JP5491315B2 - テロメラーゼ由来抗原ペプチド - Google Patents
テロメラーゼ由来抗原ペプチド Download PDFInfo
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- JP5491315B2 JP5491315B2 JP2010177870A JP2010177870A JP5491315B2 JP 5491315 B2 JP5491315 B2 JP 5491315B2 JP 2010177870 A JP2010177870 A JP 2010177870A JP 2010177870 A JP2010177870 A JP 2010177870A JP 5491315 B2 JP5491315 B2 JP 5491315B2
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- telomerase
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Description
添付の図面を参照しながら、実施例のみにより、本発明をさらに説明する。
LLRSFFYVTE、
SRLRFIPK、
LRPIVNMDYVVG、
PELYFVKVDVTGAYDTI、
KSYVQCQGIPQGSILSTLLCSLCY、
LLLRLVDDFLLVTおよび
GCVVNLRKTVVから、あるいはhTRT配列中のNakamura等(1997, Science 277, 955-959)により同定されたようなモチーフT、1、2、A、B’、C、DまたはEのいずれか、即ちモチーフ:
WLMSVYVVELLRSFFYVTETTFQKNRLFFYRKSVWSKLQSIGIRQHLK、
EVRQHREARPALLTSRLRFIPKPDG、
LRPIVNMDYVVGARTFRREKRAERLTSRV、
PPPELYFVKVDVTGAYDTIPQDRLTEVIASIIKP、
KSYVQCQGIPQGSILSTLLCSLCYGDMENKLFAGI、
LLRLVDDFLLVTPHLTH、
AKTFLRTLVRGVPEYGCVVNLRKTVV および HGLFPWCGLLLからのものである。
本明細書中に記載した方法および組成物に用いられ得る、テロメラーゼ配列の他の場所に由来する別の組の適切なペプチドは、表2に記載されている。
a)ペプチドは合成的に生成され、したがって、形質転換癌遺伝子、あるいはは有害作用を生じ得るその他の部位または物質を含まない。
b)ペプチドは、単独で用いられて細胞免疫を誘導し得る。
c)ペプチドは、他の望ましくない応答の副作用を伴わずに、特定の種類のT細胞応答に対して標的化され得る。
(a)異なる配列を有する、例えばテロメラーゼタンパク質配列の異なる部分に対応するペプチドの混合物、
(b)重複配列を有するが、しかし異なるHLA対立遺伝子を適合するのに適したペプチドの混合物、
(c)混合物(a)および(b)の両方の混合物、
(d)いくつかの混合物(a)の混合物、
(e)いくつかの混合物(b)の混合物、
(f)いくつかの混合物(a)およびいくつかの混合物(b)の混合物。
ペプチドは、連続流動固相ペプチド合成を用いることにより合成した。適当な側鎖保護を有するN−a−Fmoc−アミノ酸を用いた。ペンタフルオロフェニルエステルとしてカップリングするために、あるいはカップリングの前にTBTUまたはジイソプロピルカルボジイミド活性化を用いることにより、Fmoc−アミノ酸を活性化した。各カップリング後のFmocの選択的除去のために、DMF中の20%ピペリジンを用いた。適切な掃去剤を含有する95%TFAにより、樹脂からの切断および側鎖保護の最終除去を実施した。ペプチドを精製し、逆相(C18)HPLCにより分析した。電子噴霧質量分光計(Finnigan mat SSQ710)を用いて、ペプチドの同一性を確認した。
(a)ペプチドは少なくとも8アミノ酸長であり、ならびにテロメラーゼタンパク質の断片であり、そして
(b)ペプチドはその全長で、または抗原提示細胞によるプロセッシング後に、T細胞応答を誘導可能である。
図1
図面1(図1)は、配列番号9および10のテロメラーゼペプチドで免疫感作されたHLA−A2(A2/Kb)遺伝子導入マウスにおけるテロメラーゼ(hTERT)反応性細胞傷害性Tリンパ球(CTL)の誘導を説明する。標準HLA−A2拘束インフルエンザ(58−66)ペプチドを対照として用いた。各々マウス5匹の3群に、107の放射線照射ペプチドパルス化(100μg/ml)同系脾臓細胞の皮下注入を週2回投与した。2回目の注射の1週間後に、マウスを屠殺し、それらの脾臓を採取した。標準技法により脾臓細胞を調製し、抗原提示細胞としてのペプチドパルス化(10μg/ml)放射線照射自系脾臓細胞との同時培養により、プライム化した動物からの細胞をin vitroで5日間再刺激後、51Cr放出アッセイにおいて、HLA−H2(A2/Kb)でトランスフェクト化したhTERT発現標的細胞(Jurkat)に対する細胞傷害性を検査した。
(実験的放出値cpm−自発的放出値cpm)/(総cpm−自発的放出値cpm)×100
図面2(図2)は、配列番号2、3、4および7のテロメラーゼ(hTERT)由来ペプチドを用いた結腸癌患者(TT)からの末梢血T細胞のin vitro刺激の結果を示す。in vitro培養を以下のように実施した:3連の105単核細胞を、5%CO2中の加湿インキュベーター中での15%プール化加熱不活性化ヒト血清を補足したX−VIVO 10培地中で6日間、インキュベートした。ペプチドは、培地中に30μg/mlの最終濃度で、培養全体に存在していた。ペプチドを含有しない培養物を対照として用いた。配列番号4のペプチドでT細胞を刺激した場合に、バックグラウンド値よりも高い増殖応答が観察された。これらの結果は、癌患者からの血液がテロメラーゼ(hTERT)由来ペプチドに特異的な循環系T細胞を含有するということを実証する。これらの結果は、テロメラーゼ(hTERT)の酵素サブユニットがヒトにおいては免疫原であり、患者に成育中の腫瘍によって過剰発現されると、テロメラーゼ特異的T細胞応答を自発的に生じ得る、ということを実証する。さらに、この患者におけるテロメラーゼ特異的応答の一構成成分は、本明細書中に記載した配列番号4のペプチドに対して向けられる。この知見は、配列番号4のペプチドがヒトにおける癌ワクチンとしても用いられ得る、ということを示す。本図面は、慣用的T細胞増殖アッセイの結果を説明するが、この場合、末梢血単核細胞(105)を、指示されたようなペプチドと共に7日間、3連で培養後、収穫した。培養物の増殖能力を測定するために、3H−チミジン(3.7×104Bq/ウエル)を培養物に一夜付加した後、収穫した。値は、3回の平均計数/分(cpm)として示されている。
図面3および4(図3および図4)は、進行性膵臓癌の患者から得られた腫瘍浸潤リンパ球(TILs)の反応性を示す。T細胞を、腫瘍生検により採取し、in vitroで順次増殖させて、T細胞株を樹立した。T細胞株は、CD3+、CD4+およびCD8−であり、テロメラーゼペプチドとの応答において特異的に増殖した。図3の結果は、培地単独の対照と比較した場合の、配列番号2および3のペプチドを認識するT細胞を示す。図4の結果は、配列番号2のペプチドを認識するT細胞を示す。組換え体ヒトインターロイキン2(rIL−2)との同時培養によりTILを増やし、14日後に、配列番号2、3、4および7のペプチドを用いて、標準増殖アッセイで試験した。
LMSVYVVEL FLHWLMSVYVVELLRSFFYVTE
ELLRSFFYV EARPALLTSRLRFIPK
YVVELLRSF DGLRPIVNMDYVVGAR
VVELLRSFF GVPEYGCVVNLRKVVNF
SVYVVELLR
VELLRSFFY
YVTETTFQK
RLFFYRKSV
SIGIRQHLK
RPALLTSRL
ALLTSRLRF
LLTSRLRFI
RPIVNMDYV
LRPIVNMDY
YVVGARTFR
VVGARTFRR
GARTFRREK
ARTFRREKP
PPELYFVKV
ELYFVKVDV
FVKVDVTGA
IPQDRLTEV
DRLTEVIAS
RLTEVIASI
IPQGSILSTL
ILSTLLCSL
LLRLVDDFL
RLVDDFLLV
VPEYGCVVN
VPEYGCVVNL
TLVRGVPEY
FLRTLVRGV
GVPEYGCVV
VVNLRKTVV
GLFPWCGLL
YAETKHFLY
ISDTASLCY
DTDPRRLVQ
AQDPPPELY
LTDLQPYMR
QSDYSSYAR
ILAKFLHWL
ELLRSFFYV
LLARCALFV
WLCHQAFLL
RLVDDFLLV
RLFFYRKSV
LQLPFHQQV
RLGPQGWRL
SLQELTWKM
NVLAFGFAL
VLLKTHCPL
FLLVTPHLT
TLTDLQPYM
RLTEVIASI
FLDLQVNSL
SLNEASSGL
ILSTLLCSL
LLGASVLGL
VLAFGFALL
LQPYMRQFV
LMSVYVVEL
RLPQRYWQM
RQHSSPWQV
YLPNTVTDA
NMRRKLFGV
RLTSRVKAL
LLQAYRFHA
LLDTRTLEV
YMRQFVAHL
LLTSRLRFI
CLVCVPWDA
LLSSLRPSL
FMCHHAVRI
LQVNSLQTV
LVAQCLVCV
CLKELVARV
FLRNTKKFI
ALPSDFKTI
VLVHLLARC
VQSDYSSYA
SVWSKLQSI
KLPGTTLTA
QLSRKLPGT
ELYFVKVDV
GLLLDTRTL
WMPGTPRRL
SLTGARRLV
VVIEQSSSL
LPSEAVQWL
QAYRFHACV
GLFDVFLRF
KLFGVLRLK
RLREEILAK
TLVRGVPEY
GLPAPGARR
GLFPWCGLL
KLTRHRVTY
VLPLATFVR
ELVARVLQR
DPRRLVQLL
FVRACLRRL
SVREAGVPL
AGRNMRRKL
LARCALFVL
RPAEEATSL
LPSDFKTIL
LPSEAVQWL
LPGTTLTAL
RPSFLLSSL
LPNTVTDAL
RPALLTSRL
RCRAVRSLL
MPRAPRCRA
GIRRDGLLL
VLRLKCHSL
YMRQFVAHL
SLRTAQTQL
QMRPLFLEL
LLRLVDDFL
FVQMPAHGL
HASGPRRRL
VVIEQSSSL
RVISDTASL
CVPAAEHRL
RVKALFSVL
NVLAFGFAL
LVARVLQRL
FAGIRRDGL
HAQCPYGVL
RAQDPPPEL
AYRFHACVL
HAKLSLQEL
GAKGAAGPL
TASLCYSIL
APRCRAVRS
GARRLVETI
AQCPYGVLL
HAKTFLRTL
EATSLEGAL
KAKNAGMSL
AQTQLSRKL
AGIRRDGLL
VLRLKCHSL
ILKAKNAGM
DPRRLVQLL
GAKGAAGPL
FAGIRRDGL
GARRRGGSA
HAKTFLRTL
HAKLSLQEL
LARCALFVL
EHRLREEIL
NMRRKLFGV
CAREKPQGS
LTRHRVTYV
RRFLRNTKK
RRDGLLLRL
RREKRAERL
RRLVETIFL
LRFMCHHAV
RRYAVVQKA
KRAERLTSR
RRKLFGVLR
RRRGGSASR
RRLPRLPQR
RRLGPQGWR
LRGSGAWGL
HREARPALL
VRRYAVVQK
ARTSIRASL
HRVTYVPLL
LRSHYREVL
MRPLFLELL
HRAWRTFVL
MRRKLFGVL
LRLVDDFLL
LRRVGDDVL
YRKSVWSKL
QRLCERGAK
FRALVAQCL
SRKLPGTTL
LRRLVPPGL
RRSPGVGCV
RRVGDDVLV
VRGCAWLRR
VRSLLRSHY
ARTFRREKR
SRSLPLPKR
IRASLTFNR
LREEILAKF
IRRDGLLLR
QRGDPAAFR
LRPIVNMDY
ARRLVETIF
ARPALLTSR
LRPSLTGAR
LRLKCHSLF
FRREKRAER
ARGGPPEAF
CRAVRSLLR
GRTRGPSDR
RRRLGCERA
LRELSEAEV
ARCALFVLV
RPAEEATSL
DPRRLVQLL
RPSFLLSSL
LPSEAVQWL
RPALLTSRL
LPSDFKTIL
RPPPAAPSF
LPRLPQRYW
LPNTVTDAL
LPGTTLTAL
LAKFLHWLM
KAKNAGMSL
GSRHNERRF
KALFSVLNY
SPLRDAVVI
RAQDPPPEL
MPAHGLFPW
AEVRQHREA
REAGVPLGL
EEATSLEGA
LEAAANPAL
QETSPLRDA
REVLPLATF
KEQLRPSFL
REKPQGSVA
LEVQSDYSS
REARPALLT
EEDTDPRRL
REEILAKFL
CERGAKNVL
DDVLVHLLA
GDMENKLFA
YERARRPGL
Claims (27)
- テロメラーゼペプチドであって、該ペプチドは9〜25のアミノ酸からなり、配列番号2(EARPALLTSRLRFIPK)、3(DGLRPIVNMDYVVGAR)、4(GVPEYGCVVNLRKTVVNF)、9(ILAKFLHWL)、もしくは10(ELLRSFFYV)の配列を含む、テロメラーゼペプチド(但し、配列番号2、3、4,9および10の各アミノ酸配列からなるペプチドは除く。)。
- 癌の治療または予防の方法に用いるための、請求項1に記載のテロメラーゼペプチド。
- テロメラーゼタンパク質に対して向けられたT細胞応答が発生可能である、請求項2に記載のテロメラーゼペプチド。
- テロメラーゼに対するT細胞応答が哺乳類で誘発されるように、癌に罹患しているかまたは罹患すると考えられる哺乳類に治療的有効量のテロメラーゼペプチドを投与することを含む方法に使用するための、請求項2または3に記載のテロメラーゼペプチド。
- 誘導された前記T細胞応答は細胞傷害性T細胞応答である、請求項3または4に記載のテロメラーゼペプチド。
- 請求項1に記載のペプチドをコードする核酸。
- 癌の治療または予防の方法に用いるための、請求項6に記載の核酸。
- 請求項1に記載の少なくとも1つのテロメラーゼペプチド、あるいは請求項6に記載の少なくとも1つの核酸を、医薬的に許容可能な担体または希釈剤と一緒に含む医薬組成物。
- 請求項1に記載の少なくとも1つのテロメラーゼペプチド、および癌遺伝子または突然変異体癌抑制タンパク質またはペプチドに対するT細胞応答を誘導可能な少なくとも1つのペプチドの組合せを、医薬的に許容可能な担体または希釈剤と一緒に含む医薬組成物。
- 以下の癌:乳癌、前立腺癌、膵臓癌、結腸−直腸癌、肺癌、悪性黒色腫、白血病、リンパ腫、卵巣癌、頸部癌および胆管癌のいずれかの治療または予防に用いるための請求項8または9に記載の医薬組成物。
- 請求項1に記載の少なくとも1つのテロメラーゼペプチド、あるいは請求項6に記載の少なくとも1つの核酸を医薬的に許容可能な担体または希釈剤と混合することを含む、請求項8に記載の医薬組成物の製造方法。
- 請求項1に記載の少なくとも1つのテロメラーゼペプチドを、癌遺伝子または突然変異体癌抑制タンパク質またはペプチドに対してT細胞応答を誘導可能な少なくとも1つのペプチド、および医薬的に許容可能な担体または希釈剤と混合することを含む、請求項9に記載の医薬組成物の製造方法。
- 前記癌遺伝子タンパク質またはペプチドは突然変異体p21−rasタンパク質またはペプチドである、請求項9に記載の医薬組成物。
- 前記癌遺伝子タンパク質またはペプチドは突然変異体p21−rasタンパク質またはペプチドである、請求項12に記載の医薬組成物の製造方法。
- 前記癌抑制タンパク質またはペプチドは網膜芽細胞腫またはp53タンパク質またはペプチドである、請求項9に記載の医薬組成物
- 前記癌抑制タンパク質またはペプチドは網膜芽細胞腫またはp53タンパク質またはペプチドである、請求項12に記載の医薬組成物の製造方法。
- 癌の治療または予防のための薬剤を製造するためのペプチドの使用であって、該ペプチドは配列番号2、3、4、9、10のいずれか1つの配列からなり、該治療または予防はT細胞応答の発生を含み、該応答は、各々の配列番号2、3、4、9、10の1つの配列からなるペプチドに対する応答である、該ペプチドの使用。
- 癌の治療または予防のための薬剤を製造するための核酸の使用であって、該核酸は配列番号2、3、4、9、10のいずれか1つの配列からなるペプチドをコードし、該治療または予防はT細胞応答の発生を含み、該応答は、各々の配列番号2、3、4、9、10の1つの配列からなるペプチドに対する応答である、該核酸の使用。
- 前記治療または予防が、テロメラーゼに対するT細胞応答が哺乳類で誘発されるように、癌に罹患しているかまたは罹患すると考えられる哺乳類に治療的有効量のテロメラーゼペプチドを投与することを含む、請求項17に記載の使用。
- 誘導された前記T細胞応答は細胞傷害性T細胞応答である、請求項17〜19のいずれか1項に記載の使用。
- 前記薬剤が、医薬的に許容可能な担体または希釈剤と一緒に、前記ペプチドまたは前記核酸を含む医薬組成物である、請求項17〜20のいずれか1項に記載の使用。
- 前記薬剤が、配列番号2、3、4、9、10のいずれか1つの配列からなるペプチド、および癌遺伝子または突然変異体癌抑制タンパク質またはペプチドに対してT細胞応答を誘導可能な少なくとも1つのペプチドを、医薬的に許容可能な担体または希釈剤とともに含む、請求項17、19、20または21のいずれか1項に記載の使用。
- 前記癌遺伝子タンパク質またはペプチドは突然変異体p21−rasタンパク質またはペプチドである、請求項22に記載の使用。
- 前記癌抑制タンパク質またはペプチドは網膜芽細胞腫またはp53タンパク質またはペプチドである、請求項22に記載の使用。
- 前記癌が、乳癌、前立腺癌、膵臓癌、結腸−直腸癌、肺癌、悪性黒色腫、白血病、リンパ腫、卵巣癌、頸部癌および胆管癌から選択される、請求項17〜24のいずれか1項に記載の使用。
- 哺乳類における腫瘍細胞を認識および破壊可能なTリンパ球の生成方法であって、テロメラーゼ特異的Tリンパ球を生成するのに十分な量でのペプチドの存在下で、哺乳類から採取されたTリンパ球試料を培養することを含み、該ペプチドは配列番号2、3、4、9、10のいずれか1つの配列からなり、テロメラーゼ特異的Tリンパ球は、各々の配列番号2、3、4、9、10の1つの配列からなるペプチドに対する応答を発生する、該生成方法。
- 請求項26の方法により生じる、テロメラーゼ特異的Tリンパ球。
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JP2010177870A Expired - Lifetime JP5491315B2 (ja) | 1998-07-08 | 2010-08-06 | テロメラーゼ由来抗原ペプチド |
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JP2000558840A Expired - Lifetime JP4618657B2 (ja) | 1998-07-08 | 1999-06-30 | テロメラーゼ由来抗原ペプチド |
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US (2) | US7030211B1 (ja) |
EP (4) | EP2258383B1 (ja) |
JP (2) | JP4618657B2 (ja) |
CN (1) | CN100376290C (ja) |
AR (2) | AR020601A1 (ja) |
AT (2) | ATE247484T1 (ja) |
AU (1) | AU756094B2 (ja) |
CA (2) | CA2336743C (ja) |
CY (1) | CY1109978T1 (ja) |
CZ (1) | CZ303215B6 (ja) |
DE (2) | DE69910580T3 (ja) |
DK (2) | DK1362597T3 (ja) |
ES (2) | ES2341170T5 (ja) |
HK (1) | HK1039068B (ja) |
HU (1) | HU230007B1 (ja) |
NO (1) | NO313834B1 (ja) |
PL (1) | PL203815B1 (ja) |
PT (2) | PT1362597E (ja) |
TW (1) | TWI261617B (ja) |
WO (1) | WO2000002581A1 (ja) |
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KR20200085927A (ko) * | 2012-07-20 | 2020-07-15 | 주식회사 젬백스앤카엘 | 항염증 활성을 갖는 펩티드 및 이를 포함하는 조성물 |
KR20220061282A (ko) * | 2012-05-11 | 2022-05-12 | 주식회사 젬백스앤카엘 | 항염증 활성을 갖는 펩티드 및 이를 포함하는 조성물 |
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