JPWO2014136814A1 - 新規ctlエピトープ5連結ペプチド - Google Patents
新規ctlエピトープ5連結ペプチド Download PDFInfo
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- JPWO2014136814A1 JPWO2014136814A1 JP2015504352A JP2015504352A JPWO2014136814A1 JP WO2014136814 A1 JPWO2014136814 A1 JP WO2014136814A1 JP 2015504352 A JP2015504352 A JP 2015504352A JP 2015504352 A JP2015504352 A JP 2015504352A JP WO2014136814 A1 JPWO2014136814 A1 JP WO2014136814A1
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- pep4
- pep5
- pep3
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- A—HUMAN NECESSITIES
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
Description
からなる群より、重複して選択されてもよい5つのペプチドがリンカーを介してそれぞれ連結されてなる、エピトープ5連結ペプチドであって、
以下の(1)〜(12)より選択される一又は複数の特徴を有する、上記エピトープ5連結ペプチド:
(1) リンカーを介してN末端側より順にPEP5とPEP2が隣り合う配列を含む;
(2) リンカーを介してN末端側より順にPEP2とPEP4が隣り合う配列を含む;
(3) リンカーを介してN末端側より順にPEP4とPEP6が隣り合う配列を含む;
(4) リンカーを介してN末端側より順にPEP6とPEP3が隣り合う配列を含む;
(5) リンカーを介してN末端側より順にPEP4とPEP1が隣り合う配列を含む;
(6) リンカーを介してN末端側より順にPEP1とPEP3が隣り合う配列を含む;
(7) リンカーを介してN末端側より順にPEP4とPEP2が隣り合う配列を含む;
(8) リンカーを介してN末端側より順にPEP1とPEP4が隣り合う配列を含む;
(9) リンカーを介してN末端側より順にPEP5とPEP1が隣り合う配列を含む;
(10) リンカーを介してN末端側より順にPEP6とPEP5が隣り合う配列を含む;
(11) C末端にPEP2を含む;ならびに、
(12) C末端にPEP3を含む。
(a)PEP5-PEP2-PEP4-PEP7-PEP3;
(b)PEP5-PEP2-PEP7-PEP3-PEP4;
(c)PEP4-PEP6-PEP5-PEP7-PEP3;
(d)PEP5-PEP2-PEP4-PEP6-PEP3;
(e)PEP5-PEP2-PEP4-PEP1-PEP3;
(f)PEP4-PEP5-PEP2-PEP7-PEP3;
(g)PEP7-PEP3-PEP4-PEP5-PEP2;
(h)PEP5-PEP7-PEP3-PEP4-PEP2;
(i)PEP6-PEP1-PEP4-PEP5-PEP2;
(j)PEP6-PEP5-PEP1-PEP4-PEP2;
(k)PEP4-PEP5-PEP1-PEP6-PEP3;
(l)PEP7-PEP2-PEP4-PEP5-PEP3;
(m)PEP4-PEP2-PEP7-PEP5-PEP3;
(n)PEP7-PEP2-PEP5-PEP4-PEP3;
(o)PEP5-PEP2-PEP7-PEP4-PEP3;または、
(p)PEP5-PEP2-PEP4-PEP3-PEP7;
なお、式中「-」はリンカーを示す。
本発明の「エピトープ5連結ペプチド」は、同一及び/又は異なる腫瘍抗原分子由来のCTLエピトープペプチドから選ばれる5つのペプチドを、リンカーを介して直鎖状に連結して1分子としたペプチドを意味する。
PEP1:KLVERLGAA(配列番号1[WO 0l/Ol1044]);
PEP2:ASLDSDPWV(配列番号2[WO 02/010369]);
PEP3:LLQAEAPRL(配列番号3[WO 00/12701]);
PEP4:DYSARWNEI(配列番号4[特開平11-318455号公報]);
PEP5:VYDYNCHVDL(配列番号5[WO 00/12701]);
PEP6:LYAWEPSFL(配列番号6[特開2003-000270号公報]);
PEP7:QIRPIFSNR(配列番号7[Cancer lmmunol. lmmunother. 2007,56(5), 689-698])。
(1)リンカーを介してN末端側より順にPEP5とPEP2が隣り合う配列を含む;
(2)リンカーを介してN末端側より順にPEP2とPEP4が隣り合う配列を含む;
(3)リンカーを介してN末端側より順にPEP4とPEP6が隣り合う配列を含む;
(4)リンカーを介してN末端側より順にPEP6とPEP3が隣り合う配列を含む;
(5)リンカーを介してN末端側より順にPEP4とPEP1が隣り合う配列を含む;
(6)リンカーを介してN末端側より順にPEP1とPEP3が隣り合う配列を含む;
(7)リンカーを介してN末端側より順にPEP4とPEP2が隣り合う配列を含む;
(8)リンカーを介してN末端側より順にPEP1とPEP4が隣り合う配列を含む;
(9)リンカーを介してN末端側より順にPEP5とPEP1が隣り合う配列を含む;
(10)リンカーを介してN末端側より順にPEP6とPEP5が隣り合う配列を含む;
(11)C末端にPEP2を含む;ならびに、
(12)C末端にPEP3を含む。
(I)N末端にN末端側より順に、
PEP5とPEP2、
PEP6とPEP5、又は、
PEP4とPEP6、
がリンカーを介して隣り合う配列を含む、ならびに/あるいは、
(II)C末端にN末端側より順に、
PEP7とPEP3;
PEP4とPEP3;
PEP6とPEP3;
PEP1とPEP3;
PEP5とPEP2;
PEP4とPEP2;又は、
PEP5とPEP3
がリンカーを介して隣り合う配列を含む。
(a)PEP5-PEP2-PEP4-PEP7-PEP3;
(b)PEP5-PEP2-PEP7-PEP3-PEP4;
(c)PEP4-PEP6-PEP5-PEP7-PEP3;
(d)PEP5-PEP2-PEP4-PEP6-PEP3;
(e)PEP5-PEP2-PEP4-PEP1-PEP3;
(f)PEP4-PEP5-PEP2-PEP7-PEP3;
(g)PEP7-PEP3-PEP4-PEP5-PEP2;
(h)PEP5-PEP7-PEP3-PEP4-PEP2;
(i)PEP6-PEP1-PEP4-PEP5-PEP2;
(j)PEP6-PEP5-PEP1-PEP4-PEP2;
(k)PEP4-PEP5-PEP1-PEP6-PEP3;
(l)PEP7-PEP2-PEP4-PEP5-PEP3;
(m)PEP4-PEP2-PEP7-PEP5-PEP3;
(n)PEP7-PEP2-PEP5-PEP4-PEP3;
(o)PEP5-PEP2-PEP7-PEP4-PEP3;または、
(p)PEP5-PEP2-PEP4-PEP3-PEP7。
本発明のエピトープ5連結ペプチドは、慣用の液相合成法、固相合成法などのペプチド合成法、自動ペプチド合成機によるペプチド合成などによって製造することができる(Kelley et al., Genetics Engineering Principles and Methods, Setlow, J.K. eds., Plenum Press NY. (1990) Vol.12, p.1-19;S tewart et al., Solid-Phase Peptide Synthesis (1989) W.H. Freeman Co.; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p.5132、「新生化学実験講座1 タンパク質IV」(1992)日本生化学会編,東京化学同人)。ペプチド合成は、各アミノ酸の、結合しようとするα−アミノ基とα−カルボキシル基以外の官能基を保護したアミノ酸類を用意し、それぞれのアミノ酸のα−アミノ基とα−カルボキシル基との間でペプチド結合形成反応を行う。通常、ペプチドのC末端に位置するアミノ酸残基のカルボキシル基を適当なスペーサー又はリンカーを介して固相に結合しておく。上で得られたジペプチドのアミノ末端の保護基を選択的に除去し、次のアミノ酸のα−カルボキシル基との間でペプチド結合を形成する。このような操作を連続して行い側基が保護されたペプチドを製造し、最後に、すべての保護基を除去し、固相から分離する。保護基の種類や保護方法、ペプチド結合法の詳細は、上記の文献に詳しく記載されている。
本発明のエピトープ5連結ペプチドを用いて、CTLエピトープペプチドに特異的であり、がん細胞を傷害するCTLをin vitroにて取得することができる。CTLエピトープペプチドを用いたCTLのin vitroにおける誘導方法は公知であり(例えば、特開2006−14637号公報)、本発明においてもこれらの手法を利用することができる。例えば、健常人又はがん患者由来の末梢血単核球(PBMC)中のプレート接着細胞をGM-CSF、IL-4等のサイトカインの存在下で培養して樹状細胞(DC)を誘導する。この樹状細胞に、本発明のエピトープ5連結ペプチドをパルスした後、X線照射を行うことにより、抗原提示細胞(stimulator)を調製する。DCが使用できない場合は、健常人または同じがん患者由来の末梢血単核 (PBMC)に本発明のエピトープ5連結ペプチドをパルスした後、X線照射を行ったものを用いてもよい。次いで、健常人由来の末梢血単核球(PBMC)又はがん患者由来の末梢血単核球(PBMC)又は所属リンパ節リンパ球(responder)を加えて、IL-2, IL-4, IL-7等のサイトカイン存在下で培養する。その後さらに、本発明のエピトープ5連結ペプチドを上述の通りパルスして得た抗原提示細胞を加えて再刺激を行い、IL-2等のサイトカイン存在下にてさらに培養する。
本発明のエピトープ5連結ペプチドは、がんの免疫療法に使用する医薬組成物の有効成分として利用することができる。
本発明の医薬組成物は、幅広いがん患者、例えばHLA-A2、HLA-A24、HLA-A26およびHLA-A3スーパータイプからなる群から選択されるHLAタイプ陽性患者群に投与することが可能であり、治療開始前にHLA型検査を要することなく治療を開始することができる。
CTLエピトープペプチド、及びエピトープ5連結ペプチドは、市販のペプチド合成機Prelude(Protein Technologies, Inc.)を用いて、固相合成法(Fmoc法)にて合成した。得られた各種合成ペプチドはYMC-Pack Pro C18カラム(YMC Co., Ltd.)及びHPLCシステム(Gilson)にて精製し、凍結乾燥後冷温暗所にて保存し、以降に示す実施例に供した。
エピトープ5連結ペプチドを大塚蒸留水(大塚製薬工場)にて2mg/mLないし4mg/mLに調製し、B Braun Injektシリンジに充填した。別のシリンジに等量のIncomplete Freund’s adjuvant(IFA)を充填後、両シリンジをGPシリンジコネクタで接続し、エピトープ5連結ペプチド溶液とIFAをよく混合させることでエマルジョンを調製した。これをマウス(HLA-A2.1 transgenic,HLA-A24 transgenic (Taconic))の尾根部周辺に100μLずつ週1回、計2回投与した。最終投与1週間後、マウスより鼠径部リンパ節を回収した。リンパ節細胞懸濁液をComplete Medium(RPMI-1640,10% heat-inactivated FBS,100U/mL Penicillin,100μg/mL Streptomycin,50μM 2-Mercaptoethanol)にて5×106cells/mLに調製し、標的CTLエピトープペプチド(最終濃度10μg/mL)、recombinant mouse IL-15(最終濃度100ng/mL)、recombinant mouse IL-21(最終濃度100ng/mL)をそれぞれ加え1mL/wellで24 well plateへ播種後、37℃、5%CO2インキュベーター内で8日間培養した。8日後、細胞を回収しMurine IFN-γ ELISpot Kit(GEN-PROBE)添付のanti IFN-γ抗体固相化プレートに1×105cells/wellで播種した。続けて、同系マウス脾臓より調製し30GyのX線を照射した脾臓細胞を同一wellへ抗原提示細胞として1×105cells/well播種後、標的CTLエピトープペプチド、またはnegative control ペプチド(最終濃度10μg/mL)を加え、37℃、5%CO2インキュベーター内で一晩インキュベートした。翌日、キットの添付文書に従いIFN-γ産生細胞スポットを発色させた。IFN-γ産生細胞スポット数はELISPOTアナライザー(Immunospot S6,Cellular Technology Ltd.)にて定量した。CTLエピトープペプチド特異的CTLの誘導は、当該試験により得られた標的CTLエピトープペプチド添加ウェルのIFN-γ産生細胞スポット数が、negative controlペプチド添加ウェルのそれに比し有意に高い(Student’s t-test, p<0.05)場合、陽性と判断した。なお、negative controlペプチドとしては、WT1またはHer2を用いた。さらに、CTL誘導強度を可視化する目的で、(標的CTLエピトープペプチド添加ウェルの平均IFN-γ産生細胞スポット数)-(negative controlペプチド添加ウェルの平均IFN-γ産生細胞スポット数)= Δとした時、10≦Δ<100の場合を陽性、100≦Δ<200の場合を中陽性、200≦Δの場合を強陽性として表した。
xMAP Multi-Analyte COOH Microspheres(Luminex corporation、以下ビーズという)に、以下の手順でペプチドを固相化した。MES buffer(0.1M MES-NaOH,pH7.0)でビーズを洗浄後、遠心分離により上清を除去した。これを二回繰り返した後、75μLのMES bufferでビーズを懸濁した。そこへ、1mg/mLに調製したCTLエピトープペプチド溶液を100μL加え、さらに10mg/mL EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride)を5μL加えよく混合した後、30℃、暗所で一晩反応させた。翌日、遠心分離により上清を除去した後、1M Tris-HClを125μL加え、30℃、暗所で30分間インキュベートした。上清除去後、wash buffer(PBS(-),0.05% Tween20)二回洗浄後、イムノブロック(DSファーマバイオメディカル)に懸濁することで、CTLエピトープペプチドの固相化を完了した。
本発明のエピトープ5連結ペプチドを大塚蒸留水(大塚製薬工場)にて2mg/mLに調製し、B Braun Injektシリンジに充填した。別のシリンジに等量のIFAを充填後、両シリンジをGPシリンジコネクタで接続し、該エピトープ5連結ペプチド溶液とIFAをよく混合させることでエマルジョンを調製した。これをCBF1マウス(C57BL/6×Balb/c F1)尾根部周辺に100μLずつ週1回、計3回にわたり投与した。最終投与1週間後、マウスより採血し血清サンプルを得た。対照群として、PEP2、PEP3、PEP4、PEP5、PEP7の各ペプチド混合物(各1mg/mL)を用いてエマルジョンを調製し、エピトープ5連結ペプチドと同じスケジュールにて投与した(mixture投与群)。
Claims (10)
- 以下のCTLエピトープペプチド:配列番号1で表されるペプチド(PEP1)、配列番号2で表されるペプチド(PEP2)、配列番号3で表されるペプチド(PEP3)、配列番号4で表されるペプチド(PEP4)、配列番号5で表されるペプチド(PEP5)、配列番号6で表されるペプチド(PEP6)、及び、配列番号7で表されるペプチド(PEP7)、
からなる群より、重複して選択されてもよい5つのペプチドがリンカーを介してそれぞれ連結されてなる、エピトープ5連結ペプチドであって、
以下の(1)〜(12)より選択される一又は複数の特徴を有する、上記エピトープ5連結ペプチド:
(1) リンカーを介してN末端側より順にPEP5とPEP2が隣り合う配列を含む;
(2) リンカーを介してN末端側より順にPEP2とPEP4が隣り合う配列を含む;
(3) リンカーを介してN末端側より順にPEP4とPEP6が隣り合う配列を含む;
(4) リンカーを介してN末端側より順にPEP6とPEP3が隣り合う配列を含む;
(5) リンカーを介してN末端側より順にPEP4とPEP1が隣り合う配列を含む;
(6) リンカーを介してN末端側より順にPEP1とPEP3が隣り合う配列を含む;
(7) リンカーを介してN末端側より順にPEP4とPEP2が隣り合う配列を含む;
(8) リンカーを介してN末端側より順にPEP1とPEP4が隣り合う配列を含む;
(9) リンカーを介してN末端側より順にPEP5とPEP1が隣り合う配列を含む;
(10) リンカーを介してN末端側より順にPEP6とPEP5が隣り合う配列を含む;
(11) C末端にPEP2を含む;ならびに、
(12) C末端にPEP3を含む。 - N末端にN末端側より順に、PEP5とPEP2、PEP6とPEP5、又は、PEP4とPEP6がリンカーを介して隣り合う配列を含む、ならびに/あるいは、C末端にN末端側より順に、PEP7とPEP3、PEP4とPEP3、PEP6とPEP3、PEP1とPEP3、PEP5とPEP2、PEP4とPEP2、又は、PEP5とPEP3がリンカーを介して隣り合う配列を含む、請求項1に記載のエピトープ5連結ペプチド。
- 以下の(a)〜(p)より選択される配列を含む、請求項2に記載のエピトープ5連結ペプチド:
(a)PEP5-PEP2-PEP4-PEP7-PEP3;
(b)PEP5-PEP2-PEP7-PEP3-PEP4;
(c)PEP4-PEP6-PEP5-PEP7-PEP3;
(d)PEP5-PEP2-PEP4-PEP6-PEP3;
(e)PEP5-PEP2-PEP4-PEP1-PEP3;
(f)PEP4-PEP5-PEP2-PEP7-PEP3;
(g)PEP7-PEP3-PEP4-PEP5-PEP2;
(h)PEP5-PEP7-PEP3-PEP4-PEP2;
(i)PEP6-PEP1-PEP4-PEP5-PEP2;
(j)PEP6-PEP5-PEP1-PEP4-PEP2;
(k)PEP4-PEP5-PEP1-PEP6-PEP3;
(l)PEP7-PEP2-PEP4-PEP5-PEP3;
(m)PEP4-PEP2-PEP7-PEP5-PEP3;
(n)PEP7-PEP2-PEP5-PEP4-PEP3;
(o)PEP5-PEP2-PEP7-PEP4-PEP3;または、
(p)PEP5-PEP2-PEP4-PEP3-PEP7。
なお、式中「-」はリンカーを示す。 - リンカーがアミノ酸リンカーである、請求項1〜3のいずれか1項に記載のエピトープ5連結ペプチド。
- アミノ酸リンカーが、アルギニンを2個連結したアルギニンダイマーである、請求項4に記載のエピトープ5連結ペプチド。
- 請求項1〜5のいずれか1項に記載のエピトープ5連結ペプチドを用いて、末梢血リンパ球を刺激することにより得られるCTL。
- 請求項1〜5のいずれか1項に記載のエピトープ5連結ペプチド、又は、請求項6に記載のCTLを有効成分として含有する、がんを治療又は予防するための医薬組成物。
- 免疫療法剤である、請求項7に記載の医薬組成物。
- 請求項1〜5のいずれか1項に記載のエピトープ5連結ペプチド、又は、請求項6に記載のCTLをがん患者に投与することを含む、がんの治療方法。
- 請求項1〜5のいずれか1項に記載のエピトープ5連結ペプチド、又は、請求項6に記載のCTLを被験者に投与することを含む、がんに対する被験者の免疫方法。
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EP2966092A1 (en) | 2016-01-13 |
US9701729B2 (en) | 2017-07-11 |
BR112015021162A2 (pt) | 2017-10-10 |
TW201438731A (zh) | 2014-10-16 |
JP6077641B2 (ja) | 2017-02-08 |
TWI561243B (ja) | 2016-12-11 |
KR101851666B1 (ko) | 2018-04-24 |
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