JP2008514187A - 先天性免疫応答及び自己免疫疾患の阻害法及び阻害用組成物 - Google Patents
先天性免疫応答及び自己免疫疾患の阻害法及び阻害用組成物 Download PDFInfo
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Abstract
Description
本出願は、2004年9月1日に出願された米国仮特許出願第60/606,833号の利益を主張する。当該文献をその全てについて本明細書に援用する。
i. 式:X1GGGGX2X3(配列番号 )[式中、X1、X2、及びX3はヌクレオチドである。但し、X1=C又はAである場合、X2X3はAAではない]で表されるヌクレオチド配列を含むオリゴヌクレオチド;
ii. ヌクレオチド配列:5'-TGCNm-3'[式中、各Nはヌクレオチドであり、mは5〜約50の整数であり、そして配列N1-Nmは少なくとも1のGCジヌクレオチドを含む]からなるオリゴヌクレオチド;又は
iii. ヌクレオチド配列:TGCNmTCCTGGAGGGGTTGT-3'(配列番号 )[式中、各Nはヌクレオチドであり、そしてmは0〜約100の整数である]を含むオリゴヌクレオチド
を含むキットであって、当該オリゴヌクレオチドが適切な容器内に存在し、そして当該キットが個体を免疫調節する際にオリゴヌクレオチドを使用するための取扱説明書を含む、前記キットが本明細書において提供される。
本発明の実施にあたり、他に記載がない限り、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学、及び免疫学の慣用技術を利用するであろう。これらは当該技術分野の範囲内である。かかる技術は、Molecular Cloning: A Laboratory Manual、第二版(Sambrookら、1989); Oligonucleotide Synthesis (MJ. Gait編, 1984); Animal Cell Culture (R.I. Freshney編, 1987); Handbook of Experimental Immunology (D. M. Weir & CC. Blackwell編); Gene Transfer Vectors for Mammalian Cells (J. M. Miller & M. P. Calos編, 1987); Current Protocols in Molecular Biology (F. M. Ausubelら編, 1987); PCR: The Polymerase Chain Reaction, (Mullisら編、1994); Current Protocols in Immunology (J. E. Coliganら編, 1991 ); The Immunoassay Handbook (D. Wild,編、Stockton Press NY, 1994); Bioconjugate Techniques(Greg T. Hermanson編、Academic Press, 1996);及びMethods of Immunological Analysis (R. Masseyeff, W. H. Albert及びN. A. Staines編, Weinheim: VCH Verlags gesellschaft mbH, 1993)などの文献に十分に説明されている。
単数形「a」、「an」、及び「the」は、他に記載がない限り複数形を含む。例えばIRP(「an IRP」)は、1以上のIRPを含む。
本発明は、個体における先天性免疫応答を調節するための免疫調節配列(IRS)、免疫調節ポリヌクレオチド(IRP)、及び免疫調節化合物(IRC)を提供する。本発明の各IRP及びIRCは、少なくとも1のIRSを含む。
本発明に従って、IRP又はIRCは、少なくとも1の免疫調節配列を含む。ある場合では、免役調節配列(IRS)は5'-G,C-3'配列を含む。ある場合では、IRSは、当該ポリヌクレオチドの5'末端又はその付近で、少なくとも1のTGCトリヌクレチド配列を含む(つまり、5'-TGC)。ある場合では、IRSは、5'-GGGG-3'配列を含む。ある場合では、IRSは5'-GGGG-3'配列を含まない。従って、ある場合では、IRP又はIRCは5'-GGGG-3'配列を含まない。ある場合では、5'-GGGG-3'配列を含むIRP又はIRCは、一本鎖形態において使用されるとき特に有効である。ある場合では、5'-GGGG-3'配列を含むIRP又はIRCは、ホスホチオエート骨格を用いて作成される場合に特に有効である。
N1-S1-N2 (I)
N1-S1-N2-S2-N3 (II)
N1-S1-N2-S2-[Nv-Sv]A (III)
[式中、Aは1〜約100の間の整数であり、そして[Nv-Sv]は、非核酸スペーサー部分に結合された核酸部分のA個のさらなる繰り返しを示す。下付きの「v」は、N及びSが「[Nv-Sv]の各反復のうちから独立して選ばれるということを指し、「A」はある場合1〜約10、ある場合1〜3、ある場合丁度1、2、3、4、又は5である]
に合致する。幾つかの実施態様において、Aは1、2、3、4、又は5の下限と、10、20、50、又は100から独立して選ばれる上限により定義される範囲内の整数である(例えば、3〜10)。
[Nv]A---Sp (IV)
[Sv-Nv]A---Sp (V)
(S1-N1)-Sp--(Nv)A (VI)
[式中、Spは、「A」の数量の独立して選択された核酸部分Nv又は(核酸部分に共有結合されたスペーサー部分を含む)Sv-Nvに共有結合された多価スペーサーである]
に記載される。式IV及びVでは、Aは少なくとも3である。式IV及びVの様々な実施態様では、Aは3〜100(を含めた)整数であるが、Aは約3、5、10、50、又は100の下限と、約5、7、10、50、100、150、200、250、又は500から独立して選択される上限により定義される範囲内の整数であってもよく、或いは、Aは500を超えてもよい。式VIでは、Aは少なくとも2であり、2、5、10、50、又は100の下限と5、10、50、100、150、200、250、又は500のうちから独立して選択される上限により定義される範囲の整数であり、或いは500を超える整数であってもよい。
(N1)2-グリセロール-N1 (IVa)
(N2-HEG)2-グリセロール-N1 (IVb)
(N1-HEG-N2)2-グリセロール-N1 (IVc)
[(N1)2-グリセロール-N1]2-グリセロール-N1 (IVd)
を含む。
N1-S1 (VII)
を含む。
N1-(HEG)15 (VIIa)
N1-HEG-プロピル-HEG-プロピル-HEG (VIIb)
を含む。
(C3)15は、ホスホロチオエート・エステルを介して結合される15個のプロピルリンカーを意味し;(グリセロール)15は、ホスホロチオエート・エステルを介して結合される15個のグリセロール・リンカーを意味し;(TEG)8は、ホスホロチオエート・エステルを介して結合された8個のトリエチレングリコール・リンカーを意味し;そして(HEG)4は、ホスホロチオエート・エステルを介して結合された4個のヘキサエチレングリコール・リンカーを意味する]
を含む。あるマルチユニットのスペーサーが正味として負電荷を有すること、そして当該負電荷を、例えばエステル結合モノマーユニットの数を増加させることにより増加させることができるということが認められよう。
a)固体支持体に3'-で結合されたヌクレオシド又は核酸の5'-水酸基から保護基を取り除き、
b)活性化ヌクレオシド・ホスホロアミダイトを、当該5'-水酸基に結合させ、
c)ホスファイト・トリエステルを酸化してホスフェート・トリエステルに酸化し、そして
d)未反応の5'-水酸基をキャッピングする
を繰り返し反復することにより一般的に合成される。ホスホロチオエート結合を含むDNA又はRNAは、酸化ステップが硫化ステップに置き換えられることを除いて、上に記載される様に製造される。所望されるオリゴヌクレオチド配列が合成された場合、当該オリゴヌクレオチドは、支持体から外され、ホスフェート・トリエステル基を、ホスフェートジエステルに脱保護し、そしてアンモニア水又は他の塩基を用いて当該ヌクレオシド塩基を脱保護する。例えば、Beaucage (1993) "Oligodeoxyribonucleotide Synthesis" in PROTOCOLS FOR OLIGONUCLEOTIDES AND ANALOGS, SYNTHESIS AND PROPERTIES (Agrawal編) Humana Press, Totowa, NJ;Warnerら、(1984) DNA 3:401 ;Tangら、(2000) Org. Process Res. Dev. 4: 194- 198;Wyrzykiewicaら、(1994) Bioorg. & Med. Chem. Lett. 4: 1519-1522;Radhakrishnaら、(1989) J. Org. Chem. 55:4693-4699;及び米国特許第4,458,066号を参照のこと。合成配列の核酸部分を自動的に合成するプログラム可能な機械が広く使用されている。例として、Expedite 8909自動化DNA合成機(Perseptive Biosystem, Framington MA); ABI 394 (Applied Biosystems, Inc., Foster City, CA);及びOligoPilot II(Amersham Pharmacia Biotech, Piscataway, NJ)が挙げられる。
R1S(CH2CH2O)nCH2CH2O(CH2)mCO2R2
[式中、n=0〜200、m=1又は2、R1=H又は保護基、例えばトリチル、R2=H又はアルキル又はアリールである]
を有するリンカー、例えば4-ニトロフェニルエステルを含む。これらのリンカーは、チオール反応基、例えば、ハロアセイル(haloaceyl)、マレイアミド(maleiamide)などを含む分子を、アミド結合を介してアミノ基を含む第二分子へとチオエーテルを介して結合させるのに有用である。結合の順番を変化させることができ、つまり、チオエーテル結合は、アミド結合が形成された後又は前に形成されてもよい。他の有用なリンカーは、Sulfo-SMCC(スルホスクシンイミジル4-[N-マレイミドメチル]-シクロヘキサン-1-カルボキシラート)Pierce Chemical Co. 製品番号22322; Sulfo-EMCS(N-[ε-マレイミドカプロイルオキシル・スルホスクシンイミド・エステル) Pierce Chemical Co.製品番号22307; Sulfo-GMBS(N-[γ-マレイミドブチリルオキシ]スルホスクシンイミド・エステル)Pierce chemical co.製品番号22324(Pierce Chemical Co., Rockford, IL)、及び一般式:マレイミド-R-C(O)NHSエステル[式中、R=アルキル、環状アルキル、エチレングリコールのポリマーなど]の類似の化合物を含む。
IRP又はIRCは、個体に直接投与することができるか、又はそれらは、細胞へのIRP又はIRCデリバリー及び/又は細胞による取り込みを高めるために組成物又は複合体中で投与することができる。組成物又は複合体は、2以上の異なるIRP及び/又はIRC種を細胞に共デリバリーすることを高めるために使用することができる。ある実施態様では、IRCとIRPの混合物は、少なくとも1のIRC及びIRP種をデリバリーするために複合体形成されてもよい。かかるデリバリー組成物又は複合体は、非限定的に、本明細書に記載され、そして当該技術分野に知られている封入複合体及びコロイド様分散システムを含む。かかるデリバリー組成物は、水中油型乳濁液、ミセル、及びリポソームを含む。デリバリー組成物又は複合体は、本明細書に記載される様に、リンカー分子に結合されたIRP及び/又はIRC、プラットホーム分子、ナノ粒子又はマイクロ粒子を含む。かかる結合は、両方とも共有及び非共有結合を含む。他に記載がない限り、IRPについて使用するため本明細書に開示される複合体及び組成物は、IRCに関して使用するのに適している。
本発明は、個体、好ましくは哺乳動物、より好ましくはヒトにおいて免役応答を調節する方法であって、当該個体に本明細書に記載されるIRS含有ポリヌクレオチドを投与することを含む、前記方法を提供する。本発明により提供される免役調節方法は、非限定的に、免役刺激性核酸分子、例えば細菌DNAにより刺激される免役応答を抑制及び/又は阻害する方法を含む。本発明はまた、TLR7/8及び/又はTLR9誘導性の細胞応答を阻害する方法を提供する。本発明は、非限定的に自己免疫に関連する症候を含む、不所望の免役活性に付随する症候を改善するための方法を提供する。
IRP又はIRCは、本明細書に記載されるように他の医薬品と組み合わせて投与することができ、そして生理的に許容されるその担体と組み合わせることができる(及びその様なものとして本発明はこれらの組成物を含む)。IRP又はIRCは、本明細書に記載されるもののいずれであってもよい。
本発明はキットを提供する。ある実施態様では、本発明のキットは、一般的に本明細書に記載される任意のIRP及び/又はIRCを含む1以上の容器を含む。当該キットは、さらに、本明細書に記載される方法のいずれか(例えば、免役刺激核酸に応答する抑制、TLR-7/8及び/又はTLR-9依存性応答の抑制、自己免疫疾患の1以上の症状の改善、慢性炎症性疾患の症状の改善、ウイルスに応答したサイトカイン産生の低下)についてIRP及び/又はIRCを使用することに関する適切な使用説明のセット、一般的に書面の使用説明書を含む。
免役調節ポリヌクレオチド(IRP)(つまり、少なくとも1のIRSを含むポリヌクレオチド)又は対照サンプルを、ヒト及びマウス細胞において先天性免役応答の免役調節(IR)活性についてアッセイした。IR活性を、サイトカイン応答、細胞成熟、及び細胞増殖を含む先天性免役応答の幾つかの指標を測定することによりアッセイした。他に記載がない限り、試験されたポリヌクレオチドは、完全に改変されたホスホロチオエートオリゴデオキシヌクレオチドであった。
本明細書に記載されるように、IRPは、TLR-9シグナル伝達に関連する活性又は応答を阻害する。IRP活性並びにTLR-9及び他のTLRに関連する活性又は応答をさらに調査するために、実験を行った。
一連の実験において、マウス脾臓細胞は、様々なIRP又は対照オリゴヌクレオチドと共に、R848(TLR7/8シグナル伝達)又はISNA配列番号75(1018)(TLR-9シグナル伝達)のいずれかで刺激した。表1は、2回の実験からの結果を含む。与えられた値は、R848単独でのIL-6応答に比較した、IRP又は対照オリゴヌクレオチドの存在下でのIL-6応答の割合である。
マウス脾臓細胞を、ISNA配列番号75(1018)(0.7μM)又はR848(1μM)単独で、及びIRP配列番号17(869)、IRP配列番号27(661)、IRP配列番号52(954)の増加量と共に活性化した。図16A-16Bに記載されるように、IRP配列番号17(869)及びIRP配列番号52(954)は、ISNA配列番号75(1018)に応答したIL-6産生の強力な阻害剤であり、一方IRP配列番号27(661)及びIRP配列番号52(954)は、R848の活性化の強力な阻害剤である。
配列番号 DV019:5'-TGCTCCTGGAGGGGTTG
配列番号 DV020:5'-TGCTCCTGGAGGGGTT
配列番号 DV021:5'-TGCTCCTGGAGGGGT
配列番号 DV022:5'-TGCTCCTGGAGGGG
配列番号 DV023:5'-TGCTCCTGGAGGG
配列番号 DV024:5'-TGCTCCTGGAGG
である。
Claims (43)
- 以下の式:
X1GGGGX2X3(配列番号 )
[式中、X1、X2、及びX3はヌクレオチドである。但し、X1=C又はAである場合、X2X3はAAではない]
で表されるヌクレオチド配列を含むオリゴヌクレオチド。 - X1がC又はAである、請求項1に記載のオリゴヌクレオチド。
- 以下の式:
GGNmX1GGGGX2X3(配列番号 )
[式中、
mは1〜約100又は1〜約20の整数であり、
各Nはヌクレオチドであり、そして
X1、X2、及びX3がヌクレオチドである。
但し、X1=C又はAである場合、X2X3はAAではない]
で表されるヌクレオチド配列を含む、請求項1に記載のオリゴヌクレオチド。 - X1がC又はAである、請求項3に記載のオリゴヌクレオチド。
- 以下の式:
NiTCCNj(GG)kNmX1GGGGX2X3(配列番号 )
[式中、
各Nはヌクレオチドであり、
iは1〜約50の整数であり、
jは1〜約50の整数であり、
kは0又は1であり、
mは1〜約20の整数であり、
X1、X2、及びX3はヌクレオチドである。
但し、X1=C又はAである場合、X2X3はAAではない]
で表されるヌクレオチド配列を含むオリゴヌクレオチド。 - X1がC又はAである、請求項5に記載のオリゴヌクレオチド。
- 以下の式:
X1X2X3GGGGAA(配列番号 )
[式中、
X1、X2、及びX3はヌクレオチドである。
但し、X3=C又はAである場合、X1X2は、GGではない]
で表されるヌクレオチド配列を含む、オリゴヌクレオチド。 - 少なくとも1のGがZ'により置き換えられ、ここでZ'=7-デアザGである、請求項1に記載のオリゴヌクレオチド。
- 少なくとも1のGがZ'により置き換えられ、ここでZ'=7-デアザGである、請求項3に記載のオリゴヌクレオチド。
- 少なくとも1のGがZ'により置き換えられ、ここでZ'=7-デアザGである、請求項5に記載のオリゴヌクレオチド。
- 少なくとも1のGがZ'により置き換えられ、ここでZ'=7-デアザGである、請求項7に記載のオリゴヌクレオチド。
- 以下の配列:
5'-TGCTTGCAAGCTTGCAAGCA-3'(配列番号 (C661) 又は当該配列の断片であって、少なくとも10塩基のパリンドローム部分を含む断片を含むオリゴヌクレオチド。 - 以下の:
5'-TGCNm-3'
[式中、
Nはヌクレオチドであり、
mは5〜約50の整数であり、そして
配列N1〜Nmは、少なくとも1のGCジヌクレオチドを含む]
で表されるヌクレオチド配列からなるオリゴヌクレオチド。 - ヌクレオチド配列:5'-TGCNmA-3'からなる、請求項13に記載のオリゴヌクレオチド。
- ヌクレオチド配列:5'-TGCNmCA-3'からなる、請求項13に記載のオリゴヌクレオチド。
- ヌクレオチド配列:5'-TGCNmGCA-3'からなる、請求項13に記載のオリゴヌクレオチド。
- 以下のヌクレオチド配列:
TGCNmTCCTGGAGGGGTTGT-3'(配列番号 )
[式中、
各Nはヌクレオチドであり、そして
mは0〜約100の整数である]
を含むオリゴヌクレオチド。 - 前記配列N1-Nmが、配列:5'-TTGACAGCTTGACAGCA-3'(配列番号 )の断片を含む、請求項17に記載のオリゴヌクレオチド。
- 以下のヌクレオチド配列:
5'-TGCRRZNYY-3'(配列番号 )
[式中、
ZはCを除く任意のヌクレオチドであり、
Nは任意のヌクレオチドであり、そして
さらにここで、ZがG又はイノシンでない場合、Nはグアノシン又はイノシンである]
を含むオリゴヌクレオチド。 - 以下のヌクレオチド配列:
5'-TGCRRZNYm-3'(配列番号 )
[式中、
ZはCを除く任意のヌクレオチドであり、
Nは任意のヌクレオチドであり、
Yはピリミジンヌクレオチドであり、
mは2〜100の整数であり、そして
ここで、ZがG又はイノシンでない場合、Nはグアノシン又はイノシンである]
を含むオリゴヌクレオチド。 - 免疫系の細胞を請求項1に記載のオリゴヌクレオチドと接触させることを含む免役応答の阻害方法であって、当該細胞を免役応答に寄与する細胞からの応答を阻害するために有効な量の当該オリゴヌクレオチドと接触させる、前記方法。
- 個体において免疫応答を調節する方法であって、個体における免役応答を調節するために十分な量の請求項1に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 個体において免疫応答を調節する方法であって、個体において免役応答を調節するために十分な量の請求項13に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 個体において免疫応答を調節する方法であって、個体において免役応答を調節するために十分な量の請求項17に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 個体においてTLR7/8依存性先天性免役応答を阻害する方法であって、個体においてTLR7/8依存性サイトカイン産生を抑制するために十分な量の請求項13に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 個体においてTLR9依存性先天性免役応答を阻害する方法であって、個体においてTLR9依存性サイトカイン産生を抑制するために十分な量の請求項1に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 個体においてTLR9依存性先天性免役応答及びTLR7/8依存性先天性免役応答を阻害する方法であって、個体においてTLR9依存性サイトカイン産生及びTLR7/8依存性サイトカイン産生を抑制するために十分な量の請求項13に記載のオリゴヌクレオチドを当該個体に投与することを含む、前記方法。
- 自己免疫疾患の1以上の症状を改善する方法であって、請求項1に記載のオリゴヌクレオチドの有効量を自己免疫疾患を患う個体に投与することを含む、前記方法。
- 前記自己免疫疾患が、全身性エリテマトーデス(SLE)及びリューマチ様関節炎からなる群から選ばれる、請求項28に記載の方法。
- 自己免疫疾患の1以上の症状を改善する方法であって、請求項13に記載のオリゴヌクレオチドを、自己免疫疾患を患う個体に投与することを含む、前記方法。
- 前記自己免疫疾患が、SLE及びリューマチ様関節炎からなる群から選ばれる、請求項30に記載の方法。
- 請求項17に記載のオリゴヌクレオチドの有効量を、自己免疫疾患を患う個体に投与することを含む、自己免疫疾患の1以上の症状を改善する方法。
- 前記自己免疫疾患が、全身性エリテマトーデス(SLE)及びリューマチ様関節炎からなる群から選ばれる、請求項32に記載の方法。
- 自己免疫疾患の発達を予防又は遅延する方法であって、請求項1に記載のオリゴヌクレオチドの有効量を、自己免疫疾患を発達させるリスクのある個体に投与することを含む、前記方法。
- 自己免疫疾患の発達を予防又は遅延する方法であって、請求項13に記載のオリゴヌクレオチドの有効量を、自己免疫疾患を発達させるリスクのある個体に投与することを含む、前記方法。
- 自己免疫疾患の発達を予防又は遅延する方法であって、請求項17に記載のオリゴヌクレオチドの有効量を、自己免疫疾患を発達させるリスクのある個体に投与することを含む、前記方法。
- 炎症性疾患又は障害の1以上の症状を改善する方法であって、当該方法が、請求項1に記載のオリゴヌクレオチドの有効量を、炎症性疾患又は障害を患う個体に投与することを含む、前記方法。
- 炎症性疾患又は障害の1以上の症状を改善する方法であって、当該方法が、請求項13に記載のオリゴヌクレオチドの有効量を、炎症性疾患又は障害を患う個体に投与することを含む、前記方法。
- 炎症性疾患又は障害の1以上の症状を改善する方法であって、当該方法が、請求項17に記載のオリゴヌクレオチドの有効量を、炎症性疾患又は障害を患う個体に投与することを含む、前記方法。
- 請求項1に記載のオリゴヌクレオチドの有効量を、慢性病原体感染又は疾患を患う個体に投与することを含む、慢性病原体刺激を抑制する方法。
- 適切な容器中に請求項1に記載のオリゴヌクレオチドを含み、そして個体の免役調節において当該オリゴヌクレオチドを使用するための説明書を含むキット。
- 適切な容器中に請求項13に記載のオリゴヌクレオチドを含み、そして個体の免役調節においてオリゴヌクレオチドを使用するための説明書を含むキット。
- 適切な容器中に請求項17に記載のオリゴヌクレオチドを含み、そして個体の免役調節においてオリゴヌクレオチドを使用するための説明書を含むキット。
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WO2006028742A2 (en) | 2006-03-16 |
KR20070047837A (ko) | 2007-05-07 |
CN101052643A (zh) | 2007-10-10 |
US20150050296A1 (en) | 2015-02-19 |
CN101052643B (zh) | 2016-01-06 |
CA2578775C (en) | 2016-05-03 |
AU2012203156B2 (en) | 2012-09-20 |
ES2543207T3 (es) | 2015-08-17 |
ES2385657T3 (es) | 2012-07-27 |
NZ553581A (en) | 2011-04-29 |
AU2005282889A1 (en) | 2006-03-16 |
EP1794174B1 (en) | 2012-06-06 |
DK1794174T3 (da) | 2012-07-09 |
PT1794174E (pt) | 2012-08-16 |
WO2006028742A8 (en) | 2006-08-24 |
PL1794174T3 (pl) | 2012-11-30 |
SI1794174T1 (sl) | 2012-09-28 |
US8759305B2 (en) | 2014-06-24 |
JP2012191939A (ja) | 2012-10-11 |
US20070238678A1 (en) | 2007-10-11 |
EP2305693B1 (en) | 2015-07-15 |
AU2005282889B2 (en) | 2012-03-15 |
EP2305693A1 (en) | 2011-04-06 |
HK1156039A1 (zh) | 2012-06-01 |
WO2006028742A3 (en) | 2006-10-12 |
KR101268877B1 (ko) | 2013-05-31 |
AU2012203156A1 (en) | 2012-06-21 |
EP1794174A2 (en) | 2007-06-13 |
CA2578775A1 (en) | 2006-03-16 |
JP5775024B2 (ja) | 2015-09-09 |
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