘍部位に集積することになることが実証された。ここでは、インスリンを封入したHEVNPの表面が、Cy5.5 NHSエステル(ルミプローブ)と300:1(Cy5.5:HEVNP)のモル比で、0.01MのPBS(pH7.2)を含む緩衝液中で室温にて2時間、続いて4℃で一晩のインキュベートにより改変される。次に、遊離のCy5.5 NHSエステルは、7000MWCOの脱塩カラム(Zeba Spin脱塩カラム、Thermo Scientific社)により除去される。Cy5.5は682nmで励起極大を、702nmで発光極大を、及び250,000cm−1M−1のモル吸光係数を有する。
細胞レベルでのHEVNP分布を研究するため、高圧凍結法及び凍結固定を用いて包埋した組織の肝臓の生検を行う。抽出組織はホルムアルデヒドで弱く固定された後、試料ホルダーに置かれる。次に凍結された組織は、樹脂ブロック内で固定され、ウルトラミクロトームを用いて薄片化され、透過電子顕微鏡法(TEM)を用いて検査される。HEVNPは金原子クラスター又は10nmのフェライト酸化物粒子のいずれかによってコントラストを加えることにより確認される。電子密度の高いHEVNP粒子は、TEMによりID付けされるのに十分なコントラストを与える。
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Claims (16)
- (a)E型肝炎ウイルス(HEV)オープンリーディングフレーム2(ORF2)タンパク質の少なくとも一部を含み、且つHEVウイルス様粒子(VLP)を形成可能である改変されたカプシドタンパク質、及び
(b)前記改変されたカプシドタンパク質により形成された前記HEV VLP内に封入されたインスリンタンパク質又はインスリンタンパク質をコードする核酸
を含む、組成物。 - 前記改変されたカプシドタンパク質は、HEV ORF2タンパク質の全長未満であり、配列番号1、2、3、4、5、又は6のHEV ORF2タンパク質の452〜606番目のセグメントを含み、且つHEV ORF2タンパク質の前記部分に配列番号1、2、3、4、5、又は6の483〜490番目、530〜535番目、554〜561番目、573〜577番目、582〜593番目、又は601〜603番目のセグメント内で挿入された異種ポリペプチド配列を含む、請求項1に記載の組成物。
- 前記異種ポリペプチド配列は、配列番号1、2、3、4、5、又は6の残基Y485の直後に挿入されている、請求項2に記載の組成物。
- 前記異種ポリペプチドは、RGDペプチド又は環状RGDペプチドである、請求項2又は請求項3に記載の組成物。
- 前記改変されたカプシドタンパク質は、酸及びタンパク質分解に対し安定なHEV VLPを形成可能であり、且つ化学的に誘導体化されていてもよいシステイン又はリシンで置換された配列番号1、2、3、4、5、又は6のY485、T489、S533、N573、又はT586のうちの少なくとも1つの残基を有する、請求項1に記載の組成物。
- 前記システイン又はリシンがアルキル化、アシル化、アリール化、サクシニル化、酸化、又は検出可能な標識若しくは肝細胞標的化リガンドと結合されている、請求項4に記載の組成物。
- 前記検出可能な標識が蛍光色素分子、超常磁性標識、MRI造影剤、陽電子放出同位体、又は原子番号が20より大きい第3〜18族の元素のクラスターを含む、請求項6に記載の組成物。
- 前記検出可能な標識が金ナノクラスターを含む、請求項7に記載の組成物。
- 前記肝細胞標的化リガンドがRGDペプチド又は環状RGDペプチドである、請求項6に記載の組成物。
- 医薬的に許容可能な非薬効成分(excipient)をさらに含む、請求項9に記載の組成物。
- 経口投与用に処方されている、請求項9に記載の組成物。
- 肝細胞を請求項1〜請求項11のいずれか一項に記載の組成物と接触させることを含む、インスリンの標的化送達方法。
- 前記肝細胞は患者の体内にあり、前記接触させる工程が請求項1に記載の組成物を前記患者へ投与することを含む、請求項12に記載の方法。
- 前記投与は経口投与である、請求項12に記載の方法。
- 前記改変されたカプシドタンパク質が金ナノクラスターに結合したシステイン又はリシンを含む、請求項13に記載の方法。
- 前記患者は糖尿病と診断された患者である、請求項13に記載の方法。
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WO2015179321A2 (en) * | 2014-05-19 | 2015-11-26 | The Regents Of The University Of California | Chemically activated nanocapsid functionalized for cancer targeting |
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CA2645177A1 (en) * | 2006-03-09 | 2007-09-13 | Transgene S.A. | Hepatitis c virus non structural fusion protein |
CA2660029A1 (en) * | 2006-08-04 | 2008-02-07 | Nastech Pharmaceutical Company Inc. | Compositions for intranasal delivery of human insulin and uses thereof |
US8906863B2 (en) * | 2009-02-27 | 2014-12-09 | The Regents Of The University Of California | Proteolysis-resistant capsid of chimeric hepatitis E virus as an oral delivery vector |
US10640785B2 (en) * | 2011-11-22 | 2020-05-05 | The Children's Hospital Of Philadelphia | Virus vectors for highly efficient transgene delivery |
WO2015101666A1 (en) * | 2014-01-03 | 2015-07-09 | Fundación Biofísica Bizkaia | VLPs, METHODS FOR THEIR OBTENTION AND APPLICATIONS THEREOF |
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JP2013517245A (ja) * | 2010-01-12 | 2013-05-16 | ノヴォ ノルディスク アー/エス | インスリンペプチドを経口投与するための医薬組成物 |
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