JP2016525873A - T細胞バランス遺伝子発現、組成物およびその使用方法 - Google Patents
T細胞バランス遺伝子発現、組成物およびその使用方法 Download PDFInfo
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Abstract
Description
本出願は、参照により全体として本明細書に組み込まれる、2013年2月27日に出願された米国仮特許出願第61/770,036号明細書の利益を主張する。
本発明は、以下の助成金のもと政府支援により行われた:National Institute of Healthにより授与されたPioneer Grant DP1OD003958−01;National Institute of Healthにより授与されたPioneer Grant DP1OD003958−03;National Institute of Healthにより授与されたCenters of Excellence in Genomics Science Grant 1P50HG006193−01;National Human Genome Research Instituteにより授与されたGrant 1P01HG005062−01;National Institute of Healthにより授与されたGrant DP1OD003893、National Institute of Healthにより授与されたGrant NS30843、National Institute of Healthにより授与されたGrant NS045937、National Institute of Healthにより授与されたGrant AI 73748、National Institute of Healthにより授与されたGrant AI45757、National Institute of Healthにより授与されたGrant P01AI056299およびNational MS Society,New Yorkにより授与されたGrant RG2571。政府は、本発明における一定の権利を有する。
本発明はまた、種々の治療および/または診断指標において有用な遺伝子シグネチャーを決定する方法を提供する。これらの方法の目的は、目的プロセスに関して情報を与える遺伝子の小さいシグネチャーを選択することである。基本概念は、異なるタイプの情報は、ゲノム全体(>20kの遺伝子)の「スペース」の、関連遺伝子のサブセットへの異なる分類を伴い得ることである。この方針は、シグネチャーサイズに対する制約を考慮し、これらの分類の最良のカバレッジを有するように設計される。例えば、この方針の一部の実施形態において、2つのタイプの情報:(i)時間的発現プロファイル;および(ii)機能的アノテーションが存在する。第1の情報源は、遺伝子を、共発現される遺伝子のセットに分類する。情報源は、遺伝子を、共機能的遺伝子のセットに分類する。次いで、遺伝子の小さいセットを、それぞれのセットからの所望の数の代表物、例えば、それぞれの共発現セットからの少なくとも10個の代表物およびそれぞれの共機能的セットからの少なくとも10個の代表物が存在するように選択する。複数の情報源を用いる作業(ひいては、複数の分類を「被覆」する目的)の問題は、コンピュータ科学の理論において集合被覆として公知である。この問題は最適性に対して解決することができない一方(そのNP困難性に起因)、それは、小倍数内で近似させることができる。一部の実施形態において、それぞれのセットからの代表物の所望数は、1つ以上、少なくとも2つ、5つ以上、10以上、15以上、20以上、25以上、30以上、35以上、40以上、50以上、60以上、70以上、80以上、90以上、または100以上である。
本発明は、種々の診断および/または治療指標において使用されるT細胞関連遺伝子シグネチャーを提供する。例えば、本発明は、種々の診断および/または治療指標において有用なTh17関連シグネチャーを提供する。本発明に関する「シグネチャー」は、限定されるものではないが、核酸と、その多型、突然変異物、変異体、改変物、サブユニット、断片、および他の分析物または試料由来計測物を包含する。
本明細書に提供される組成物および方法のいずれかにおいて使用される好適なT細胞モジュレート剤としては、抗体、可溶性ポリペプチド、ポリペプチド剤、ペプチド剤、核酸剤、核酸リガンド、または小分子剤が挙げられる。非限定的な例として、好適なT細胞モジュレート剤または1つ以上のT細胞モジュレート剤との組合せで使用される薬剤を、以下の表10に示す。
手短に述べると、遺伝子発現プロファイルを、18個の時点(0.5時間から72日間)において、Th17条件(IL−6、TGF−β1)または対照(Th0)下で、AffymetrixマイクロアレイHT_MG−430Aを使用して計測した。4つの推論法にわたるコンセンサスを使用して示差的に発現された遺伝子を検出し、自動導出されたkを用いるk平均法を使用して遺伝子をクラスタリングする。時間的調節相互作用を、調節因子の推定標的(例えば、ChIPseqに基づく)と、標的遺伝子のクラスタ(4つのクラスタリングスキームを使用)との間の有意な(p<5*10−5およびエンリッチメント倍率>1.5)重複を検索することにより推定した。ネットワークベースおよび発現ベース特性を使用して摂動についての候補を辞書的に順序付けした。siRNA送達にSiNWを使用して摂動を行った。これらの方法を以下により詳細に記載する。
P=(1+#同等のより良好なFスコアを有するランダム化データセット)/(1+#ランダム化データセット)
Th17分化の転写時間経過
ナイーブCD4+T細胞のTh17細胞への分化を、TGF−β1およびIL−6を使用して誘導し、抗炎症サイトカインTGF−β1および炎症促進性サイトカインIL−6の組合せにより誘導されたナイーブCD4+T細胞のTh17細胞への分化の間に72時間の時間経過に沿って18個の時点においてマイクロアレイを使用して転写プロファイルを計測した(図1、図6A、図6Bおよび図6C、実施例1の方法の部参照)。対照として、mRNAプロファイルを、分化サイトカインの添加なしで活性化された細胞(Th0)について計測した。Th17分化の間に特異的に示差的に発現された1,291個の遺伝子を、Th17分化細胞と対照細胞とを比較することにより同定し(実施例1の方法の部参照)、区別される時間的プロファイルを示す20個の共発現クラスタに分けた(k平均クラスタリング、実施例1の方法の部参照、図1bおよび図7)。これらのクラスタを使用して応答を特性決定し、下記のとおり調節ネットワークモデルを再構築した(図2a)。
動的調節相互作用の推定
クラスタ(図1b)のそれぞれが、関連する時点において活性である調節因子を共有する遺伝子を包含することが仮定された。これらの調節因子を予測するため、公開されているゲノムプロファイルからの調節因子−標的会合の一般ネットワークをアセンブルした(Linhart,C.,Halperin,Y.& Shamir,R.Transcription factor and microRNA motif discovery:the Amadeus platform and a compendium of metazoan target sets.Genome research 18,1180−1189,doi:10.1101/gr.076117.108(2008);Zheng,G.et al.ITFP:an integrated platform of mammalian transcription factors.Bioinformatics 24,2416−2417,doi:10.1093/bioinformatics/btn439(2008);Wilson,N.K.et al.Combinatorial transcriptional control in blood stem/progenitor cells:genome−wide analysis of ten major transcriptional regulators.Cell Stem Cell 7,532−544,doi:10.1016/j.stem.2010.07.016(2010);Lachmann,A.et al.in Bioinformatics Vol.26 2438−2444(2010);Liberzon,A.et al.Molecular signatures database(MSigDB)3.0.Bioinformatics 27,1739−1740,doi:10.1093/bioinformatics/btr260(2011);Jiang,C.,Xuan,Z.,Zhao,F.& Zhang,M.TRED:a transcriptional regulatory element database,new entries and other development.Nucleic Acids Res 35,D137−140(2007);Elkon,R.,Linhart,C.,Sharan,R.,Shamir,R.& Shiloh,Y.in Genome Research Vol.13 773−780(2003);Heng,T.S.& Painter,M.W.The Immunological Genome Project:networks of gene expression in immune cells.Nat.Immunol.9,1091−1094,doi:10.1038/ni1008−1091(2008))(図2a、実施例1の方法の部参照)。
初代T細胞のナノワイヤベース摂動
キー因子が欠失したノックアウトマウスからのナイーブCD4+T細胞の応答の試験が強力な方針である一方、それはマウス株の利用可能性または新たなマウスを生成する能力により制限される。未刺激初代マウスT細胞において、ウイルスまたは形質移入ベースsiRNA送達はほぼ不可能であった。それというのも、その送達は分化または細胞生存率のいずれかを変更するためである(Dardalhon,V.et al.Lentivirus−mediated gene transfer in primary T cells is enhanced by a central DNA flap.Gene therapy 8,190−198(2001);McManus,M.et al.Small interfering RNA−mediated gene silencing in T lymphocytes.The Journal of Immunology 169,5754(2002))。したがって、ケイ素ナノワイヤ(NW)をベースとする新たな送達技術(Shalek et al.,Proc Natl Acad Sci U.S.A.2010;Shalek,A.K.et al.Nanowire−Mediated Delivery Enables Functional Interrogation of Primary Immune Cells:Application to the Analysis of Chronic Lymphocytic Leukemia.Nano Lett.12,6498−6504,doi:10.1021/nl3042917(2012))を使用し、siRNAをナイーブT細胞中に、それらを活性化させずに効率的に(>95%)送達するようにそれを最適化した(図3bおよびc)(Shalek et al.,Nano Lett 2012)。
新規因子の検証および特性決定
本明細書に提示される試験は、正または負の因子の12個(Th17細胞に関連しなかった12個の新規因子の11個を含む;図4b、淡灰色ハロー)の役割をフォーカスした。それぞれの因子の摂動後にRNA−Seqを使用してその予測標的(図2)が摂動により影響されるか否かを試験した(図4c、ベン図、上段)。両方のデータセット中に存在する因子の3つ(Egr2、Irf8、およびSp4)についての高度に有意な重複(p<10−5)が見出され、4番目(Smarca4)についての境界有意重複が見出され、このことはネットワーク中のエッジの質を検証した。
プロテインC受容体(PROCR)は、Th17細胞の病原性表現型を調節する
Th17細胞は近年、T細胞サブセットと同定され、炎症自己免疫応答のドライブおよびある細胞外病原体に対する保護応答の媒介に関与している。分子シグネチャーなどの因子に基づき、Th17細胞は、病原性または非病原性として分類される(例えば、Lee et al.,“Induction and molecular signature of pathogenic Th17 cells,”Nature Immunology,vol.13(10):991−999およびオンライン方法参照)。
Th細胞分化におけるFas
Fasは、FasR、CD95、APO−1、TNFRSF6としても公知であり、TNF受容体スーパーファミリーのメンバーである。FasLの結合は、カスパーゼ−8を活性化させ、アポトーシスをもたらすFADD(デスドメイン)に結合するFASトリマーをもたらす。Fasは、アポトーシス非依存性効果、例えば、肝細胞中のAkt、STAT3、およびNF−κBとの相互作用ならびに癌細胞中のNF−κBおよびMAPK経路との相互作用も呈する。
Claims (95)
- T細胞バランスをモジュレートする方法であって、T細胞またはT細胞の集団を、T細胞モジュレート剤の不存在下の前記T細胞またはT細胞の集団の分化、維持および/または機能と比較してTh17細胞、制御性T細胞(Treg)および他のT細胞サブセット間のバランスを変更することにより、前記T細胞またはT細胞の集団の分化、維持および/または機能を改変するために十分な量のT細胞モジュレート剤と接触させることを含む方法。
- 前記T細胞モジュレート剤が、表3〜9に列記されるものから選択される1つ以上の標的遺伝子または1つ以上の標的遺伝子の1つ以上の産物の発現、活性および/または機能をモジュレートする薬剤である、請求項1に記載の方法。
- 所望の遺伝子または標的遺伝子の組合せを選択し、Th17分化、維持および/もしくは機能の正の調節因子として、またはTh17分化、維持および/もしくは機能の負の調節因子として同定する、請求項2に記載の方法。
- 前記遺伝子または標的遺伝子の組合せが、Th17分化、維持および/または機能の正の調節因子であり、前記T細胞モジュレート剤が、分化、維持および/または機能を前記Th17表現型から離れてシフトさせるために十分な量のアンタゴニストである、請求項3に記載の方法。
- 前記標的遺伝子または標的遺伝子の組合せが、Th17分化、維持および/または機能の正の調節因子であり、前記T細胞モジュレート剤が、分化、維持および/または機能を前記Th17表現型に向けてシフトさせるために十分な量のアゴニストである、請求項3に記載の方法。
- 前記標的遺伝子または標的遺伝子の組合せが、Th17分化、維持および/または機能の負の調節因子であり、前記T細胞モジュレート剤が、分化、維持および/または機能を前記Th17表現型に向けてシフトさせるために十分な量のアンタゴニストである、請求項3に記載の方法。
- 前記標的遺伝子または標的遺伝子の組合せが、Th17分化、維持および/または機能の負の調節因子であり、前記T細胞モジュレート剤が、分化を前記Th17表現型および/または維持から離れてシフトさせるために十分な量のアゴニストである、請求項3に記載の方法。
- Th17分化、維持および/または機能の前記正の調節因子を、MINA、MYC、NKFB1、NOTCH、PML、POU2AF1、PROCR、RBPJ、SMARCA4、ZEB1、BATF、CCR5、CCR6、EGR1、EGR2、ETV6、FAS、IL12RB1、IL17RA、IL21R、IRF4、IRF8、ITGA3およびそれらの組合せから選択する、請求項3に記載の方法。
- Th17分化、維持および/または機能の前記正の調節因子を、MINA、PML、POU2AF1、PROCR、SMARCA4、ZEB1、EGR2、CCR6、FASおよびそれらの組合せから選択する、請求項3に記載の方法。
- Th17分化、維持および/または機能の前記負の調節因子を、SP4、ETS2、IKZF4、TSC22D3、IRF1およびそれらの組合せから選択する、請求項3に記載の方法。
- Th17分化、維持および/または機能の前記負の調節因子を、SP4、IKZF4、TSC22D3およびそれらの組合せから選択する、請求項3に記載の方法。
- 前記T細胞モジュレート剤が、Th17細胞と他のT細胞サブタイプとの間のバランスを変更する、請求項1に記載の方法。
- 前記他のT細胞サブタイプが、制御性T細胞(Treg)である、請求項12に記載の方法。
- 前記T細胞モジュレート剤が、Th17細胞へ向かうT細胞分化を誘導するために十分な量の可溶性FasポリペプチドもしくはFasに由来するポリペプチド、またはTh17細胞に向かうT細胞分化を誘導するために十分な量の、Th17細胞中のFasの発現、活性および/もしくは機能を向上もしくは増加させるアゴニストである、請求項1に記載の方法。
- 前記T細胞モジュレート剤が、制御性T細胞(Treg)、Th1細胞、またはTregおよびTh1細胞の組合せに向かう分化を誘導するために十分な量の、Fasの発現、活性および/または機能を阻害するアンタゴニストである、請求項1に記載の方法。
- 前記T細胞モジュレート剤が、病原性Th17細胞と非病原性Th17細胞との間のバランスを変更する、請求項1に記載の方法。
- 前記T細胞モジュレート剤が、Th17細胞を病原性から非病原性シグネチャーに切り替えるために十分な量の、可溶性プロテインC受容体(PROCR)ポリペプチドもしくはPROCRに由来するポリペプチド、またはTh17細胞を病原性から非病原性シグネチャーに切り替えるために十分な量の、Th17細胞中のPROCRの発現、活性および/もしくは機能を向上もしくは増加させるアゴニストである、請求項16に記載の方法。
- 前記T細胞モジュレート剤が、Th17細胞を非病原性から病原性シグネチャーに切り替えるために十分な量の、Th17細胞中のPROCRのアンタゴニストである、請求項16に記載の方法。
- 前記T細胞モジュレート剤が、抗体、可溶性ポリペプチド、ポリペプチド剤、ペプチド剤、核酸剤、核酸リガンド、または小分子剤である、請求項1〜18のいずれか一項に記載の方法。
- 前記T細胞モジュレート剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項1〜19のいずれか一項に記載の方法。
- 前記T細胞が、ナイーブT細胞、部分分化T細胞、分化T細胞、ナイーブT細胞および部分分化T細胞の組合せ、ナイーブT細胞および分化T細胞の組合せ、部分分化T細胞および分化T細胞の組合せ、またはナイーブT細胞、部分分化T細胞および分化T細胞の組合せである、請求項1〜20のいずれか一項に記載の方法。
- 腫瘍増殖の阻害が必要とされる対象における腫瘍増殖を阻害する方法であって、前記対象に治療有効量のプロテインC受容体(PROCR)の阻害剤を投与すること含む方法。
- PROCRの前記阻害剤が、抗体、可溶性ポリペプチド、ポリペプチド剤、ペプチド剤、核酸剤、核酸リガンド、または小分子剤である、請求項22に記載の方法。
- PROCRの前記阻害剤が、リポ多糖;シスプラチン;フィブリノゲン;1,10−フェナントロリン;5−N−エチルカルボキサミドアデノシン;シスタチオニン;ヒルジン;リン脂質;ドロトレコギンアルファ;VEGF;ホスファチジルエタノールアミン;セリン;ガンマ−カルボキシグルタミン酸;カルシウム;ワルファリン;エンドトキシン;クルクミン;脂質;および一酸化窒素からなる群から選択される1つ以上の薬剤である、請求項22に記載の方法。
- 細胞集団におけるTh17分化を阻害し、ならびに/またはFOXP3、インターフェロンガンマ(IFN−γ)、GATA3、STAT4、BCL6およびTBX21から選択される1つ以上の非Th17関連サイトカインもしくは非Th17関連転写調節因子の発現、活性および/もしくは機能を増加させる方法であって、T細胞を、MINA、MYC、NKFB1、NOTCH、PML、POU2AF1、PROCR、RBPJ、SMARCA4、ZEB1、BATF、CCR5、CCR6、EGR1、EGR2、ETV6、FAS、IL12RB1、IL17RA、IL21R、IRF4、IRF8、ITGA3またはそれらの組合せの発現、活性および/機能を阻害する薬剤と接触させることを含む方法。
- 前記薬剤が、MINA、PML、POU2AF1、PROCR、SMARCA4、ZEB1、EGR2、CCR6、FASまたはそれらの組合せの少なくとも1つの発現、活性および/または機能を阻害する、請求項25に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアンタゴニスト、ペプチドアンタゴニスト、核酸アンタゴニスト、核酸リガンド、または小分子アンタゴニストである、請求項25または26に記載の方法。
- 細胞集団におけるTh17分化を阻害し、ならびに/またはFOXP3、インターフェロンガンマ(IFN−γ)、GATA3、STAT4およびTBX21から選択される1つ以上の非Th17関連サイトカインもしくは非Th17関連転写調節因子の発現、活性および/もしくは機能を増加させる方法であって、T細胞を、SP4、ETS2、IKZF4、TSC22D3、IRF1またはそれらの組合せの発現、活性および/または機能を向上させる薬剤と接触させることを含む方法。
- 前記薬剤が、SP4、IKZF4、TSC22D3またはそれらの組合せの少なくとも1つの発現、活性および/または機能を向上させる、請求項28に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアゴニスト、ペプチドアゴニスト、核酸アゴニスト、核酸リガンド、または小分子アゴニストである、請求項28または29に記載の方法。
- 細胞集団におけるTh17の分化を向上させ、インターロイキン17F(IL−17F)、インターロイキン17A(IL−17A)、STAT3、インターロイキン21(IL−21)およびRAR関連オーファン受容体C(RORC)から選択される1つ以上のTh17関連サイトカインもしくは1つ以上のTh17関連転写調節因子の発現、活性および/もしくは機能を増加させ、ならびに/またはFOXP3、インターフェロンガンマ(IFN−γ)、GATA3、STAT4およびTBX21から選択される1つ以上の非Th17関連サイトカインもしくは非Th17関連転写調節因子の発現、活性および/もしくは機能を減少させる方法であって、T細胞を、SP4、ETS2、IKZF4、TSC22D3、IRF1またはそれらの組合せの発現、活性および/または機能を阻害する薬剤と接触させることを含む方法。
- 前記薬剤が、SP4、IKZF4またはTSC22D3の少なくとも1つの発現、活性および/または機能を阻害する、請求項31に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアンタゴニスト、ペプチドアンタゴニスト、核酸アンタゴニスト、核酸リガンド、または小分子アンタゴニストである、請求項31または32に記載の方法。
- 細胞集団におけるTh17の分化を向上させ、インターロイキン17F(IL−17F)、インターロイキン17A(IL−17A)、STAT3、インターロイキン21(IL−21)およびRAR関連オーファン受容体C(RORC)から選択される1つ以上のTh17関連サイトカインもしくは1つ以上のTh17関連転写調節因子の発現、活性および/もしくは機能を増加させ、ならびに/またはFOXP3、インターフェロンガンマ(IFN−γ)、GATA3、STAT4およびTBX21から選択される1つ以上の非Th17関連サイトカインもしくは非Th17関連転写調節因子の発現、活性および/もしくは機能を減少させる方法であって、T細胞を、MINA、MYC、NKFB1、NOTCH、PML、POU2AF1、PROCR、RBPJ、SMARCA4、ZEB1、BATF、CCR5、CCR6、EGR1、EGR2、ETV6、FAS、IL12RB1、IL17RA、IL21R、IRF4、IRF8、ITGA3またはそれらの組合せの発現、活性および/または機能を向上させる薬剤と接触させることを含む方法。
- 前記薬剤が、MINA、PML、POU2AF1、PROCR、SMARCA4、ZEB1、EGR2、CCR6またはFASの少なくとも1つの発現、活性および/または機能を向上させる、請求項34に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアゴニスト、ペプチドアゴニスト、核酸アゴニスト、核酸リガンド、または小分子アゴニストである、請求項34または35に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項27に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項30に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項33に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項36に記載の方法。
- 前記薬剤が、抗体である、請求項27に記載の方法。
- 前記薬剤が、抗体である、請求項30に記載の方法。
- 前記薬剤が、抗体である、請求項33に記載の方法。
- 前記薬剤が、抗体である、請求項36に記載の方法。
- 前記抗体が、モノクローナル抗体である、請求項41に記載の方法。
- 前記抗体が、モノクローナル抗体である、請求項42に記載の方法。
- 前記抗体が、モノクローナル抗体である、請求項43に記載の方法。
- 前記抗体が、モノクローナル抗体である、請求項44に記載の方法。
- 前記抗体が、キメラ、ヒト化または完全ヒトモノクローナル抗体である、請求項41に記載の方法。
- 前記抗体が、キメラ、ヒト化または完全ヒトモノクローナル抗体である、請求項42に記載の方法。
- 前記抗体が、キメラ、ヒト化または完全ヒトモノクローナル抗体である、請求項43に記載の方法。
- 前記抗体が、キメラ、ヒト化または完全ヒトモノクローナル抗体である、請求項44に記載の方法。
- 前記T細胞が、ナイーブT細胞、ナイーブT細胞および部分分化T細胞の組合せ、ナイーブT細胞および分化T細胞の組合せ、またはナイーブT細胞、部分分化T細胞および分化T細胞の組合せである、請求項25に記載の方法。
- 前記T細胞が、ナイーブT細胞、ナイーブT細胞および部分分化T細胞の組合せ、ナイーブT細胞および分化T細胞の組合せ、またはナイーブT細胞、部分分化T細胞および分化T細胞の組合せである、請求項28に記載の方法。
- 前記T細胞が、ナイーブT細胞、ナイーブT細胞および部分分化T細胞の組合せ、ナイーブT細胞および分化T細胞の組合せ、またはナイーブT細胞、部分分化T細胞および分化T細胞の組合せである、請求項31に記載の方法。
- 前記T細胞が、ナイーブT細胞、ナイーブT細胞および部分分化T細胞の組合せ、ナイーブT細胞および分化T細胞の組合せ、またはナイーブT細胞、部分分化T細胞および分化T細胞の組合せである、請求項34に記載の方法。
- 前記T細胞が、部分分化T細胞、分化T細胞、または部分分化T細胞および分化T細胞の組合せである、請求項25に記載の方法。
- 前記T細胞が、部分分化T細胞、分化T細胞、または部分分化T細胞および分化T細胞の組合せである、請求項28に記載の方法。
- 前記T細胞が、部分分化T細胞、分化T細胞、または部分分化T細胞および分化T細胞の組合せである、請求項31に記載の方法。
- 前記T細胞が、部分分化T細胞、分化T細胞、または部分分化T細胞および分化T細胞の組合せである、請求項34に記載の方法。
- 前記T細胞が、Th17T細胞であり、前記薬剤を、前記Th17T細胞の表現型をモジュレートしてTh17T細胞表現型以外のCD4+T細胞表現型を産生するために十分な量で投与する、請求項25または28に記載の方法。
- 前記T細胞が、Th17T細胞以外のCD4+T細胞であり、前記薬剤を、非Th17T細胞の表現型をモジュレートしてTh17T細胞表現型を産生するために十分な量で投与する、請求項31または34に記載の方法。
- Th17分化、維持および/または機能に関連するシグネチャー遺伝子、遺伝子シグネチャーまたは他の遺伝子エレメントを同定する方法であって、
a)T細胞を、Th17分化の阻害剤またはTh17分化を向上させる薬剤と接触させること;および
b)ステップ(a)により発現がモジュレートされたシグネチャー遺伝子、遺伝子シグネチャーまたは他の遺伝子エレメントを同定すること
を含む方法。 - c)Th17分化の阻害剤またはTh17分化を向上させる薬剤と接触させたT細胞中でステップ(b)において同定された前記シグネチャー遺伝子、遺伝子シグネチャーまたは遺伝子エレメントの発現を摂動させること;および
d)ステップ(c)により発現がモジュレートされた標的遺伝子を同定すること
をさらに含む、請求項63に記載の方法。 - Th17分化の前記阻害剤が、表3〜9に列記されるものから選択される標的遺伝子または1つ以上の標的遺伝子の1つ以上の産物の発現、活性および/または機能を阻害する薬剤である、請求項63または64に記載の方法。
- Th17分化の前記阻害剤が、MINA、MYC、NKFB1、NOTCH、PML、POU2AF1、PROCR、RBPJ、SMARCA4、ZEB1、BATF、CCR5、CCR6、EGR1、EGR2、ETV6、FAS、IL12RB1、IL17RA、IL21R、IRF4、IRF8、ITGA3またはそれらの組合せの発現、活性および/または機能を阻害する薬剤である、請求項63または64に記載の方法。
- 前記薬剤が、MINA、PML、POU2AF1、PROCR、SMARCA4、ZEB1、EGR2、CCR6またはFASの少なくとも1つを発現、活性および/または機能を阻害する、請求項66に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアンタゴニスト、ペプチドアンタゴニスト、核酸アンタゴニスト、核酸リガンド、または小分子アンタゴニストである、請求項66に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアンタゴニスト、ペプチドアンタゴニスト、核酸アンタゴニスト、核酸リガンド、または小分子アンタゴニストである、請求項67に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項66に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項67に記載の方法。
- Th17分化の前記阻害剤が、SP4、ETS2、IKZF4、TSC22D3、IRF1またはそれらの組合せの発現、活性および/または機能を向上させる薬剤である、請求項63または64に記載の方法。
- 前記薬剤が、SP4、IKZF4、TSC22D3またはそれらの組合せの少なくとも1つの発現、活性および/または機能を向上させる、請求項72に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアゴニスト、ペプチドアゴニスト、核酸アゴニスト、核酸リガンド、または小分子アゴニストである、請求項72に記載の方法。
- 前記薬剤が、抗体、可溶性ポリペプチド、ポリペプチドアゴニスト、ペプチドアゴニスト、核酸アゴニスト、核酸リガンド、または小分子アゴニストである、請求項73に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項72に記載の方法。
- 前記薬剤が、表10に列記されるものから選択される1つ以上の薬剤である、請求項73に記載の方法。
- Th17分化の誘導をモジュレートする方法であって、T細胞を、IRF1、IRF8、IRF9、STAT2、STAT3、IRF7、STAT1、ZFP281、IFI35、REL、TBX21、FLI1、BATF、IRF4、AES、AHR、ARID5A、BCL11B、BCL3、CBFB、CBX4、CHD7、CITED2、CREB1、E2F4、EGR1、EGR2、ELL2、ETS1、ETS2、ETV6、EZH1、FOXO1、GATA3、GATAD2B、HIF1A、ID2、IKZF4、IRF2、IRF3、JMJD1C、JUN、LEF1、LRRFIP1、MAX、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF21A、PML、PRDM1、RELA、RUNX1、SAP18、SATB1、SMAD2、SMARCA4、SP100、SP4、STAT4、STAT5B、STAT6、TFEB、TP53、TRIM24、ZFP161、およびそれらの任意の組合せから選択される1つ以上の標的遺伝子または1つ以上の標的遺伝子の1つ以上の産物の発現、活性および/または機能をモジュレートする薬剤と接触させることを含む方法。
- Th17表現型の発生およびTh17T細胞の増幅をモジュレートする方法であって、T細胞を、IRF8、STAT2、STAT3、IRF7、JUN、STAT5B、ZPF2981、CHD7、TBX21、FLI1、SATB1、RUNX1、BATF、RORC、SP4、AES、AHR、ARID3A、ARID5A、ARNTL、ASXL1、BATF、BCL11B、BCL3、BCL6、CBFB、CBX4、CDC5L、CEBPB、CREB1、CREB3L2、CREM、E2F4、E2F8、EGR1、EGR2、ELK3、ELL2、ETS1、ETS2、ETV6、EZH1、FOSL2、FOXJ2、FOXO1、FUS、HIF1A、HMGB2、ID1、ID2、IFI35、IKZF4、IRF3、IRF4、IRF9、JUNB、KAT2B、KLF10、KLF6、KLF9、LEF1、LRRFIP1、MAFF、MAX、MAZ、MINA、MTA3、MYC、MYST4、NCOA1、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF21A、PML、POU2AF1、POU2F2、PRDM1、RARA、RBPJ、RELA、RORA、SAP18、SKI、SKIL、SMAD2、SMAD7、SMARCA4、SMOX、SP1、SS18、STAT1、STAT5A、STAT6、SUZ12、TFEB、TLE1、TP53、TRIM24、TRIM28、TRPS1、VAV1、ZEB1、ZEB2、ZFP161、ZFP62、ZNF238、ZNF281、ZNF703、およびそれらの任意の組合せから選択される1つ以上の標的遺伝子または1つ以上の標的遺伝子の1つ以上の産物の発現、活性および/または機能をモジュレートする薬剤と接触させることを含む方法。
- Th17細胞の安定化をモジュレートし、および/またはTh17関連インターロイキン23(IL−23)シグナリングをモジュレートする方法であって、T細胞を、STAT2、STAT3、JUN、STAT5B、CHD7、SATB1、RUNX1、BATF、RORC、SP4、IRF4、AES、AHR、ARID3A、ARID5A、ARNTL、ASXL1、ATF3、ATF4、BATF3、BCL11B、BCL3、BCL6、C21ORF66、CBFB、CBX4、CDC5L、CDYL、CEBPB、CHMP1B、CIC、CITED2、CREB1、CREB3L2、CREM、CSDA、DDIT3、E2F1、E2F4、E2F8、EGR1、EGR2、ELK3、ELL2、ETS1、ETS2、EZH1、FLI1、FOSL2、FOXJ2、FOXO1、FUS、GATA3、GATAD2B、HCLS1、HIF1A、ID1、ID2、IFI35、IKZF4、IRF3、IRF7、IRF8、IRF9、JARID2、JMJD1C、JUNB、KAT2B、KLF10、KLF6、KLF7、KLF9、LASS4、LEF1、LRRFIP1、MAFF、MAX、MEN1、MINA、MTA3、MXI1、MYC、MYST4、NCOA1、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF13、PHF21A、PML、POU2AF1、POU2F2、PRDM1、RARA、RBPJ、REL、RELA、RNF11、RORA、RUNX2、SAP18、SAP30、SERTAD1、SIRT2、SKI、SKIL、SMAD2、SMAD4、SMAD7、SMARCA4、SMOX、SP1、SP100、SS18、STAT1、STAT4、STAT5A、STAT6、SUZ12、TBX21、TFEB、TGIF1、TLE1、TP53、TRIM24、TRPS1、TSC22D3、UBE2B、VAV1、VAX2、XBP1、ZEB1、ZEB2、ZFP161、ZFP36L1、ZFP36L2、ZNF238、ZNF281、ZNF703、ZNRF1、ZNRF2、およびそれらの任意の組合せから選択される1つ以上の標的遺伝子または1つ以上の標的遺伝子の1つ以上の産物の発現、活性および/または機能をモジュレートする薬剤と接触させることを含む方法。
- 初期のTh17分化、維持および/または機能に関連する標的遺伝子の1つ以上をモジュレートする方法であって、前記標的遺伝子を、
(a)AES、AHR、ARID5A、BATF、BCL11B、BCL3、CBFB、CBX4、CHD7、CITED2、CREB1、E2F4、EGR1、EGR2、ELL2、ETS1、ETS2、ETV6、EZH1、FLI1、FOXO1、GATA3、GATAD2B、HIF1A、ID2、IFI35、IKZF4、IRF1、IRF2、IRF3、IRF4、IRF7、IRF9、JMJD1C、JUN、LEF1、LRRFIP1、MAX、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF21A、PML、PRDM1、REL、RELA、RUNX1、SAP18、SATB1、SMAD2、SMARCA4、SP100、SP4、STAT1、STAT2、STAT3、STAT4、STAT5B、STAT6、TFEB、TP53、TRIM24、ZFP161、およびそれらの任意の組合せからなる群から選択される初期のTh17分化、維持および/または機能に関連するものとして表5に列記される標的遺伝子の1つ以上;
(b)FAS、CCR5、IL6ST、IL17RA、IL2RA、MYD88、CXCR5、PVR、IL15RA、IL12RB1、およびそれらの任意の組合せからなる群から選択される初期のTh17分化、維持および/または機能に関連するものとして表6に列記される標的遺伝子の1つ以上;
(c)EIF2AK2、DUSP22、HK2、RIPK1、RNASEL、TEC、MAP3K8、SGK1、PRKCQ、DUSP16、BMP2K、PIM2、およびそれらの任意の組合せからなる群から選択される初期のTh17分化、維持および/または機能に関連するものとして表7に列記される標的遺伝子の1つ以上;
(d)HK2、CDKN1A、DUT、DUSP1、NADK、LIMK2、DUSP11、TAOK3、PRPS1、PPP2R4、MKNK2、SGK1、BPGM、TEC、MAPK6、PTP4A2、PRPF4B、ACP1、CCRN4L、およびそれらの任意の組合せからなる群から選択される初期のTh17分化、維持および/または機能に関連するものとして表8に列記される標的遺伝子の1つ以上;ならびに
(e)CD200、CD40LG、CD24、CCND2、ADAM17、BSG、ITGAL、FAS、GPR65、SIGMAR1、CAP1、PLAUR、SRPRB、TRPV2、IL2RA、KDELR2、TNFRSF9、およびそれらの任意の組合せからなる群から選択される初期のTh17分化、維持および/または機能に関連するものとして表9に列記される標的遺伝子の1つ以上
から選択する方法。 - 中期のTh17分化、維持および/または機能に関連する標的遺伝子の1つ以上をモジュレートする方法であって、前記標的遺伝子を、
(a)AES、AHR、ARID3A、ARID5A、ARNTL、ASXL1、BATF、BCL11B、BCL3、BCL6、CBFB、CBX4、CDC5L、CEBPB、CHD7、CREB1、CREB3L2、CREM、E2F4、E2F8、EGR1、EGR2、ELK3、ELL2、ETS1、ETS2、ETV6、EZH1、FLI1、FOSL2、FOXJ2、FOXO1、FUS、HIF1A、HMGB2、ID1、ID2、IFI35、IKZF4、IRF3、IRF4、IRF7、IRF8、IRF9、JUN、JUNB、KAT2B、KLF10、KLF6、KLF9、LEF1、LRRFIP1、MAFF、MAX、MAZ、MINA、MTA3、MYC、MYST4、NCOA1、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF21A、PML、POU2AF1、POU2F2、PRDM1、RARA、RBPJ、RELA、RORA、RUNX1、SAP18、SATB1、SKI、SKIL、SMAD2、SMAD7、SMARCA4、SMOX、SP1、SP4、SS18、STAT1、STAT2、STAT3、STAT5A、STAT5B、STAT6、SUZ12、TBX21、TFEB、TLE1、TP53、TRIM24、TRIM28、TRPS1、VAV1、ZEB1、ZEB2、ZFP161、ZFP62、ZNF238、ZNF281、ZNF703、およびそれらの任意の組合せからなる群から選択される中期のTh17分化、維持および/または機能に関連するものとして表5に列記される標的遺伝子の1つ以上;
(b)IL7R、ITGA3、IL1R1、CCR5、CCR6、ACVR2A、IL6ST、IL17RA、CCR8、DDR1、PROCR、IL2RA、IL12RB2、MYD88、PTPRJ、TNFRSF13B、CXCR3、IL1RN、CXCR5、CCR4、IL4R、IL2RB、TNFRSF12A、CXCR4、KLRD1、IRAK1BP1、PVR、IL12RB1、IL18R1、TRAF3、およびそれらの任意の組合せからなる群から選択される中期のTh17分化、維持および/または機能に関連するものとして表6に列記される標的遺伝子の1つ以上;
(c)PSTPIP1、PTPN1、ACP5、TXK、RIPK3、PTPRF、NEK4、PPME1、PHACTR2、HK2、GMFG、DAPP1、TEC、GMFB、PIM1、NEK6、ACVR2A、FES、CDK6、ZAK、DUSP14、SGK1、JAK3、ULK2、PTPRJ、SPHK1、TNK2、PCTK1、MAP4K3、TGFBR1、HK1、DDR1、BMP2K、DUSP10、ALPK2、およびそれらの任意の組合せからなる群から選択される中期のTh17分化、維持および/または機能に関連するものとして表7に列記される標的遺伝子の1つ以上;
(d)HK2、ZAP70、NEK6、DUSP14、SH2D1A、ITK、DUT、PPP1R11、DUSP1、PMVK、TK1、TAOK3、GMFG、PRPS1、SGK1、TXK、WNK1、DUSP19、TEC、RPS6KA1、PKM2、PRPF4B、ADRBK1、CKB、ULK2、PLK1、PPP2R5A、PLK2、およびそれらの任意の組合せからなる群から選択される中期のTh17分化、維持および/または機能に関連するものとして表8に列記される標的遺伝子の1つ以上;ならびに
(e)CTLA4、CD200、CD24、CD5L、CD9、IL2RB、CD53、CD74、CAST、CCR6、IL2RG、ITGAV、FAS、IL4R、PROCR、GPR65、TNFRSF18、RORA、IL1RN、RORC、CYSLTR1、PNRC2、LOC390243、ADAM10、TNFSF9、CD96、CD82、SLAMF7、CD27、PGRMC1、TRPV2、ADRBK1、TRAF6、IL2RA、THY1、IL12RB2、TNFRSF9、およびそれらの任意の組合せからなる群から選択される中期のTh17分化、維持および/または機能に関連するものとして表9に列記される標的遺伝子の1つ以上
から選択する方法。 - 後期のTh17分化、維持および/または機能に関連する標的遺伝子の1つ以上をモジュレートする方法であって、前記標的遺伝子を、
(a)AES、AHR、ARID3A、ARID5A、ARNTL、ASXL1、ATF3、ATF4、BATF、BATF3、BCL11B、BCL3、BCL6、C21ORF66、CBFB、CBX4、CDC5L、CDYL、CEBPB、CHD7、CHMP1B、CIC、CITED2、CREB1、CREB3L2、CREM、CSDA、DDIT3、E2F1、E2F4、E2F8、EGR1、EGR2、ELK3、ELL2、ETS1、ETS2、EZH1、FLI1、FOSL2、FOXJ2、FOXO1、FUS、GATA3、GATAD2B、HCLS1、HIF1A、ID1、ID2、IFI35、IKZF4、IRF3、IRF4、IRF7、IRF8、IRF9、JARID2、JMJD1C、JUN、JUNB、KAT2B、KLF10、KLF6、KLF7、KLF9、LASS4、LEF1、LRRFIP1、MAFF、MAX、MEN1、MINA、MTA3、MXI1、MYC、MYST4、NCOA1、NCOA3、NFE2L2、NFIL3、NFKB1、NMI、NOTCH1、NR3C1、PHF13、PHF21A、PML、POU2AF1、POU2F2、PRDM1、RARA、RBPJ、REL、RELA、RNF11、RORA、RORC、RUNX1、RUNX2、SAP18、SAP30、SATB1、SERTAD1、SIRT2、SKI、SKIL、SMAD2、SMAD4、SMAD7、SMARCA4、SMOX、SP1、SP100、SP4、SS18、STAT1、STAT3、STAT4、STAT5A、STAT5B、STAT6、SUZ12、TBX21、TFEB、TGIF1、TLE1、TP53、TRIM24、TRPS1、TSC22D3、UBE2B、VAV1、VAX2、XBP1、ZEB1、ZEB2、ZFP161、ZFP36L1、ZFP36L2、ZNF238、ZNF281、ZNF703、ZNRF1、ZNRF2、およびそれらの任意の組合せからなる群から選択される後期のTh17分化、維持および/または機能に関連するものとして表5に列記される標的遺伝子の1つ以上;
(b)IL7R、ITGA3、IL1R1、FAS、CCR5、CCR6、ACVR2A、IL6ST、IL17RA、DDR1、PROCR、IL2RA、IL12RB2、MYD88、BMPR1A、PTPRJ、TNFRSF13B、CXCR3、IL1RN、CXCR5、CCR4、IL4R、IL2RB、TNFRSF12A、CXCR4、KLRD1、IRAK1BP1、PVR、IL15RA、TLR1、ACVR1B、IL12RB1、IL18R1、TRAF3、IFNGR1、PLAUR、IL21R、IL23R、およびそれらの任意の組合せからなる群から選択される後期のTh17分化、維持および/または機能に関連するものとして表6に列記される標的遺伝子の1つ以上;
(c)PTPLA、PSTPIP1、TK1、PTEN、BPGM、DCK、PTPRS、PTPN18、MKNK2、PTPN1、PTPRE、SH2D1A、PLK2、DUSP6、CDC25B、SLK、MAP3K5、BMPR1A、ACP5、TXK、RIPK3、PPP3CA、PTPRF、PACSIN1、NEK4、PIP4K2A、PPME1、SRPK2、DUSP2、PHACTR2、DCLK1、PPP2R5A、RIPK1、GK、RNASEL、GMFG、STK4、HINT3、DAPP1、TEC、GMFB、PTPN6、RIPK2、PIM1、NEK6、ACVR2A、AURKB、FES、ACVR1B、CDK6、ZAK、VRK2、MAP3K8、DUSP14、SGK1、PRKCQ、JAK3、ULK2、HIPK2、PTPRJ、INPP1、TNK2、PCTK1、DUSP1、NUDT4、TGFBR1、PTP4A1、HK1、DUSP16、ANP32A、DDR1、ITK、WNK1、NAGK、STK38、BMP2K、BUB1、AAK1、SIK1、DUSP10、PRKCA、PIM2、STK17B、TK2、STK39、ALPK2、MST4、PHLPP1、およびそれらの任意の組合せからなる群から選択される後期のTh17分化、維持および/または機能に関連するものとして表7に列記される標的遺伝子の1つ以上;
(d)ZAP70、PFKP、NEK6、DUSP14、SH2D1A、INPP5B、ITK、PFKL、PGK1、CDKN1A、DUT、PPP1R11、DUSP1、PMVK、PTPN22、PSPH、TK1、PGAM1、LIMK2、CLK1、DUSP11、TAOK3、RIOK2、GMFG、UCKL1、PRPS1、PPP2R4、MKNK2、DGKA、SGK1、TXK、WNK1、DUSP19、CHP、BPGM、PIP5K1A、TEC、MAP2K1、MAPK6、RPS6KA1、PTP4A2、PKM2、PRPF4B、ADRBK1、CKB、ACP1、ULK2、CCRN4L、PRKCH、PLK1、PPP2R5A、PLK2、およびそれらの任意の組合せからなる群から選択される後期のTh17分化、維持および/または機能に関連するものとして表8に列記される標的遺伝子の1つ以上;
(e)CTLA4、TNFRSF4、CD44、PDCD1、CD200、CD247、CD24、CD5L、CCND2、CD9、IL2RB、CD53、CD74、ADAM17、BSG、CAST、CCR6、IL2RG、CD81、CD6、CD48、ITGAV、TFRC、ICAM2、ATP1B3、FAS、IL4R、CCR7、CD52、PROCR、GPR65、TNFRSF18、FCRL1、RORA、IL1RN、RORC、P2RX4、SSR2、PTPN22、SIGMAR1、CYSLTR1、LOC390243、ADAM10、TNFSF9、CD96、CAP1、CD82、SLAMF7、PLAUR、CD27、SIVA1、PGRMC1、SRPRB、TRPV2、NR1H2、ADRBK1、GABARAPL1、TRAF6、IL2RA、THY1、KDELR2、IL12RB2、TNFRSF9、SCARB1、IFNGR1、およびそれらの任意の組合せからなる群から選択される後期のTh17分化、維持および/または機能に関連するものとして表9に列記される標的遺伝子の1つ以上
から選択する方法。 - 対象における免疫応答を診断する方法であって、表1に列記されるものおよび表2に列記されるものから選択される1つ以上のシグネチャー遺伝子または1つ以上のシグネチャー遺伝子の1つ以上の産物の発現、活性および/または機能のレベルを検出すること、ならびに前記検出レベルを、シグネチャー遺伝子または遺伝子産物発現、活性および/または機能の対照レベルと比較することを含み、前記検出レベルと前記対照レベルとの差が、前記対象における免疫応答の存在を示す方法。
- 前記免疫応答が、自己免疫応答である、請求項84に記載の方法。
- 前記免疫応答が、炎症応答である、請求項84に記載の方法。
- 対象における免疫応答をモニタリングする方法であって、表1または表2に列記されるものから選択される1つ以上のシグネチャー遺伝子または1つ以上のシグネチャー遺伝子の1つ以上の産物の発現、活性および/または機能の第1のレベルを、第1の時点において検出すること、表1または表2に列記されるものから選択される前記1つ以上のシグネチャー遺伝子または1つ以上のシグネチャー遺伝子の1つ以上の産物の発現、活性および/または機能の第2のレベルを、第2の時点において検出すること、ならびに発現、活性および/または機能の前記第1の検出レベルと、発現、活性および/または機能の前記第2の検出レベルとを比較することを含み、前記第1および第2の検出レベルの変化が、前記対象における前記免疫応答の変化を示す方法。
- 前記免疫応答が、自己免疫応答である、請求項87に記載の方法。
- 前記免疫応答が、炎症応答である、請求項87に記載の方法。
- 対象における免疫応答をモニタリングする方法であって、T細胞の集団を前記対象から第1の時点において単離すること、前記T細胞集団内のT細胞サブタイプの第1の比を第1の時点において決定すること、T細胞の集団を前記対象から第2の時点において単離すること、前記T細胞集団内のT細胞サブタイプの第2の比を第2の時点において決定すること、ならびにT細胞サブタイプの前記第1および第2の比を比較することを含み、前記第1および第2の検出比の変化が、前記対象における前記免疫応答の変化を示す方法。
- 前記第1の比および前記第2の比が、前記第1および第2のT細胞集団中のTh17細胞のレベルと非Th17細胞との比較を含む、請求項90に記載の方法。
- 前記非Th17細胞が、制御性T細胞(Treg)である、請求項90に記載の方法。
- 前記第1の比および前記第2の比が、前記第1および第2のT細胞集団中の病原性Th17細胞のレベルと非病原性Th17細胞との比較を含む、請求項90に記載の方法。
- 前記免疫応答が、自己免疫応答である、請求項90に記載の方法。
- 前記免疫応答が、炎症応答である、請求項90に記載の方法。
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WO2014134351A2 (en) | 2014-09-04 |
CA2902940A1 (en) | 2014-09-04 |
KR20150126882A (ko) | 2015-11-13 |
US10822587B2 (en) | 2020-11-03 |
RU2015140941A3 (ja) | 2018-03-06 |
EP2961849A2 (en) | 2016-01-06 |
RU2015140941A (ru) | 2017-03-30 |
CN105593373A (zh) | 2016-05-18 |
WO2014134351A3 (en) | 2014-12-31 |
US20150361396A1 (en) | 2015-12-17 |
AU2014223344A1 (en) | 2015-10-01 |
IL240881A0 (en) | 2015-10-29 |
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