JP2015524849A - 神経変性疾患に対するエキソソームに基づく治療法 - Google Patents
神経変性疾患に対するエキソソームに基づく治療法 Download PDFInfo
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Abstract
Description
本出願は、2012年8月15日に提出された米国仮特許出願第61/683,596号に対する優先権の恩典を主張するものであり、参照によりその全体として本明細書によって組み入れられる。
本発明は、国立神経疾患・脳卒中研究所(National Institutes of Neurological Disorders and Stroke)によって授与された契約第NS-19108号、国立衛生研究所の国立小児保健発達研究所(National Institute of Child Health and Human Development)によって授与された第HD-09402号、および国立先進トランスレーショナル科学センター(National Center for Advancing Translational Sciences)によって授与された第1UH2TR000918号の下で政府支援によりなされた。政府は、本発明においてある程度の権利を有する。
本発明は、概して、医学および神経学の分野に関する。特に、態様は、多発性硬化症(MS)および脱髄に関連した他の神経学的疾患などの脱髄性疾患の治療に向けられている。
MSは、世界中で100万人を超える人々に影響を及ぼしている一般的な神経学的疾病である。その有病率は人種間および地理的緯度間で変動し、北および中央ヨーロッパにおける100,000人あたり100人超から南ヨーロッパにおける100,000人あたり50人に及ぶ。MSは、若年および中年成人における神経学的障害の最も一般的な原因である。疾病発症は、患者の約50%で30歳より前、患者の25%で30〜40歳の間、および患者の残り25%で40〜50歳の間である。女性 対 男性の比率は2:1である。
I.序論
いくつかの局面において、本発明は、概して、インビトロで再構成された小胞などの脂質ナノ小胞、または酸化ストレスを受けるように誘導されているもしくは酸化ストレスによって刺激されている細胞から得られたエキソソームを伴う方法および組成物に関する。該方法および組成物は、神経学的疾患、特に脱髄疾患のリスクがあるまたは脱髄疾患を有する対象を治療するのに適している。本発明は、酸化ストレスを受けるように誘導されているまたは酸化ストレスによって刺激されている細胞に由来するエキソソームなど、ある特定のエキソソームが髄鞘形成能を増強させ得るという発見に部分的に基づく。
「エキソソーム」とは、多様な異なる細胞から放出されるナノ小胞である。これらの小さな小胞は、大きな多小胞エンドソームに由来し、細胞外環境に分泌され得る。エキソソーム放出/放散(shedding)の正確なメカニズムは、依然として不明のままである。それらは、後期エンドソームの境界膜からの陥入および出芽によって形成されるように見え、サイトゾルを含有する小胞、およびそれらの表面上に膜結合型細胞タンパク質の細胞外ドメインを曝露する小胞をもたらす。電子顕微鏡法を用いると、調査は、内部小胞の細胞外環境への分泌につながる、多小胞エンドソームと原形質膜との融合プロファイルを示した。
本発明のある特定の局面において、脳の健康または他の関連疾病の改善のための新規な治療様態として、エキソソームを調製しかつ使用してよい。
本発明のある特定の態様において、マイクロRNA(miRNAと略記される)を含む単離エキソソームまたは脂質ナノ小胞を、脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者を治療するための方法および組成物に用いてよい。特定の態様において、miRNAには、miR-7a、miR-9、miR-9*、miR-17、miR-18a、miR-19a、miR-19b、miR-20a、miR-92a-1、miR-23a、miR-23a*、miR-23b、miR-32、miR-128、miR-138、miR-138*、miR-184、miR-199a-5p、miR-214、miR-219、miR-338、miR-338*、miR-27a、miR-27b、miR-106a、miR-124、miR-141、miR-144、miR-145、miR-146a、miR-181a、miR-200a、miR-451、miR-532-5p、およびmiR-665のうちの1種、2種、またはすべてが含まれてよい。特定の態様において、miRNAには、miR-219、miR-138、miR-338、およびmiR-199a-5pのうちの1種、2種、またはすべてが含まれてよい。例えば、miRNAはmiR-219およびmiR-138であってよく;miRNAはmiR-219およびmiR-338であってよく;miRNAはmiR-219およびmiR-199a-5pであってよい。
予防される、治療される、または診断される対象となる疾病は、本明細書において記載される組成物または方法の投与による療法または予防に適しているであろう対象に影響を及ぼす任意の疾病であり得る。例えば、疾病は、酸化ストレスに対する抵抗性を増加させる核酸または他の治療用作用物質を含有するエキソソームまたは脂質ナノ小胞を投与するための療法に適している疾病であってよい。特定の例において、脱髄性疾患を治療するための、酸化ストレスを受けるように誘導されているまたは酸化ストレスによって刺激されている細胞に由来する単離エキソソームを含む組成物を投与する工程を伴う方法および組成物が提供され得る。
いくつかの態様において、治療用作用物質または診断用作用物質を、エレクトロポレーションまたは当技術分野において公知の他の方法などによって、対象への送達のためのエキソソームに負荷してよい。治療用作用物質は、治療用核酸、タンパク質もしくは抗体フラグメント、または小分子であってよい。
本明細書において記述される薬学的組成物のいくつかの態様において、核酸はサイトカインをコードする。「サイトカイン」という用語は、もう一方の細胞に対して細胞間調節因子として作用する、一方の細胞集団によって放出されるタンパク質に対する総称である。核酸配列は、サイトカインの全長核酸配列、ならびに全長配列に由来する任意の長さの非全長配列をコードし得る。上述のように、配列は、特異的宿主細胞においてコドン選好性を提供するために導入され得る、天然の1つまたは複数の配列の縮重コドンを含むことがさらに理解される。
治療用核酸の他の例には、酵素をコードする核酸が含まれる。例には、ACPデサチュラーゼ、ACPヒドロキシラーゼ、ADP-グルコースピロホリラーゼ(pyrophorylase)、ATPアーゼ、アルコールデヒドロゲナーゼ、アミラーゼ、アミログルコシダーゼ、カタラーゼ、セルラーゼ、シクロオキシゲナーゼ、デカルボキシラーゼ、デキストリナーゼ、エステラーゼ、DNAポリメラーゼ、RNAポリメラーゼ、ヒアルロン(hyaluron)シンターゼ、ガラクトシダーゼ、グルカナーゼ、グルコースオキシダーゼ、GTPアーゼ、ヘリカーゼ、ヘミセルラーゼ、ヒアルロニダーゼ、インテグラーゼ、インベルターゼ、イソメラーゼ、キナーゼ、ラクターゼ、リパーゼ、リポキシゲナーゼ、リアーゼ、リゾチーム、ペクチンエステラーゼ、ペルオキシダーゼ、ホスファターゼ、ホスホリパーゼ、ホスホリラーゼ、ポリガラクツロナーゼ、プロテイナーゼ、ペプチダーゼ(peptidease)、プラナーゼ(pullanase)、リコンビナーゼ、逆転写酵素、トポイソメラーゼ、キシラナーゼ、またはレポーター遺伝子が含まれるが、それらに限定されるわけではない。
治療用核酸には、ホルモンをコードする核酸も含まれる。例には、成長ホルモン、プロラクチン、胎盤性ラクトゲン、黄体形成ホルモン、卵胞刺激ホルモン、絨毛性ゴナドトロピン、甲状腺刺激ホルモン、レプチン、副腎皮質刺激ホルモン、アンジオテンシンI、アンジオテンシンII、β-エンドルフィン、β-メラニン細胞刺激ホルモン、コレシストキニン、エンドセリンI、ガラニン、胃抑制ペプチド、グルカゴン、インスリン、リポトロピン、ニューロフィジン、ソマトスタチン、カルシトニン、カルシトニン遺伝子関連ペプチド、β-カルシトニン遺伝子関連ペプチド、悪性腫瘍因子の高カルシウム血症、副甲状腺ホルモン関連タンパク質、副甲状腺ホルモン関連タンパク質、グルカゴン様ペプチド、パンクレアスタチン、膵臓ペプチド、ペプチドYY、PHM、セレクチン、血管作動性腸管ペプチド、オキシトシン、バソプレッシン、バソトシン、エンケファリンアミド、メトルフィンアミド(metorphinamide)、αメラニン細胞刺激ホルモン、心房性ナトリウム利尿因子、アミリン、アミロイドP構成成分、副腎皮質刺激ホルモン放出ホルモン、成長ホルモン放出因子、黄体形成ホルモン放出ホルモン、ニューロペプチドY、サブスタンスK、サブスタンスP、および甲状腺刺激ホルモン放出ホルモンが含まれるが、それらに限定されるわけではない。
本明細書において記述される核酸は、抗体またはそのフラグメントをコードしてよい。「抗体」という用語は、抗原結合領域を有する任意の抗体様分子を指すために用いられ、Fab'、Fab、F(ab')2、単一ドメイン抗体(DAB)、Fv、scFv(一本鎖Fv)などの抗体フラグメントを含む。様々な抗体ベースの構築物およびフラグメントを調製するおよび使用するための技術は、当技術分野において周知である。抗体を調製するおよび特徴付けするための手段も、当技術分野において周知である。本明細書において使用するとき、「抗体」という用語は、IgG、IgM、IgA、IgD、およびIgEなどの任意の免疫学的結合物質を広く指すことを意図する。一般的に、IgGおよび/またはIgMが好ましく、なぜならそれらは生理学的状況で最もよく見られる抗体であり、かつなぜならそれらは実験室環境で最も容易に作製されるからである。
いくつかの局面におけるエキソソームまたは小胞は、診断用核酸である核酸を含んでよい。「診断用核酸」とは、疾病または健康関連状態の診断に適用され得る核酸である。「診断用核酸」の定義には、1種または複数種のレポータータンパク質をコードする核酸配列も含まれる。「レポータータンパク質」とは、細胞または組織内に存在する場合に、検出可能であり、かつ細胞内に存在している他の遺伝子配列またはコードされたポリペプチドと区別可能であるアミノ酸配列を指す。いくつかの態様において、治療用遺伝子をレポーターに融合させてよく、または別個のタンパク質として産生してよい。例えば、関心対象の遺伝子およびレポーターを、共トランスフェクション(共感染)により別個の送達ビヒクル中の別個のプロモーターによって、または同じ送達ビヒクル中の別個のプロモーターによって誘導してよい。加えて、2種の遺伝子を、例えば内部リボソーム進入部位によって同じプロモーターに、または二方向性プロモーターに連結させてよい。そのような技術を用いると、関心対象の遺伝子およびレポーターの発現が相関する。ゆえに、関心対象の遺伝子の発現の位置、量、および持続期間を計測し得る。関心対象の遺伝子は、例えば腫瘍抑制遺伝子またはアポトーシス促進遺伝子などの抗癌遺伝子であってよい。
ある特定の局面において、前記方法における使用のための組成物または作用物質は、薬学的に許容される担体に適切に含有されている。担体は非毒性の生体適合性であり、かつ作用物質の生物学的活性に有害な影響を及ぼさないように選択される。本発明のいくつかの局面における作用物質は、錠剤、カプセル剤、粉末、顆粒、軟膏、溶液、デポジトリー(depositories)、吸入剤、および経口的、非経口的、または外科的な投与を可能にする注射液など、固体、半固体、ゲル、液体、または気体の形態で、局部的送達(すなわち、骨格筋または他の組織など、身体の特異的位置への)または全身的送達のための調製物中に製剤化されてよい。本発明のある特定の局面は、医療デバイス等を被覆することによる、組成物の局部的投与も企図する。
いくつかの態様は、診断用および治療用のキットなどのキット、ならびにエキソソームを調製するおよび/または送達するためのキットに関係する。例えば、キットは、本明細書において記載される1種または複数種の薬学的組成物、および任意でそれらの使用のための取扱説明書を含んでよい。キットは、そのような組成物の投与を達成するための1種または複数種のデバイスも含んでよい。例えば、対象キットは、薬学的組成物、および脱髄疾患を有するまたは脱髄疾患のリスクがある患者への該組成物の直接投与を達成するためのカテーテルを含んでよい。他の態様において、対象キットは、送達デバイスとともに使用するための、調合薬として任意で製剤化されたまたは凍結乾燥された、単離エキソソームのプレフィルドアンプルを含んでよい。
以下の実施例は、本発明の好ましい態様を実証するために含まれる。次に続く実施例に開示される技術は、本発明の実践において上手く機能することが本発明者によって発見された技術を表し、ゆえにその実践のための好ましい様式を構成すると見なされ得ることが、当業者によって解されるべきである。しかしながら、当業者であれば、本開示に照らして、多くの変化が、開示される具体的態様においてなされ得、かつ本発明の精神および範囲から逸脱することなく、類似のまたは同様の結果をなおも獲得し得ることを解するべきである。
本発明者らは、ラット用のMarlau式EEケージを確立して、EE曝露された(図7A〜7F)ラットの末梢血(図2A〜2C)由来のエキソソーム(図1)が、富化されていない(NE)対応物と比較して、OSを低下させ得るかどうかおよび髄鞘形成を促進し得るかどうかを試験した。
老化による認知低下はOSの増加とともに生じ(Sohal & Weindruch, 1996)、若齢動物の全身環境は、老化したCNSの局面を若返らせ得る(Ruckh, et al., 2012)。したがって、著者らは、若齢動物由来のエキソソームが、細胞老化の重大な局面であるOSを緩和し得る(図3A〜3C)という仮説を立てた。実際に、著者らは、老化ラットではなく若齢ラットの血液由来のエキソソームが、海馬薄片培養物におけるOSを有意に(p≦0.001)減少させることを見出した。さらに、若齢エキソソームのこの栄養的効果は、エキソソームをUV光に曝露することによって無効になり得、若齢エキソソーム内のRNA種が関与していることを示唆した。具体的な値は、対照:1.00±0.1;若齢:0.59±0.04(p≦0.001);老化:0.90±0.09;若齢+UV:0.95±0.05;(n=9/群)であった。
本発明者らは、次に、健常な組織におけるベースラインのミエリン含量を改善し得る若齢エキソソームが、脱髄の実験モデルの後の髄鞘再生も改善し得るという仮説を立てた。実際に、本発明者らは、若齢エキソソーム、若齢-EEエキソソーム、および老化-EEエキソソームが、リゾレシチンへの一時的曝露によって誘導された急性脱髄の後の回復を有意に(p≦0.001)改善させることを実証した(図9A〜9B)。リゾレシチンへの曝露の直後に、培養物を、若齢動物、若齢-EE動物、または老化-EE動物に由来するエキソソームで処理した。5日後、髄鞘再生の開始時に、培養物を収集し、MBP含量をウェスタンブロットにより解析した(図9B)。リゾレシチン(Lyso)曝露は、対照と比較して、すべての群においてMBPの有意な(*p<0.001;n=6〜16)低下を誘発したが、一方でエキソソーム曝露は、リゾレシチン単独に関して見られるものと比較して、髄鞘再生の有意な(#p<0.001)増加を促進した。同様に、リゾレシチン処理の5日後に収集された薄片培養物も、O4陽性細胞の存在の有意な(*p<0.001;n=4〜8/群)増加を明らかにした。すべてのエキソソーム処理は、リゾレシチン処理単独に関して見られるものを上回って、O4染色を有意に増強させた(#p<0.001)。O1染色も、リゾレシチン処理の5日後に有意に増加した(*p<0.001;n=3〜4/群)が、一方でエキソソーム処理に関してさらなる増加は見られず、エキソソームは、成熟オリゴデンドロサイトを存続させることによって髄鞘再生を直接増加させ得ることを示唆した。有意性は、ANOVA+事後Holm-Sidak検定によって判定された。
本発明者らは、樹状細胞由来のエキソソームを調査した。エキソソームは、それらの親細胞の細胞質の無作為抽出サンプルを含有しないが、特異的なmRNA、miRNA、およびタンパク質に富んでいる(Bobrie, et al., 2011)。このカーゴはプロテアーゼおよびRNアーゼによる分解から保護され、一方で小胞は間質空間内にあり、レシピエント細胞によっていったん取り込まれると生物活性を保持する。ゆえに、それらは、そうでなければ遺伝子発現に基づき個々の細胞に限定されるであろう、シグナル伝達および酵素活性の移行を容易にする(Lee, et al., 2011)。最近の研究によれば、OSに曝露された免疫細胞は、OSに対する抵抗性の増加を近隣細胞に伝えるエキソソームを放出することが示されている(Eldh, et al., 2010)。重要なことには、この効果は曝露の2時間後に見られ、最も可能性が高い抗オキシダントである防御タンパク質へのエキソソームmRNAの急速な翻訳(Eldh, et al., 2010)、またはオキシダント/抗オキシダント系関連miRNAの産生を暗示する。
OSの緩和および髄鞘形成/髄鞘再生の増加のためのエキソソームの供給源として、樹状細胞を用いることができる。エキソソームを用いて、外傷性脳損傷および新生児脳損傷も治療し得る。
IFNγは、生理的な条件性ホルメシス(Kraig, et al., 2010)と一致した、有害および有益な脳効果を有する。IFNγは、多発性硬化症のモデルであるEAEによる脱髄を悪化させる。それにもかかわらず、疾病の発症前の低レベルのIFNγは脱髄を防御し、効果は、オリゴデンドロサイトの酸化ストレス応答を伴う(OSR;Lin, et al., 2008)。また、拡延性抑制(SD)は、ラット海馬薄片培養物におけるMBPの一時的な(7日間ではなく、1および3日間の)下降を誘発し(Kunkler, et al., 2006)、かつ脱髄は、インビボでのSD感受性を増加させる(Merkler, et al., 2009)。
T細胞により分泌されるインターフェロンガンマ(IFN-γ)の、酸化ストレス(OS)および多発性硬化症における脱髄に対する有害な影響は十分に認識されている。しかしながら、疾病発症前の低レベルのIFN-γは、EEによってもたらされるもののように、脱髄を防御しかつOSを低下させることも知られている。SDはIFN-γを上昇させ、かつSD閾値(SDT)は脱髄の実験モデルにおいて減少しており、SDにおけるT細胞の関与を示唆している。本発明者らは、ラット海馬薄片培養物内にT細胞を見出したため、本発明者らは、この調製物を利用して、拡延性抑制閾値、OS、およびMBPレベルに対するIFN-γのT細胞介在性効果を探索した。SDは、7日間で徐々に回復するMBPの有意な喪失、SDTの有意な初期減少、およびOSの有意な増加を誘発した。MBP喪失は、T細胞枯渇、IFN-γの中和、および中性スフィンゴミエリナーゼ-2の遮断によって無効になった。重要なことには、IFN-γを薄片上にパルスして、EEの段階的変化(例えば、活動−休止)を模擬した場合、有意であるが逆の効果が見られ、対照を上回ってSDTは増加し、OSは低下し、かつMBPは上昇した。ストレスを受けた免疫細胞によって分泌されるエキソソームはOSに対する防御を与え得るように、本発明者らは、次に、これらの栄養的効果におけるエキソソームの関与を調べた。結果は、IFN-γで刺激された薄片培養物に由来するエキソソームが、段階的な低レベルのIFN-γでの処理の効果を模擬することを裏付けた。最後に、内因性スフィンゴミエリナーゼ阻害剤であるグルタチオンは、ミクログリアにおいて有意に増加しており、ミエリンを増加させることにおけるそれらの関与を示唆した。これらの結果は、SDの予防のための、および延長として片頭痛の予防ための、新規な治療標的としてのIFN-γのパルス適用を支持する。
脳への外傷性損傷は、脳のミエリン産生細胞であるオリゴデンドロサイトの喪失、脱髄、および損傷した脳エリアが適切に髄鞘再生し得ないという不全に関連している(Flygt, et al., 2013)。しかしながら、新たな証拠によれば、損傷した脳は、適切に刺激された場合に髄鞘再生し得ることが表されている(Powers, et al., 2013)。
新生児脳損傷は、低髄鞘形成に関連した、オリゴデンドロサイトへの損傷を一般的にもたらす(Kauer & Ling EA, 2009)。環境富化された動物の血清に由来するエキソソーム、ならびにインビトロでIFNγ刺激樹状細胞に由来するエキソソームは、オリゴデンドロサイト分化および関連したミエリン産生を促進するため、本発明者らは、新生児虚血性脳損傷に対するこれらの潜在的な治療用作用物質の影響を判定した。
Claims (37)
- 酸化ストレスを受けるように誘導されている細胞から得られた単離エキソソームを含む薬学的組成物の有効量を患者に投与する工程を含む、脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者を治療するための方法。
- 脱髄性疾患が、認知低下、アルツハイマー病、パーキンソン病、脳卒中、てんかん、片頭痛、多発性硬化症、またはニューロパチーである、請求項1に記載の方法。
- 脱髄性疾患が、多発性硬化症またはニューロパチーである、請求項2に記載の方法。
- 患者が、吸入により経鼻的に、または静脈内に組成物を投与される、請求項1に記載の方法。
- 単離エキソソームが、少なくとも2種の異なるタイプのエキソソームを有する、請求項1に記載の方法。
- 細胞が、免疫細胞、神経細胞、または脂肪細胞である、請求項1に記載の方法。
- 細胞が免疫細胞である、請求項6に記載の方法。
- 細胞が神経細胞である、請求項6に記載の方法。
- 細胞が、サイトカインまたはオキシダントによって誘導されている、請求項1に記載の方法。
- サイトカインがIFN-γである、請求項9に記載の方法。
- 細胞が、前記患者から得られた細胞である、請求項1に記載の方法。
- 細胞が、前記患者が18歳未満であるときに前記患者から得られた細胞である、請求項11に記載の方法。
- 細胞が、前記患者が1歳未満であるときに前記患者から得られた細胞である、請求項12に記載の方法。
- 単離エキソソームが、少なくとも、外部から添加された治療用作用物質を含む、請求項1に記載の方法。
- 外部から添加された治療用作用物質がsiRNAである、請求項14に記載の方法。
- 単離エキソソームが、miR-219、miR-138、またはmiR-199aを含む、請求項1に記載の方法。
- 単離エキソソームが、抗オキシダント系タンパク質をコードするmRNAを含む、請求項1に記載の方法。
- a)外部からの酸化ストレスを受けるように誘導されている神経細胞を得る工程であって、該神経細胞がエキソソームを産生する、工程;および
b)産生されたエキソソームを単離する工程
を含む、酸化ストレスを受けるように誘導されている神経細胞から単離エキソソームを得る方法。 - 単離エキソソームを含む薬学的組成物の有効量を、脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者に投与する工程をさらに含む、請求項18に記載の方法。
- 脱髄性疾患が、認知低下、アルツハイマー病、パーキンソン病、脳卒中、てんかん、片頭痛、多発性硬化症、またはニューロパチーである、請求項19に記載の方法。
- 脱髄性疾患が、多発性硬化症またはニューロパチーである、請求項20に記載の方法。
- 酸化ストレスを誘導する条件下で細胞を培養する工程をさらに含む、請求項18に記載の方法。
- 細胞が、サイトカインによって誘導されている、請求項18に記載の方法。
- サイトカインがIFN-γである、請求項23に記載の方法。
- 細胞が、患者から得られた細胞である、請求項18に記載の方法。
- 細胞が、前記患者が18歳未満であるときに前記患者から得られる、請求項25に記載の方法。
- 細胞が、前記患者が1歳未満であるときに前記患者から得られる、請求項26に記載の方法。
- 請求項18〜27のいずれか一項に記載の方法に従って得られた、単離エキソソーム。
- 請求項28に記載の単離エキソソームと、薬学的に許容される担体とを含む、薬学的組成物。
- 請求項29に記載の薬学的組成物の有効量を患者に投与する工程を含む、脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者を治療するための方法。
- miR-219、miR-138、およびmiR-199aのうちの少なくとも2種を含む、単離脂質ナノ小胞。
- miR-219およびmiR-138を含む、請求項31に記載の単離脂質ナノ小胞。
- ヒト細胞から得られた、請求項31に記載の単離脂質ナノ小胞。
- 脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者から得られた、請求項33に記載の単離脂質ナノ小胞。
- インビトロで再構成された、請求項31に記載の単離脂質ナノ小胞。
- 請求項31〜35のいずれか一項に記載の単離脂質ナノ小胞と、薬学的に許容される担体とを含む、薬学的組成物。
- 請求項36に記載の薬学的組成物の有効量を患者に投与する工程を含む、脱髄性疾患のリスクがあるまたは脱髄性疾患を有する患者を治療するための方法。
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EP (1) | EP2885414B1 (ja) |
JP (1) | JP2015524849A (ja) |
AU (1) | AU2013302526B2 (ja) |
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AU2013302526B2 (en) | 2018-03-22 |
US11369634B2 (en) | 2022-06-28 |
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EP2885414B1 (en) | 2020-09-23 |
US20150216899A1 (en) | 2015-08-06 |
US10231997B2 (en) | 2019-03-19 |
US20190160097A1 (en) | 2019-05-30 |
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