JP4926231B2 - 二量体化ペプチド - Google Patents
二量体化ペプチド Download PDFInfo
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- JP4926231B2 JP4926231B2 JP2009260957A JP2009260957A JP4926231B2 JP 4926231 B2 JP4926231 B2 JP 4926231B2 JP 2009260957 A JP2009260957 A JP 2009260957A JP 2009260957 A JP2009260957 A JP 2009260957A JP 4926231 B2 JP4926231 B2 JP 4926231B2
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Description
(1) 少なくとも1つのシステイン残基を含みかつ7〜30個のアミノ酸残基からなる、CTL誘導活性を有する癌抗原ペプチドを生じさせる2つのペプチド単量体が相互にジスルフィド結合により結合しているペプチド二量体;
(2) CTL誘導活性を有する癌抗原ペプチドを生じさせる、上記(1)記載のペプチド二量体;
(3) 2つのペプチド単量体が1または2個のジスルフィド結合により結合している、上記(1)または(2)記載のペプチド二量体;
(4) ペプチド単量体が癌抑制遺伝子産物WT1に由来する、上記(1)〜(3)のいずれか記載のペプチド二量体;
(5) ペプチド単量体がCys Xaa Thr Trp Asn Gln Met Asn Xaa(配列番号:72)(第2位のXaaは、Tyr、Phe、MetおよびTrpからなる群より選ばれる1つのアミノ酸残基を示し、第9位のXaaは、Phe、Leu、Ile、TrpおよびMetからなる群より選ばれる1つのアミノ酸残基を示す)である、上記(1)〜(4)のいずれか記載のペプチド二量体:
(6) ペプチド単量体がCys Met Thr Trp Asn Gln Met Asn Leu(配列番号:11)、 Asp Phe Lys Asp Cys Glu Arg Arg Phe(配列番号:18)、Ala Tyr Pro Gly Cys Asn Lys Arg Tyr(配列番号:19)、Asn Ala Pro Tyr Leu Pro Ser Cys Leu(配列番号:20)、Gly Cys Asn Lys Arg Tyr Phe Lys Leu(配列番号:21)、Arg Trp Pro Ser Cys Gln Lys Lys Phe (配列番号:22)、Asp Ser Cys Thr Gly Ser Gln Ala Leu(配列番号:23)およびCys Tyr Thr Trp Asn Gln Met Asn Leu(配列番号:44)からなる群より選ばれる、上記(1)〜(4)のいずれか記載のペプチド二量体;
(7) 上記(1)〜(6)のいずれか記載のペプチド二量体と製薬的に許容されうる担体とを含有してなる医薬組成物;
(8) 癌ワクチンとして使用される、上記(7)に記載の医薬組成物;
(9) 上記(1)〜(6)のいずれか記載のペプチド二量体における、癌ワクチンを製造するための使用;および
(10) 癌を治療または予防するための方法であって、上記(1)〜(6)のいずれか記載のペプチド二量体の治療または予防に有効な量を、それを必要としているWT1陽性の患者に投与する方法:
に関する。
Ala(A) :アラニン残基、Arg(R):アルギニン残基、Asn(N):アスパラギン残基、Asp(D):アスパラギン酸残基、Cys(C):システイン残基、Gln(Q):グルタミン残基、Glu(E):グルタミン酸残基、Gly(G):グリシン残基、His(H):ヒスチジン残基、Ile(I):イソロイシン残基、Leu(L):ロイシン残基、Lys(K):リジン残基、Met(M):メチオニン残基、Phe(F):フェニルアラニン残基、Pro(P):プロリン残基、Ser(S):セリン残基、Thr(T):トレオニン残基、Trp(W):トリプトファン残基、Tyr(Y):チロシン残基、Val(V):バリン残基。
1. 保護ペプチド樹脂(H-Cys(Trt)-Tyr(Trt)-Thr(tBu)-Trp(Boc)-Asn(Trt)-Gln(Trt)-Met-Asn(Trt)-Leu-Alko-Resinの合成
Fmoc-Leu-Alko-樹脂(ここに、Alkoはp−アルコキシベンジルアルコール)12g(渡辺化学製;0.81mmol/g)をAdvanced ChemTech社製ACT90型固相合成機の500ml反応槽内に入れ、一旦この樹脂をDMF等で洗浄後(工程1)、25%Pip(ピペリジン)で処理(3分×1回及び15分×1回)してFmoc基を切断後(工程2)、再びDMF等で樹脂を洗浄し(工程1)、Pipを除去した。この反応槽内に、Fmoc-Asn(Trt)-OH 29.36gとHOBT(1−ヒドロキシベンゾトリアゾール)7.5gをNMP(N−メチルピロリジノン)150mlに溶解した溶液を加え、更にDIPCI(N,N’−ジイソプロピルカルボジイミド)7.6mlを加えて 30分間室温撹拌を行った(工程3)。30分後、NMPで樹脂を洗浄し(工程4)、Fmoc-Asn(Trt)-OH 29.36gとHOBT 7.5gを用いて再度カップリング反応を行い(工程5)、Fmoc-Asn(Trt)-Leu-Alko樹脂を合成した。その後、工程2の脱保護操作を行い、H-Asn(Trt)-Leu-Alko-樹脂とした。次いで、工程1の洗浄操作を行い、Fmoc-Met-OH 18.27g、Fmoc-Gln(Trt)-OH 30.04g、Fmoc-Asn(Trt)-OH29.36g、Fmoc-Trp(Boc) -OH 25.91g、Fmoc-Thr(tBu)-OH 19.56g、Fmoc-Tyr(tBu)-OH22.60g、Fmoc-Cys(Trt)-OH 28.82gを順次加え、工程3のカップリング反応を行った。但しFmoc-Thr(tBu)-OHについてはカップリングを3回繰り返して行った後、得られた樹脂をDMFで洗浄後、25%AC2O(無水酢酸)で15分×2回で未反応のアミノ基をキャッピングした。N末端のFmoc-Cys(Trt)-OHを縮合後、工程2の脱保護操作を行い、工程6の洗浄操作を実施し、H-Cys(Trt)- Tyr(Trt)-Thr(tBu)-Trp(Boc) -Asn(Trt)- Gln(Trt)-Met-Asn(Trt)-Leu-Alko-Resinを得た。上記合成工程の概要を表33に示す。
上記操作によって得られた保護ペプチド樹脂(H-Cys(Trt)-Tyr(Trt)-Thr(tBu)-Trp(Boc)-Asn(Trt)-Gln(Trt)-Met-Asn(Trt)-Leu-Alko-Resin 14.06gにReagent K(5%フェノール/ 5%チオアニソール/5%H2O/2.5%エタンジチオール/TFA溶液)100mlとトリイソプロピルシラン (TIPS) 15mlを加え、室温で2.5時間攪拌した。その後、ジエチルエーテル約500mlを加え、グラスフィルターで濾過を行い、Reagent Kとジエチルエーテルを濾液として除いた。濾上物を約100mlのジエチルエーテルで3回洗浄し、洗浄後の濾上物に約100mlのTFAを加える操作を3回繰り返して行い、目的物を含む濾液を約300ml得た。この濾液を濃縮してTFAを除き、アセトニトリル約50mlと20%酢酸水約250ml加え凍結乾燥し、パウダー状の粗ペプチド(H-Cys-Tyr-Thr-Trp-Asn-Gln-Met-Asn-Leu-OH、配列番号:44)6.12gを得た。
得られた粗ペプチド749mgをTFA 10mlに溶解し、HPLC(Shimazu製;LC8AD型)1液=H2O/0.1%TFAで平衡化しているYMC社製 ODS C18 5cmΦ×50cmLのカラムにHPLCのポンプでチャージした。その状態で約30分間保ち、30分後、2液=CH3CN/0.1%TFAの濃度を30分間で0%から15%迄上昇した。その後、更に330分かけて28%まで2液の濃度を上昇させ、目的とするペプチドの溶出液を220nmのUVでモニターしながら、目的物を含む分画を集めた。集めた分画を、YMC社製ODS C18 4.6mmΦ×25cmLカラムをセットしたHPLC(日立製 L-4000型)で1液=H2O/0.1%TFAと2液=CH3CN/0.1%TFAの溶出液で、2液=CH3CN/0.1%TFAの濃度を17%で平衡化しているカラムに注入し、220nmのUVでモニターしながら2液の濃度47%まで30分間で上昇させ、保持時間14.79分の目的ペプチド単量体の精製品227.5mgを得た。
・アミノ酸分析
加水分解:1%フェノール/6N塩酸水、110℃ 10時間
分析法:ニンヒドリン法
Asx:1.71(2) Thr:0.75(1) Glx:1.07(1) Met:0.91(1) * Leu:(1) Tyr:0.82(1)
*) Leu=基準アミノ酸 ( ) 内 理論値
・質量分析:LC/MS M+1=1173.0 (理論値=1172.36)
・アミノ酸配列分析:N末2残基目 Tyrから、C末Leuまで順次確認した。
次式で示される二量体の合成:
粗ペプチド二量体158mgをDMSO 9mlに溶解し、HPLC(Shimazu製;LC8AD型)に1液=H2O/1%AcOHで平衡化しているYMC社製ODS C18 5cmΦ×50cmLのカラムにHPLCのポンプでチャージした。その状態で約30分間保ち、30分後、2液=CH3CN/1%AcOHの濃度を360分間で0%から40%迄上昇した。その後、目的とする二量体の溶出液を220nmのUVでモニターしながら、自動分画装置により目的物を含む分画を集めた。集めた分画を、YMC社製ODS C18 4.6mmΦ×25cmLカラムをセットしたHPLC(日立製 L-4000型)で1液=H2O/0.1%TFAと2液=CH3CN/0.1%TFAの溶出液で、2液=CH3CN/0.1%TFAの濃度を17%で平衡化しているカラムに注入し、220nmのUVでモニターしながら2液の濃度を0%から47%まで30分で上昇させ、保持時間20.51分の目的とするペプチド二量体精製品46.6mgを得た。
FAB.MS 2365.0 (理論値 2342.70) Na+ F=0.25%
ペプチド二量体によるCTL誘導
実施例1にて調製したペプチド二量体のCTL誘導能をHLA-A24トランスジェニックマウス(Int. J. Cancer: 100, 565, 2002)を用いて評価した。ペプチド二量体をジメチルスルホキシド(DMSO)で溶解し、40mg/mlのペプチド溶液を作製した。このペプチド溶液35μlを581μlの10mMリン酸緩衝液(pH7.5)に添加してペプチド懸濁液を調製した。このペプチド懸濁液550μlとMontanide ISA51(Seppic社)700μlを連結したガラスシリンジを用いて混合し、エマルションを作製して投与液を調製した。
Claims (1)
- 2つのCys Met Thr Trp Asn Gln Met Asn Leu(配列番号:11)が相互にジスルフィド結合により結合している、ペプチド二量体。
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CA2440303C (en) * | 2001-03-22 | 2013-03-19 | Haruo Sugiyama | Wt1 modified peptide |
WO2002097044A2 (en) * | 2001-05-25 | 2002-12-05 | Thomas Jefferson University | Alternative splice forms of proteins as basis for multiple therapeutic modalities |
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SI1731605T1 (sl) * | 2004-03-31 | 2010-07-30 | Internat Inst Of Cancer Immunolog Inc | Peptidi antigena karcinoma izvedeni iz WT1 |
RU2396088C2 (ru) * | 2005-02-04 | 2010-08-10 | СУРВАК АпС | Вакцина на основе пептидов сурвивина |
CN101336249A (zh) | 2005-11-30 | 2008-12-31 | 株式会社癌免疫研究所 | 新型肽化合物 |
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ATE443722T1 (de) * | 2006-02-23 | 2009-10-15 | Fibrex Medical Res & Dev Gmbh | Peptide und peptidderivate, ihre herstellung sowie ihre verwendung zur herstellung einer therapeutisch und/oder prophylaktisch wirksamen pharmazeutischen zusammensetzung |
CA2886619A1 (en) | 2006-12-28 | 2008-07-10 | International Institute Of Cancer Immunology, Inc. | Hla-a*1101-restricted wt1 peptide and pharmaceutical composition comprising the same |
CN104774910B (zh) | 2007-02-27 | 2018-04-10 | 株式会社癌免疫研究所 | 活化辅助t细胞的方法以及用于该方法的组合物 |
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JP6294868B2 (ja) | 2013-03-12 | 2018-03-14 | 大日本住友製薬株式会社 | 液体水性組成物 |
DK2982681T3 (en) * | 2013-03-29 | 2018-12-10 | Sumitomo Dainippon Pharma Co Ltd | WT1 ANTIGENPEPTIDKONJUGATVACCINE |
JP6671956B2 (ja) * | 2013-03-29 | 2020-03-25 | 大日本住友製薬株式会社 | Erap1によるトリミング機能をきっかけとしたコンジュゲートワクチン |
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SI1731605T1 (sl) | 2004-03-31 | 2010-07-30 | Internat Inst Of Cancer Immunolog Inc | Peptidi antigena karcinoma izvedeni iz WT1 |
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US20060217297A1 (en) | 2006-09-28 |
EP1584627A4 (en) | 2006-03-15 |
CN101851275A (zh) | 2010-10-06 |
AU2004204031B2 (en) | 2010-03-04 |
KR20120054644A (ko) | 2012-05-30 |
JPWO2004063217A1 (ja) | 2006-06-01 |
KR101399678B1 (ko) | 2014-05-27 |
HK1141539A1 (en) | 2010-11-12 |
BRPI0406800B8 (pt) | 2021-05-25 |
ES2332590T3 (es) | 2010-02-09 |
CN1756763B (zh) | 2010-05-26 |
US20100292164A1 (en) | 2010-11-18 |
JP2010047603A (ja) | 2010-03-04 |
HK1081975A1 (en) | 2006-05-26 |
DE602004023476D1 (de) | 2009-11-19 |
WO2004063217A1 (ja) | 2004-07-29 |
EP2154145A3 (en) | 2010-05-19 |
CA2513701C (en) | 2013-06-18 |
EP2154145A2 (en) | 2010-02-17 |
CN1756763A (zh) | 2006-04-05 |
BRPI0406800A8 (pt) | 2016-11-01 |
US8242084B2 (en) | 2012-08-14 |
AU2004204031A1 (en) | 2004-07-29 |
BRPI0406800A (pt) | 2006-01-17 |
KR20050098863A (ko) | 2005-10-12 |
ATE444969T1 (de) | 2009-10-15 |
CA2513701A1 (en) | 2004-07-29 |
EP1584627A1 (en) | 2005-10-12 |
BRPI0406800B1 (pt) | 2020-08-11 |
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