JP2006193534A - ポリエピトープキャリアタンパク質 - Google Patents
ポリエピトープキャリアタンパク質 Download PDFInfo
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- JP2006193534A JP2006193534A JP2006104679A JP2006104679A JP2006193534A JP 2006193534 A JP2006193534 A JP 2006193534A JP 2006104679 A JP2006104679 A JP 2006104679A JP 2006104679 A JP2006104679 A JP 2006104679A JP 2006193534 A JP2006193534 A JP 2006193534A
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Abstract
【解決手段】少なくとも5つのCD4+ T細胞エピトープを含む、キャリアタンパク質であって、一実施形態においては、上記CD4+エピトープが、病原性の細菌またはウイルスに由来し、さらなる実施形態においては、上記CD4+エピトープが、破傷風トキシン、Plasmodium falciparumサーカムスポロザイトタンパク質、B型肝炎表面抗原、B型肝炎核コアタンパク質、インフルエンザマトリックスタンパク質、インフルエンザ赤血球凝集素、ジフテリアトキソイド、ジフテリアトキシン変異体CRM 197、B群Neisseria meningitidis外膜タンパク質複合体、百日咳トキシンまたは熱ショックタンパク質70由来である、キャリアタンパク質。
【選択図】なし
Description
・(項目1) 少なくとも5つのCD4+ T細胞エピトープを含む、キャリアタンパク質。
・(項目2) 上記CD4+エピトープが、病原性の細菌またはウイルスに由来する、項目1に記載のキャリアタンパク質。
・(項目3) 上記CD4+エピトープが、破傷風トキシン、Plasmodium falciparumサーカムスポロザイトタンパク質、B型肝炎表面抗原、B型肝炎核コアタンパク質、インフルエンザマトリックスタンパク質、インフルエンザ赤血球凝集素、ジフテリアトキソイド、ジフテリアトキシン変異体CRM 197、B群Neisseria meningitidis外膜タンパク質複合体、百日咳トキシンまたは熱ショックタンパク質70由来である、項目1または2に記載のキャリアタンパク質。
・(項目4) 上記CD4+エピトープが、P23TT、P32TT、P21TT、PfC、P30TT、P2TT、HBVnc、HA、HbsAg、MTおよびhsp70 CD4+のエピトープから選択される、項目1〜3のいずれか1項に記載のキャリアタンパク質。
・(項目5) P23TT、P32TT、P21TT、PfC、P30TT、P2TT、HBVnc、HA、HbsAgおよびMT CD4+のエピトープを含む、項目1に記載のキャリアタンパク質。
・(項目6) P23TT、P32TT、P21TT、PfC、P30TT、P2TT、HBVnc、HA、HbsAg、MTおよびhsp70 CD4+のエピトープを含む、項目1に記載のキャリアタンパク質。
・(項目7) P23TT、P32TT、P21TT、PfC、P30TTおよびP2TT CD4+のエピトープを含む、項目1に記載のキャリアタンパク質。
・(項目8) 上記CD4+エピトープが、ヒトCD4+エピトープである、項目1〜7のいずれか1項に記載のキャリアタンパク質。
・(項目9) 1以上のN6、N10またはN19タンパク質を含む、キャリアタンパク質。
・(項目10) オリゴマー形態である、項目1〜9のいずれか1項に記載のキャリアタンパク質。
・(項目11) 多糖に結合体化されている、項目1〜10のいずれか1項に記載のキャリアタンパク質。
・(項目12) 上記多糖が、Haemophilus influenzae B型多糖である、項目11に記載のキャリアタンパク質
・(項目13) 上記多糖が、以下の生物:S.pneumoniae、N.meningitidis、S.aureus、KlebsiellaまたはS.typhimuriumのいずれか1つに由来する、項目11に記載のキャリアタンパク質。
・(項目14) 上記多糖が、共有結合によってタンパク質に結合体化されている、項目11〜13のいずれか1項に記載のキャリアタンパク質。
・(項目15) 上記多糖が、還元的アミノ化によってタンパク質に結合体化されている、項目11〜13のいずれか1項に記載のキャリアタンパク質。
・(項目16) 各多糖単位について2と10との間のタンパク質単位が存在する、項目11〜15のいずれか1項に記載のキャリアタンパク質。
・(項目17) 医薬として使用するための、項目1〜16のいずれか1項に記載のキャリアタンパク質。
・(項目18) 項目1〜16のいずれか1項に記載のキャリアタンパク質の医薬としての使用。
・(項目19) ワクチンまたはワクチンの成分としての使用のための、項目1〜16のいずれか1項に記載のキャリアタンパク質。
・(項目20) 項目1〜16のいずれか1項に記載のキャリアタンパク質の、ワクチンまたはワクチンの成分としての使用。
・(項目21) 項目1〜16のいずれか1項に記載のキャリアタンパク質を含む、ワクチン。
・(項目22) ワクチン接種の生成方法であって、哺乳動物、好ましくはヒトに項目1〜16のいずれか1項に記載のキャリアタンパク質を導入する工程を包含する、方法。
・(項目23) 莢膜形成細菌により引き起こされる疾患の制御における、防御免疫原としての使用のための、項目1〜16のいずれか1項に記載のキャリアタンパク質。
・(項目24) 項目1〜10のいずれか1項に記載のキャリアタンパク質をコードする、核酸分子。
・(項目25) DNAを含む、項目24に記載の核酸分子。
・(項目26) 項目24または項目25のいずれかに記載の核酸分子を含む、クローニングベクターまたは発現ベクター。
・(項目27) 項目26に記載のベクターで形質転換またはトランスフェクトされた、宿主細胞。
・(項目28) 項目24もしくは項目25のいずれかに記載の核酸分子、または項目26に記載のベクターによって形質転換された、トランスジェニック動物。
・(項目29) 項目1〜10のいずれか1項に記載のキャリアタンパク質の調製方法であって、項目26に記載のベクターを、宿主細胞において発現させる工程、および上記宿主細胞を上記タンパク質が発現される条件下で培養する工程、およびこのようにして発現された上記タンパク質を回収する工程を包含する、方法。
・(項目30) 項目1〜10のいずれか1項に記載のキャリアタンパク質の生成方法であって、以下の工程:
a)ペプチドエピトープをコードするオリゴヌクレオチド分子を構築する工程;
b)上記オリゴヌクレオチド分子をアニーリングさせて二重鎖を形成させる工程;
c)上記オリゴヌクレオチド二重鎖を、融合タンパク質をコードするように発現ベクター中に導入する工程;
d)上記発現ベクターを宿主細胞中に導入して、上記融合タンパク質の発現を可能にする工程;および
e)上記宿主細胞の培養物から生成される上記融合タンパク質を単離する工程、
を包含する、方法。
・(項目31) 上記融合タンパク質を多糖に結合体化させる工程をさらに含む、項目30に記載の方法。
・(項目32) 上記宿主細胞が、E.coli細菌である、項目29に記載の方法。
T細胞エピトープを含むべきである。好ましくは、このポリエピトープキャリアタンパク質は、5と50との間の縮重CD4+ T細胞エピトープ、より好ましくは5と20との間のエピトープ、さらにより好ましくは5、6、7、8、9、10、11または19の縮重CD4+ T細胞エピトープを含む。キャリアタンパク質における多数の普遍エピトープの使用は、ペプチド抗原に対して生じる免疫応答の遺伝的制限の問題を低減させることが見出されている。
Manual]。
J.3:2437]およびE.coliアルカリホスファターゼシグナル配列(phoA)[Okaら(1985)Proc.Natl.Acad.Sci.82:7212])に由来し得る。さらなる例として、種々のBacillus株由来のα−アミラーゼ遺伝子のシグナル配列が、B.subtilis由来の異種タンパク質を分泌するために使用され得る[Palvaら(1982)Proc.Natl.Acad.Sci.USA 79:5582;EPO公開第244 042号]。
(a)ペプチドエピトープをコードするオリゴヌクレオチド分子を構築する工程;
(b)このオリゴヌクレオチド分子をアニールさせて、二重鎖を形成する工程;
(c)融合タンパク質をコードするように、オリゴヌクレオチド二重鎖を発現ベクターに導入する工程;
(d)細菌宿主細胞にこの発現ベクターを導入して、融合タンパク質の発現を可能にする工程;
(e)生成された融合タンパク質をこの細菌の培養物から単離する工程。
(材料および方法)
(標準的な手順および技術の要旨)
本発明の実施は、他に示されない限り、当該分野の技術範囲内である、分子生物学、微生物学、組換えDNA、および免疫学の従来の技術を使用する。このような技術は、例えば、以下の文献に完全に説明される;Sambrook Molecular Cloning:A Labiratiry Manual,第2版(1989);DNA Cloning,第I巻および第II巻(D.N
Gloverら編、1985);Oligonulcleotide Synthesis(M.J.Gait編、1984);Nucleic Acid Hybridization(B.D.HamesおよびS.J.Higgins編、1984);Transcription and Translation(B.D.HamesおよびS.J.Higgins編、1984);Animal Cell Culuture(R.I.Freshney編、1986);Immobilised Cells and Enzymes(IRL Press,1986);B.Perbal,A Practical Guide to Molecular Cloning(1984);the Methods in Enzymologyシリーズ(Academic Press,Inc.)(特に第154巻および155巻);Gene Transfer Vectors for Mammalian Cells(J.H.MillerおよびM.P.Calos編、1987、Cold Spring Harbor Laboratory);MayerおよびWalker編(1987)、Immunochemical Methods in Cell and Molecular Biology(Academic Press,London);Scopes,(1987)Protein Purfication:Principles and Practice,第2版(Springer−Verlag,N.Y.)、ならびにHandbook of Experimental Immunology,第I〜IV巻(D.M.WeirおよびC.C.Blackwell編、1986)。
PEMBLex2プラスミドは、pEMBL8M(Dente L.およびCortese R,Meth.Enzymol.(1987),155:111−9)のEcoRI部位およびHindIII部位にλPLプロモーターおよびポリリンカーを挿入することによって、得られた。市販のベクターpTrc−HisおよびpQE30は、それぞれ、InvitrogenおよびQiagenから購入した。上記プラスミドのレシピエントとして使用したE.coli株は、pEMBLex2についてはK12ΔH1ΔTrp、pTrc−HisについてはTOP10、およびpQE30についてはTG1であった。
P2TT、P21TT、P23TT、P30TT1、P32TTおよびPfT3 T細胞エピトープ(表1)ならびにFlagペプチドをコードする相補的なオリゴデオキシリボヌクレオチド対は、DNA合成器ABI394(Perkin Elmer)およびCruachem(Glasgow,Scotland)から購入した試薬を使用して合成した。オリゴ対を、T4 DNAリガーゼ緩衝液(Boehringer Mannheim)中で別々にアニールし、そして等量の各々のアニーリング反応液を混合して、そしてT4 DNAリガーゼ(Boehringer Manheim)を使用して、3時間、室温で連結した。
合成オリゴデオキシリボヌクレオチドおよび標準的なクローニング技術(Sambrookら、1989)を使用して、4つのさらなるCD4+T細胞エピトープをN6タンパク質に付加した:HBVnc、HA、HbsAg、およびMT(表1)。HBVncおよびHAを、引き続いて2つの継続的なクローニング工程によってpTrc−N6に導入し;生じたプラスミドに、HbsAgエピトープおよびMTエピトープを1つのクローニング工程で付加した。
2つの相補的オリゴデオキシリボヌクレオチドを合成し、そしてアニールさせてHSP70 CD4+T細胞エピトープ(表1)をコードするDNAリンカーを得た。このリンカーを、pTrc−N10プラスミド中のN10コード領域の下流に、かつN10コード領域とインフレームで挿入した。TOP10 E.coli株における形質転換後、形質転換体をタンパク質発現およびDNA配列決定分析を用いて選択した。正確なコード配列を有し、かつ予期される分子量のタンパク質を発現する選択されたクローン(TOP10/pTrc−N11)のグリセロールバッチを、−80℃で保存した。
P23TTからHBsAgまでのコード領域を含むDNAフラグメントを、テンプレートとしてプラスミドpTrc−N10、および2つのオリゴヌクレオチドプライマー(これらは、PCR産物の5’末端および3’末端に、それぞれBglII制限部位およびPstI制限部位の挿入を可能にする)を使用してPCR増幅した。プラスミドpTrc−N10を、BamHIおよびPstI制限酵素で消化し、そしてBglIIおよびPstIで消化したPCR産物に連結した。TOP10細胞における形質転換、ならびにタンパク質発現およびDNA配列決定分析を用いる形質転換体の選択後、正確なコード配列を有し、かつ予期される分子量のタンパク質を発現する選択されたクローン(TOP10/pTrc−N19)のグリセロールバッチを、−80℃で保存した。
全ての組換えポリエピトープキャリアタンパク質を、同様のストラテジーを使用して精製した。手短には、E.coli培養物を、100μg/mlのアンピシリンを含む500mlのLB培地中、37℃で増殖した。0.3〜0.5のOD600で、ポリエピトープタンパク質の発現を、0.1〜1mMのIPTGを添加することによって3〜5時間誘導した。細胞を、超音波処理またはフレンチプレスで破壊し、不溶性画分を遠心分離によって収集し、緩衝液A(6M グアニジウム−HCL、100mM NaH2PO4、10mM Tris塩基、pH8)で溶解し、そして2mlのNi2+NTA樹脂(Qiagen)で吸着した。
Hib莢膜多糖は、Gotschlichら(1981)J.Biol.Chem.256:8915−8921に記載のプロトコールに従って調製され得る。
最終容量0.5mlの10mMのリン酸緩衝液、pH7中の33.4ナノモルの組換えキャリアタンパク質および669ナノモルの活性化Hibオリゴ糖を、室温で一晩緩やかに攪拌し、そして1M (NH4)2SO4、10mM ホスフェート pH7になるよう、5mlに容量を増大した。このサンプルを、1mlのPhenyl Sepharose 5/5 HRカラム(Pharmacia)上のFPLCに供した。1mlの画分を、洗浄(1M (NH4)2SO4、10mM ホスフェート pH7)および溶出(10mM ホスフェート pH7)の両方の間で収集した。非吸着物質および溶出物質に対応する2つのピークを得た。非吸着物質に対応するプールした画分および溶出ピークに対応するプールした画分を、タンパク質およびリボース含量の決定、ならびにSDS−PAGEおよびウェスタンブロット分析に供した。
PBMCのための培養培地は、以下を補充したRPMI 1640(Gibco Laboratories,Paisley,Scotland)であった;2mMのL−グルタミン、1%の非必須アミノ酸、1mMピルビン酸ナトリウム、ゲンタマイシン(50μg/ml)、および5%ヒト血清(RPMI−HS)または10%ウシ胎仔血清(RPMI−FCS)。T細胞株およびT細胞クローンの増殖のために、RPMI−HSに、1mlあたり50Uの組換えインターロイキン−2(rIL−2:Hoffmann La Roche,Nutley,NJ)を補充した。
破傷風トキソイドに免疫のある健常成体由来の凍結PBMC(105)を融解し、そして96ウェル平底マイクロプレートの2連のウェルにおいて、0.2mlのRPMI−HS(Di Tommasoら、1997)中で培養した。組換えタンパク質および破傷風トキシン(Chiron,Siena)を、最終濃度10μg/mlでウェルに添加した。培養5日後、1μCiの[3H]チミジン(比活性:5Ci/mmol、Amersham)を各ウェルに添加し、そしてDNAに組込まれた放射活性を、さらに16時間後に液体シンチレーション計数によって測定した。
2つのヒトT細胞クローン、KSMIK 140およびGG−22(それぞれ、P2TTおよびP30TTに特異的)、ならびにそれぞれのペプチドは、A.Lanzavecchia博士(Basel,Switzerland)から恵与された。T細胞(2×104)を、2連のウェルの96ウェル平底マイクロプレートで0.2mlのRPMI−FCS中で、自己由来の照射されたエプスタイン−バーウイルスで形質転換したBリンパ球(3×104)とともに培養した。合成ペプチド、および結合体化組換えタンパク質または非結合体化組換えタンパク質を、最終濃度10μg/mlで培養物に添加した。2日後、1μCiの[3H]チミジンを添加し、そして組込まれた放射活性を、さらに16時間後に液体シンチレーション計数によって測定した。
第一の実験において、アジュバントとして0.5mgの水酸化アルミニウムの存在下の、等用量の糖結合体および多糖(多糖として2.5μg)を、8匹のBALB/cマウスの群およびC57BL/6マウス(雌、7週齢)の群に、0日目、21日目および35日目に皮下注射した。マウスを、−1日目(免疫前)、20日目(免疫前2)、34目(免疫前3)、および45日目(免疫後3)に採血し、個々の血清を収集し、そしてELISAアッセイまで−80℃で保存した。
Nunc Maxisorp 96ウェル平底プレートを、1μg/ml(多糖として)のヒト血清アルブミン(HSA)とH.influenzae b型多糖との結合体(HSA−Hib)を用いて、4℃で一晩のインキュベーションによってコーティングした。洗浄後、ウェルを、PBS、pH7.2中の1%(w/v)ゼラチンを使用して、37℃でさらに3時間オーバーコーティングした。血清サンプルを、75mM NaCl、1%(w/v) BSAおよび0.05%(w/v) Tween−20を含む、5mMリン酸緩衝液、pH7.2中、1:50で希釈し、そのウェル内に二連に分注した。非処置マウス由来の血清をプールし、そして上記のように1:50で希釈し、そして8ウェルに分配した。4℃で一晩のインキュベーション後、プレートを、75mM NaClおよび0.05%(w/v) Tween−20を含む、5mMリン酸緩衝液、pH7.2で3回洗浄した。次いで、75mM NaCl、1%(w/v) BSAおよび0.05%(w/v) Tween−20を含む、5mMリン酸緩衝液、pH7.2で1:1000に希釈したアルカリホスフェート結合ヤギIgG抗マウスIgGを、各ウェルに添加し、そして37℃で3時間インキュベートした。
(ポリエピトープキャリアタンパク質の構築)
材料および方法で記載されたアプローチを使用して、本発明者らは、異なるキャリアタンパク質を発現するいくつかのE.coliクローンを作製した。以下の表は、本発明者らが組換えポリエピトープキャリアタンパク質を精製するために利用した6つのクローンのみを列挙する。
図3および4は、3つの合成タンパク質のタンパク質発現を示す。N10タンパク質(レーンC)を得るための、pTrc−His中のN6(レーンD)への、さらなる4つのエピトープ(HBVnc、HA、HBsAg、およびMT)の付加は、タンパク質発現の顕著な減少を生じた。N10の発現レベルを上昇させる試みは、単純に発現ベクター(pTrc−HisからPQE30へ)およびE.coli株(Top10からTG1へ)の変更を包含した。図3および4に見られるように、TG1中のpQE30−N10によって発現されたN10の量(レーンB)は、pTrc−N10によって発現された同一のタンパク質(レーンC)よりも特に多かった。このことは、N6タンパク質がその生物にとって最も適切なエピトープの順番でE.coli株によって効果的にアセンブリされるが、その一方、4つのさらなるエピトープの添加は、効果的に押し込まれ、従って、より天然でないことに起因する可能性があると考えられる。しかし、N10発現レベルが、単純に発現ベクター(pTrc−HisからPQE30へ)およびE.coli株(Top10からTG1へ)の変更によって顕著に増加したという事実は、エピトープの組み合わせ以外のさらなる因子がタンパク質発現において役割を担うことを示唆する。
フェニルセファロースFPLCプロトコールを使用して、本発明者らは、79.4μg/mlのタンパク質含量、および42.7μg/mlのオリゴサッカライド含量を有する、精製N6−Hib結合体を得た。
ポリペプチドに含まれるT細胞エピトープが、ヒトT細胞によって認識されるか否かを調べるために、本発明者らは、TTユニバーサルエピトープp2TTおよびp30TTに特異的なT細胞クローンを使用した(Demotzら、1993)。図11は、N6が、単純なポリペプチドとしてのみではなく、ポリサッカライドと結合体化した後もまた、両方のクローンによって認識されることを示す。注目すべきことに、N6−Hibは、P2TT特異的T細胞クローンによって、結合体化されていないN6よりもさらに良好に認識される。N10−Hibはp2TTに特異的なクローンによって認識されるが、P30TTに特異的なクローンによっては不完全に認識される。両方の場合において、N10−Hibは、合成ペプチドと同一の刺激活性を発揮する。N10クローンは、これらの実験において試験されなかった。
CRM197との比較におけるタンパク質N10およびN6のキャリア効果を、いくつかの糖結合体ワクチンにおいて、マウスでアッセイした。一旦、Hibオリゴサッカライドと結合体化したら、このキャリアタンパク質を異なるマウス系統中に注入し、それらのキャリア効果の可能性を確認した。BALB/cマウスにおいて、CRM197およびN10をキャリアタンパク質として使用した場合、等価の抗Hib応答が見出された。その一方、N6をキャリアタンパク質として使用した場合、より低い応答が見出された。この結果は、結果を力価を使用して示した場合、明らかであった。その一方で、応答動物の百分率からは、N6タンパク質キャリアを用いて得られたより低度の抗Hib応答が証明されなかった。
1.ポリエピトープタンパク質のキャリア効果は、そのサイズと直接関係する。
2.組換えポリエピトープタンパク質N10およびN19は、キャリアとしてCRM−197と匹敵し得るか、またはこれを超え得る。
3.ポリエピトープキャリアタンパク質は、キャリア誘導性抑制の影響を受けない。
Claims (1)
- 実施例に開示されるキャリアタンパク質。
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1998
- 1998-04-27 GB GBGB9808932.9A patent/GB9808932D0/en not_active Ceased
-
1999
- 1999-04-27 JP JP2000545888A patent/JP4012687B2/ja not_active Expired - Fee Related
- 1999-04-27 ES ES99916001T patent/ES2353636T3/es not_active Expired - Lifetime
- 1999-04-27 CA CA002326376A patent/CA2326376A1/en not_active Abandoned
- 1999-04-27 DE DE69942911T patent/DE69942911D1/de not_active Expired - Lifetime
- 1999-04-27 US US09/674,183 patent/US6855321B1/en not_active Expired - Fee Related
- 1999-04-27 AT AT99916001T patent/ATE486887T1/de active
- 1999-04-27 EP EP10176643A patent/EP2272861A1/en not_active Withdrawn
- 1999-04-27 WO PCT/IB1999/000844 patent/WO1999055730A2/en active Application Filing
- 1999-04-27 PT PT99916001T patent/PT1076662E/pt unknown
- 1999-04-27 EP EP99916001A patent/EP1076662B1/en not_active Expired - Lifetime
-
2005
- 2005-01-06 US US11/030,635 patent/US7538207B2/en not_active Expired - Fee Related
-
2006
- 2006-04-05 JP JP2006104679A patent/JP2006193534A/ja active Pending
-
2009
- 2009-03-25 US US12/383,545 patent/US7867498B2/en not_active Expired - Fee Related
-
2010
- 2010-12-01 US US12/957,480 patent/US20120070456A1/en not_active Abandoned
-
2011
- 2011-02-03 CY CY20111100126T patent/CY1111325T1/el unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013510882A (ja) * | 2009-11-16 | 2013-03-28 | ザ ヘンリー エム.ジャクソン ファウンデイション フォー ザ アドバンスメント オブ ミリタリー メディスン,インコーポレイティド | ポリ−グリセロールリン酸をベースにした抗グラム陽性細菌ワクチン |
Also Published As
Publication number | Publication date |
---|---|
PT1076662E (pt) | 2011-02-09 |
JP4012687B2 (ja) | 2007-11-21 |
JP2002512778A (ja) | 2002-05-08 |
US20070003566A1 (en) | 2007-01-04 |
EP1076662B1 (en) | 2010-11-03 |
ES2353636T3 (es) | 2011-03-03 |
ATE486887T1 (de) | 2010-11-15 |
CY1111325T1 (el) | 2015-08-05 |
US20120070456A1 (en) | 2012-03-22 |
EP1076662A2 (en) | 2001-02-21 |
GB9808932D0 (en) | 1998-06-24 |
US7538207B2 (en) | 2009-05-26 |
US6855321B1 (en) | 2005-02-15 |
US20090227770A1 (en) | 2009-09-10 |
DE69942911D1 (de) | 2010-12-16 |
CA2326376A1 (en) | 1999-11-04 |
EP2272861A1 (en) | 2011-01-12 |
US7867498B2 (en) | 2011-01-11 |
WO1999055730A2 (en) | 1999-11-04 |
WO1999055730A3 (en) | 2000-04-06 |
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